Skip Navigation


Epidemiologic Reviews Advance Access originally published online on September 8, 2008
Epidemiologic Reviews 2008 30(1):35-66; doi:10.1093/epirev/mxn010
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
30/1/35    most recent
mxn010v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Coley, N.
Right arrow Articles by Grand, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Coley, N.
Right arrow Articles by Grand, A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Epidemiologic Reviews © The Author 2008. Published by the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

ARTICLES

Dementia Prevention: Methodological Explanations for Inconsistent Results

Nicola Coley1,2, Sandrine Andrieu1,2,3,4, Virginie Gardette1,2,3,4, Sophie Gillette-Guyonnet1,3,5, Caroline Sanz6, Bruno Vellas1,2,3,5 and Alain Grand1,2,3,4

1 INSERM Unit 558, Toulouse, France
2 University of Toulouse III, Toulouse, France
3 Gerontopole, Toulouse University Hospital, Toulouse, France
4 Department of Epidemiology and Public Health, Toulouse University Hospital, Toulouse, France
5 Department of Geriatric Medicine, Toulouse University Hospital, Toulouse, France
6 Department of Diabetology and Metabolic Diseases, Toulouse University Hospital, Toulouse, France

Correspondence to Nicola Coley, INSERM Unit 558, Faculté de médicine, 37 allées Jules Guesde, 31073 Toulouse, France (e-mail: coley{at}cict.fr).

accepted for publication May 29, 2008.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SEARCH STRATEGY
 SUMMARY OF FINDINGS FROM...
 COMMON METHODOLOGICAL ISSUES
 MULTIPLE EXPOSURE AND...
 CONCLUSION
 REFERENCES
 
The prevention of neurodegenerative dementias, such as Alzheimer disease, is a growing public health concern, because of a lack of effective curative treatment options and a rising global prevalence. Various potential risk or preventive factors have been suggested by epidemiologic research, including modifiable lifestyle factors, such as social contacts, leisure activities, physical exercise, and diet, as well as some preventive pharmacologic strategies, such as hormone replacement therapy, nonsteroidal antiinflammatory drugs, and Ginkgo biloba. Some factors have been targeted by interventions tested in randomized controlled trials, but many of the results are in conflict with observational evidence. The aim of this paper is to review the epidemiologic data linking potential protective factors to dementia or cognitive decline and to discuss the methodological limitations that could explain conflicting results. A thorough review of the literature suggests that, even if there are consistent findings from large observational studies regarding preventive or risk factors for dementia, few randomized controlled trials have been designed specifically to prove the protective effects of interventions based on such factors on dementia incidence. Because of the multifactorial origin of dementia, it appears that multidomain interventions could be a suitable candidate for preventive interventions, but designing such trials remains very challenging for researchers.

Alzheimer disease • bias (epidemiology) • cognition disorders • dementia • epidemiologic research design • primary prevention • randomized controlled trials as topic • risk factors

APOE, apolipoprotein E • NSAID, nonsteroidal antiinflammatory drug • WHIMS, Women's Health Initiative Memory Study • WHISCA, Women's Health Initiative Study of Cognitive Aging • WHS, Women's Health Study


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SEARCH STRATEGY
 SUMMARY OF FINDINGS FROM...
 COMMON METHODOLOGICAL ISSUES
 MULTIPLE EXPOSURE AND...
 CONCLUSION
 REFERENCES
 
Neurodegenerative dementias, such as Alzheimer disease, are a growing public health concern. The global prevalence of dementia was estimated at 24.3 million in 2001 (1) and that of Alzheimer disease was estimated at 26.55 million in 2006 (2). Over the next 40 years, the prevalence is expected to quadruple, with a particularly dramatic increase in the number of cases in developing regions (1, 2). There are currently no effective treatment options for this condition, making its prevention a priority. Prevention is feasible due to the long asymptomatic latent period of this disease. Even an intervention that delayed disease onset by just a few years could dramatically reduce the burden of this disease on society and public health-care systems (3).

To this end, there has been a recent focus on the identification of potential preventive factors for dementia, and epidemiologic research has suggested various candidates, including modifiable lifestyle factors, such as social contacts, leisure activities, physical exercise, and diet, as well as some pharmacologic strategies, such as hormone replacement therapy, nonsteroidal antiinflammatory drugs (NSAIDs), and Ginkgo biloba. In addition, the treatment of vascular risk factors could be important. Some of these factors have been targeted by interventions tested in randomized controlled trials, but many of the results obtained are in conflict with those obtained in observational studies. The most well-known example of this is the Women's Health Initiative Memory Study (WHIMS) (4, 5), which suggested that hormone replacement therapy may increase the risk of dementia, contrary to results of observational studies.

The aim of this article is twofold: to explore possible methodological explanations for the divergent results in dementia observational and interventional prevention studies and to consider future research perspectives. Results from recent meta-analyses, reviews, longitudinal studies, and randomized controlled trials assessing the prevention of both dementia/Alzheimer disease and cognitive decline will be included.


   SEARCH STRATEGY
TOP
 ABSTRACT
 INTRODUCTION
 SEARCH STRATEGY
SUMMARY OF FINDINGS FROM...
 COMMON METHODOLOGICAL ISSUES
 MULTIPLE EXPOSURE AND...
 CONCLUSION
 REFERENCES
 
Recent studies (published in the last 15 years) were identified by using the search strategy outlined in table 1.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Search strategy

 

   SUMMARY OF FINDINGS FROM PROSPECTIVE LONGITUDINAL STUDIES AND RANDOMIZED CONTROLLED TRIALS
TOP
 ABSTRACT
 INTRODUCTION
 SEARCH STRATEGY
 SUMMARY OF FINDINGS FROM...
COMMON METHODOLOGICAL ISSUES
 MULTIPLE EXPOSURE AND...
 CONCLUSION
 REFERENCES
 
The associations among lifestyle, pharmacologic, and vascular risk or protective factors identified in longitudinal and experimental studies are described below and summarized in table 2.


View this table:
[in this window]
[in a new window]

  		TABLE 2. Summary of associations between risk/preventive factors and dementia or cognitive outcomes in longitudinal and experimental studies

 
Nutrition

Meta-analyses or reviews. Two reviews (6, 7) studied nutritional factors and dementia or cognitive decline. The first in 2004 (7) noted that, while there was some evidence to suggest that antioxidants, homocysteine-related vitamins, and fatty acids are related to Alzheimer disease, it was not possible at that time to generate specific dietary recommendations for Alzheimer disease prevention because of a lack of large observational studies or randomized controlled trials. The second in 2007 (6) concluded that, despite some conflicting evidence, folate and vitamin B12 seem to have a protective role on cognitive decline and dementia and that a balanced combination of several antioxidants may be required for prevention of cognitive decline or dementia.

Two Cochrane reviews (8, 9) found no evidence for a beneficial effect on cognition of folic acid with or without vitamin B12, in healthy or cognitively impaired older people, or of vitamin B6 supplementation in older people with or without vitamin B6 deficiency.

Finally, a meta-analysis of randomized controlled trials for cognitive and noncognitive disorders underlined that supplements containing high doses of beta-carotene, vitamin A, and vitamin E could increase the risk of all-cause mortality (10).

Prospective longitudinal studies. Homocysteine. Six studies, conducted mainly in elderly populations aged 65 or more years, found increased homocysteine levels to be associated with an increased risk of dementia/Alzheimer disease (11–13) or cognitive decline (14–16), one of which found this association to be modified by vitamin B12 (11). However, four studies found no association between homocysteine and dementia (17) or cognitive decline (18–21).

Vitamins B6 and B12 and folate. Eight studies have found increased intake or serum concentrations of vitamin B6 (16, 22), vitamin B12 (16, 21, 23, 24), or folate (12, 16, 22–26) in mid- or late life to have a beneficial effect on dementia/Alzheimer disease incidence or cognitive decline. Nine studies found no relation between vitamin B6 (26, 27), vitamin B12 (12, 19, 20, 22, 26–29), or folate (19–21, 27, 29) and dementia/Alzheimer disease or cognitive decline, and one (24) found that increased dietary folate intake was associated with increased cognitive decline.

Antioxidants. Fourteen studies, focusing mostly on populations aged 65 or more years, have suggested that vitamin E (30–33), vitamin C (30, 33), combined vitamins E and C (33–37), flavonoids (30, 38, 39), beta-carotene (30, 33, 40), or overall antioxidant intake (41), as well as serum selenium concentrations (42, 43), may be associated with reduced dementia/Alzheimer disease incidence or reduced cognitive decline. Five studies found no association between vitamin E (37, 44, 45), vitamin C (22, 37, 44–46), flavonoids (44), or beta-carotene (22, 31, 44–46) and dementia/Alzheimer disease or cognitive decline. Results are sometimes conflicting between dietary intakes and supplements and may be dependent on the status of the {varepsilon}4 type of apolipoprotein E (APOE) (31).

Fat intake. Moderate intake of polyunsaturated fatty acids was related to a lower risk of dementia in one study (47), and another (48) found high polyunsaturated fatty acid intake to be associated with better cognitive performance. Two studies found borderline significant relations between high polyunsaturated fatty acid intake and Alzheimer disease (49) or mild cognitive impairment (50). Higher intakes of monounsaturated fatty acids were associated with better cognitive performance in one study (48) and marginally associated with a decreased Alzheimer disease risk in another (49). One study found no association between a low intake of monounsaturated fatty acid or n-3 or n-6 polyunsaturated fatty acid and dementia (51). High plasma phosphatidylcholine docosahexaenoic acid was also associated with a lower risk of all-cause dementia, but not Alzheimer disease, in one study (52) and less cognitive decline in two other studies (53, 54).

Dietary patterns. One study suggested that a diverse diet may reduce the risk of dementia (55), and a second found a decreased risk of Alzheimer disease in subjects following a Mediterranean-style diet (56). Increased fish consumption was associated with a decreased risk of dementia in four studies (55, 57–59), but in one (57) this relation became borderline significant when education was controlled for. Two further studies found higher fish consumption to be related to lower cognitive decline (60, 61).

Experimental studies (table 3). Homocysteine-lowering vitamins. Seven randomized controlled trials have tested the effects of homocysteine-lowering vitamins (vitamin B6, vitamin B12, and/or folic acid) on cognitive performance or cognitive decline (62–68). Five (64–68) found no difference between placebo and active treatment groups, and one (62) found significant effects of 1-month vitamin B12, vitamin B6, and folate supplementation on some measures of memory performance but not on other cognitive measures. The Folic Acid and Carotid Intima-media Thickness (FACIT) Study (63) found 3-year folic acid supplementation to beneficially affect global cognitive function and the specific cognitive domains of memory and information processing.


View this table:
[in this window]
[in a new window]

  		TABLE 3. Randomized controlled prevention trials of nutritional factors

 
Antioxidants. The Women's Health Study (WHS) (69) found no benefits of vitamin E on cognition after 9.6 years of supplementation.

Multivitamins. Two randomized controlled trials (70, 71) found no effect of multivitamin supplementation (including antioxidants and homocysteine-lowering vitamins) on cognitive performance, although one (70) found some benefits in one cognitive domain for the eldest participants and those at increased risk of micronutrient deficiency.

Limitations. In the domain of nutrition, various doses of vitamins were used in randomized controlled trials. For example, folate supplements ranged from 200 µg (70) to 2,500 µg (67) per day. The lowest dose used was lower than the US Recommended Daily Allowance (RDA) (400 µg/day). In the Folic Acid and Carotid Intima-media Thickness Study (63), which found folate supplementation to have beneficial effects on cognitive decline, 800 µg were given daily to elderly individuals with raised homocysteine concentrations. Two trials (66, 67) used higher doses of folate but detected no cognitive benefits. A longitudinal study (26) found those in the highest quintile of folate intake (≥487.9 µg) to have a lower risk of developing Alzheimer disease than those in the lowest quintile (≤292.9 µg), but it is unlikely that those in the highest quintile had intakes as high as those used in some randomized controlled trials. The form of vitamins may also be important. Vitamin E exists in several different forms, more than one of which may be required for a protective effect on cognition (32). In the WHS, a supplement containing only the alpha-tocopherol form was used, and no effect was observed on cognition (69).

The duration of follow-up in the longitudinal studies was generally 3 or more years, but only two randomized controlled trials (63, 69) were of similar length. The duration of both supplementation and follow-up may affect the observed effects on cognition in randomized controlled trials, but the WHS did not observe any cognitive benefits after more than 9 years of vitamin E supplementation.

In nutritional interventions, particular attention could be paid to the sensitivity of subjects to the intervention. A trial of vitamin supplementation may be more beneficial in those with poor nutritional status than in those who already have sufficient intakes. One (63) of four trials (63, 64, 66, 68) targeting persons with a particular nutritional deficiency was able to demonstrate an effect on cognitive function. Participants in dementia prevention randomized controlled trials may be in good health or may already be receiving nutritional fortification through public health measures, and they may not be those at most risk of cognitive impairment (72).

Nutrient intakes were found to be related to dementia incidence in some longitudinal studies, but none of the randomized controlled trials used dementia incidence as an outcome.

In addition, interactions between different micro- and macronutrients should be considered, especially in terms of food groups or dietary patterns (55, 56).

The analysis of the associations between consumption of nutrients and cognition is complex, and it is unlikely that one nutrient alone will play a major role. From a public health perspective, it is important to assess in more depth the associations among groups of nutrients or particular dietary habits that may have an impact on cognition.

Social contacts, leisure activities, and physical exercise

Meta-analyses or reviews. Three reviews have assessed the effects of social and mental lifestyle factors and/or physical exercise on dementia and cognitive decline (73–75). The first (73) concluded that an active and socially integrated lifestyle in the elderly might protect against dementia, although it was suggested that the effects of social, mental, and physical lifestyle components may act through common pathways. The other two reviews (74, 75) noted some benefits of physical activity on cognition in the elderly, mainly based on longitudinal studies, but found little evidence to suggest a link with dementia/Alzheimer disease, because of a lack of randomized controlled trials in this area.

Prospective longitudinal studies. Social contacts and social engagement. Fourteen studies have found an inverse relation between the level of late-life social contacts or engagement and the risk of dementia/Alzheimer disease (76–82) or cognitive decline (83–89). Midlife social engagement was assessed by one of these studies (82) but was not found to be related to dementia risk.

Two studies (90, 91) found only certain measures of social engagement to be associated with better cognitive function, and four studies found no association between participation in social activities (92, 93) or social network or support measures (91, 94) and cognition.

Cognitive activities in late life. Twelve studies have demonstrated a relation between increased participation in cognitive activities in late life and a decreased risk of dementia (76–78, 95), Alzheimer disease (95–98), vascular dementia (95), or cognitive decline or impairment (87, 92, 93, 97, 99, 100). No studies were identified that failed to find an association between cognitive activities and outcomes, although the positive effects in one of the above-mentioned studies (87) were seen only in some specific cognitive domains.

Physical exercise. An increased frequency or intensity of physical exercise or activities in late life was associated with a decreased risk of dementia/Alzheimer disease (76, 77, 95, 101–107) or cognitive decline/impairment in 19 studies (87, 104, 108–115). However, nine studies found no association with dementia/Alzheimer disease (78, 96, 97, 116, 117) or cognitive decline/impairment (92, 118–120). Two studies examined the effects of midlife physical exercise on the risk of dementia in late life and found conflicting results (121, 122).

Leisure activity. Five studies found that high levels of leisure activities decreased the risk of dementia (77) or cognitive function (94, 111, 123) or decline (124), and one study (117) found the individual activities of traveling, odd jobs, knitting, and gardening to be associated with a reduced risk of dementia. Contrastingly, two studies (99, 125) did not find any of the individual everyday activities assessed (including social, experimental, and developmental activities) to be associated with cognition, although overall domain scores remained associated with the development of cognitive impairment in one study (99). Other studies (77, 93–95) have also assessed the effects of individual activities, in addition to activity domains, but there are no consistent results. Furthermore, two studies noted that the beneficial effects of cognitive, social, and physical activities on dementia (76) or cognitive decline (87) were greatest when older persons had high levels of participation in activities in two or more domains. Again, some results were confined to only some of the cognitive domains tested (87, 123).

Experimental studies (table 4). Cognitive training. There has been much research into the effects of cognitive training on cognition but often with major methodological limitations, such as a lack of randomization or blinding (126, 127), small sample sizes (128), or short follow-up (129, 130).


View this table:
[in this window]
[in a new window]

  		TABLE 4. Randomized controlled prevention trials of cognitive activities and physical exercise

 
Three recent methodologically sound randomized controlled trials (131–133) have considered the effects of cognitive training on cognitive function in the elderly; two were relatively small scale with short follow-up periods (131, 133). In the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) Study (132), 2,832 participants received a 6-week intervention (focused on memory, reasoning, and speed of processing) and were followed up for 5 years. All trials found cognitive training to have some beneficial effects on cognition, especially in the cognitive domains directly related to the intervention, and these effects were found to last up to 5 years in this study, which also found some effects on everyday functioning (132).

Physical exercise. Few trials have assessed the efficacy of standardized physical exercise on cognitive outcomes (134). Oken et al. (135) assessed the effects of a 6-month yoga intervention on cognition and quality of life in healthy seniors. Despite improving physical and quality-of-life measures, this intervention did not affect cognitive outcomes. Kramer et al. (136) compared two exercise interventions (aerobic vs. anaerobic) in the elderly and found after 6 months a substantial improvement in a specific domain (executive control tasks) in participants in the aerobic group, although other cognitive domains remained equivalent between groups.

Limitations. Exposure definition and measurement vary greatly among studies (73): Some used quantitative measures of numbers of social contacts or activities (77, 94, 111, 117), while others attempted to gauge their frequency or intensity (78, 95, 97) or satisfaction with social interactions (80). Several studies simultaneously assessed the effects of different types of leisure activities on dementia or cognitive decline, often grouping them into categories of "social," "physical," or "intellectual" activities (77, 78, 87, 92, 93, 95, 99). However, some activities may be associated with all three domains (e.g., traveling, going to the theater/concerts, engaging in family/charity work), making it difficult to distinguish the effects of each domain. One study (76) rated the mental, social, and physical components of each activity and then compiled domain scores, meaning that one activity could contribute to more than one domain. These researchers found that all three component scores were related to dementia risk and that the most beneficial effect was present for subjects with high scores in several components. Thus, it is hard to distinguish the effects of different exposures. Consequently, it may be hard to develop interventions concerning leisure activities on the basis of the longitudinal evidence gained so far. No randomized controlled trials have tested the effects of social engagement interventions on cognition and, although there have been various studies of cognitive training interventions, many were not methodologically sound randomized controlled trials. The randomized controlled trials described above all found some positive effects on cognition, but it is not clear if the improvements are beneficial in real-life situations, or if they affect dementia incidence.

For physical exercise, it is important to distinguish between aerobic and anaerobic exercise. The trial by Kramer et al. (136) found aerobic, but not anaerobic, exercise to improve executive function. Consistently, the yoga intervention, considered as anaerobic exercise, had no effect on cognition (135). In both studies, the duration of intervention and follow-up may have been too short to demonstrate any effect. Participants in the yoga study were healthy seniors, but exercise may be more beneficial in less healthy subjects. The participants in both trials were highly motivated to volunteer for an exercise intervention and probably differed from those who did not take part.

The frequency of exercise interventions may be important. The yoga intervention was carried out only once a week, but it may have had greater effects on cognitive function if it was carried out more often (135). It is not clear which specific aspects of cognitive function may be most affected by physical activity (137).

The window of exposure is important, even if the two longitudinal studies that assessed the effect of physical exercise in midlife report contradictory results (121, 122). The methodology was relatively similar, but the opposing results could be explained by differential adjustment for potential confounders or by the type of activity concerned. In one study (121), only leisure activities were assessed, while in the other, work-related physical activity was also considered (122). The "well-being" effect provided by leisure activities, suggested by certain authors as a mechanism explaining the beneficial effect of physical exercise on cognition, could explain the different results.

There remain several uncertainties in the domain of physical exercise, including how long exercise effects last after cessation of training or how much exercise is needed to reinstate previously observed benefits (137).

In conclusion, the results of longitudinal studies, many of which came from well-established, population-based cohort studies focused on aging, are largely concordant and suggest an inverse relation between the level of social contacts or engagement or of social, cognitive, or physical activities and the risk of dementia or cognitive decline. Although there is limited evidence from experimental studies, a mentally, physically, and socially active lifestyle is to be recommended in late life, because even if the cognitive benefits have not yet been entirely elucidated, at the very least, this lifestyle should bring about improved quality of life and overall health.

Hormone replacement therapy

Meta-analyses or reviews. Various reviews and meta-analyses have assessed the effects of hormone replacement therapy on dementia and cognition (138–145), although most were conducted before the latest published randomized controlled trials. Meta-analyses differ in the type and characteristics of included studies. Two meta-analyses found inconsistent results (139, 141) while others reported decreased risks, but most showed statistical heterogeneity (138, 141, 144) and were based on studies of poor quality (138, 139, 141, 144). It was noted that results of longitudinal studies often suggested a protective effect of hormone replacement therapy (138, 144), while earlier randomized controlled trials were inconclusive. The most recent meta-analysis (140), conducted according to Cochrane guidelines, analyzed 16 randomized controlled trials including the recent WHIMS trial. It showed "with good evidence" no improvement in cognition and a potential deleterious effect of some hormone replacement therapy regimens.

Prospective longitudinal studies. Seven studies have suggested that current or previous estrogen use alone may be associated with a decreased risk of dementia (146–148) or cognitive decline (149, 150), although in some cases effects were limited to only some specific cognitive domains or to subjects with the APOE*E4 genotype (149, 151, 152). In two of them, an increased duration of estrogen was associated with decreased risk of dementia (147, 148). One study (153) found a trend for cognitive decline in long-term users of estrogen alone.

Past or present use of estrogen plus progestin or unspecified "hormone replacement therapy" was associated with a decreased risk of dementia (154) or cognitive decline (155) in four studies, although the relation was sometimes confined to certain cognitive domains (152, 156). Four studies found no clear relation between hormone replacement therapy and cognitive decline (157–160), while two (150, 153) found an increased risk of cognitive decline in long-term users.

Experimental studies (table 5). Eight randomized controlled trials (4, 5, 144, 161–166) studied the effects of hormone replacement therapy on dementia or cognitive decline in postmenopausal women. Participants were aged 65 or more years in all except two studies (163, 164). WHIMS (4, 5) was by far the largest study with 6,500 women treated with estrogen alone (WHI-ERT), estrogen plus progestin (WHI-PERT), or placebo for more than 5 years. The Women's Health Initiative Study of Cognitive Aging (WHISCA) (165), an ancillary study of WHIMS, assessed cognitive decline in the WHI-PERT arm. The other trials involved less than 500 subjects, with shorter follow-up (from 3 months to 3 years). The type of menopause (natural or surgical) was usually not stated. This can affect the type of hormone replacement therapy and the characteristics of the women, who may differ in terms of age, and therefore prognosis for cognitive decline. The type of hormone replacement therapy (estrogen alone (4, 161, 163, 167), estrogen with or without progestin according to hysterectomy (162, 164, 166), or estrogen plus progestin (5, 165)), route of administration (mainly oral), and dose used (e.g., between 0.01 and 2 mg of estrogen daily) were variable.


View this table:
[in this window]
[in a new window]

  		TABLE 5. Randomized controlled prevention trials of hormone replacement therapy

 
Six randomized controlled trials found no association between cognition and estrogen replacement therapy with or without progestin according to hysterectomy status (161–164, 166, 167).

The three studies based on the same trial found no protective effect of hormone replacement therapy: Estrogen plus progestin was associated with an increased risk of probable dementia (5) and decline in some cognitive functions (165), and estrogen alone (4) was associated with an increased risk of the combined mild cognitive impairment-dementia endpoint.

Limitations. There has been much discussion of the conflicting results of longitudinal and experimental evidence (138, 139, 168–171). Exposure definition and measurement varied greatly between longitudinal studies with lack of precision (ever/never use or past/current/never use) and assessment at one or two time points only.

Longitudinal studies cannot control for the type and dose of hormone replacement therapy, so regimen variations could explain the discrepancies observed. For example, the type of estrogen (conjugated equine estrogen) used in WHIMS may have more deleterious cognitive effects than estradiol, which is usually assessed in longitudinal studies (168).

In summary, estrogen alone or hormone replacement therapy cannot be recommended for cognitive improvement in older postmenopausal women without cognitive impairment, because the risks (notably cardiovascular disease and stroke) outweigh the potential cognitive benefits (172).

Aspirin and other NSAIDs

Meta-analyses or reviews. Three meta-analyses of observational studies (cohort and nonprospective) were identified (173–175). Two assessed NSAIDs and aspirin (173, 174), and one assessed nonaspirin NSAIDs (175). The outcomes were Alzheimer disease alone (175), dementia/Alzheimer disease (174), and Alzheimer disease and any cognitive impairment (173). Some had more stringent inclusion criteria (175) than others (174). Only one (175) assessed the quality of the studies included, and two showed statistical heterogeneity (173, 174).

Etminan et al. (174) concluded that only nonaspirin NSAIDs, especially with long-term use, could decrease the risk of Alzheimer disease. These results should be taken with caution because of potential confounding (176) and heterogeneity. de Craen et al. (173) assessed 25 studies (21 of which studied Alzheimer disease, 10 prospectively) and reported conflicting results according to study design. Beneficial effects were attributed to bias. Szekely et al. (175) assessed 11 studies (including four prospective studies) and concluded that nonaspirin NSAIDs may prevent or delay the onset of Alzheimer disease, especially with long-term use.

A review of observational studies (177) concluded that long-term use of NSAIDs could significantly reduce the risk of dementia.

Prospective longitudinal studies. The use of NSAIDs (104, 178, 179) or aspirin (178, 180) was associated with a decreased risk of dementia or cognitive decline in four studies, although associations were restricted to some domains and age groups (180) or those with an APOE*E4 allele (179) and, in one case, the relation did not persist after sensitivity analyses (104).

However, six studies found no clear association between NSAIDs (181–184) or aspirin (182, 184–187) and dementia or cognitive decline, and one (188) found the use of aspirin to increase the risk of dementia in APOE*E4-negative individuals. Four studies found increased duration of NSAID use (178, 186, 187, 189) to be associated with a lower risk of dementia or cognitive decline, although in one, the association was restricted to APOE*E4-positive individuals (189). Contrastingly, one study (179) found no relation with duration of use.

Certain studies using the "lag time" method (i.e., excluded exposure data from 1–2 years before diagnosis) found a beneficial effect in people exposed before this 2-year period (178, 186, 187), but others did not (179).

Experimental studies (table 6). Two randomized controlled trials tested the effects of NSAIDs (190) or aspirin (191) on dementia or cognitive decline. In the Alzheimer Disease Antiinflammatory Prevention Trial (ADAPT) Study (190), specifically designed as a dementia primary prevention trial but prematurely terminated because of safety concerns, celecoxib and naproxen showed trends for increased risks of Alzheimer disease compared with placebo. The WHS cognitive cohort (191) involved 6,377 women aged over 65 years who were treated with low-dose aspirin or placebo for 9.6 years on average. Active treatment had no effect on cognitive performance or decline at either cognitive assessment.


View this table:
[in this window]
[in a new window]

  		TABLE 6. Randomized controlled prevention trials of nonsteroidal antiinflammatory agents

 
Limitations. The findings of positive observational studies could result from bias (e.g., recall, prescription (192), or publication (173) bias). However, some longitudinal studies still found a protective effect after making particular attempts to reduce bias (e.g., exposure determined from extensive national pharmacy databases (187)).

Only two randomized controlled trials have assessed the effects of NSAIDs on cognition. The Alzheimer Disease Antiinflammatory Prevention Trial Study (190) found an increased risk of dementia among subjects receiving NSAIDs, but few dementia events were observed in the shortened follow-up period, making it difficult to draw conclusions. Participants may not have benefited from NSAID treatment because of their relatively high age (≥70 years).

The WHS found no effect of aspirin on cognitive decline, despite a relatively long follow-up period. It assessed cognitive decline rather than Alzheimer disease incidence, but most longitudinal studies on aspirin found little evidence for a beneficial effect on cognitive decline (180, 184, 185, 189). Although it was not specifically designed to assess cognitive outcomes, this trial had sufficient power to detect a significant effect on cognitive decline.

The aspirin dose used in the WHS may not have been strong enough to provide an antiinflammatory effect on cognition, although one longitudinal study (180) found low-dose aspirin to protect against memory decline.

The type of NSAID is important. Although it is difficult to determine which specific NSAIDs are associated with the cognitive benefits seen in some longitudinal studies, they are probably not those used in the randomized controlled trials. Furthermore, the randomized controlled trial treatments are not those thought to have the greatest effects on the 42-amino-acid form of amyloid beta protein (193–195).

Longitudinal evidence has suggested that longer-term use of NSAIDs, beginning in midlife, may be more beneficial (187). This could explain the absence of protective effects in the randomized controlled trials. Furthermore, two studies (175, 189) suggest that NSAID use in the 2 years preceding dementia onset offers no protection.

In conclusion, the risk-benefit ratio of NSAIDs is not clear, and safety concerns have been raised with some treatments. Further clinical trials are needed to establish the cognitive effects, but the treatment used must be safe.

Ginkgo biloba supplementation

Meta-analyses or reviews. Two reviews have assessed Ginkgo biloba for secondary prevention (196, 197) and noted that, although some trials found protective effects, overall results were inconsistent.

Prospective longitudinal studies. Although other types of epidemiologic studies have provided evidence for a protective effect of Ginkgo biloba on cognition (198), one prospective longitudinal study reported no association between ginkgo use and dementia risk (199).

Experimental studies (table 7). One short-term randomized controlled trial (200) involving middle-aged subjects found a Ginkgo biloba-Panax ginseng combination to have positive effects on some measures of cognition, but another (201) found no effect of Ginkgo biloba with other supplements on cognition. A 3.5-year trial of Ginkgo biloba in 118 elderly persons aged 85 or more years found no significant effect on cognitive decline overall but did find a protective effect in compliant patients (202).


View this table:
[in this window]
[in a new window]

  		TABLE 7. Randomized controlled prevention trials of Ginkgo biloba

 
Limitations. Only one longitudinal study and three randomized controlled trials were identified. Evidence concerning the effects of Ginkgo biloba on the prevention of dementia or cognitive decline is therefore limited. In light of the apparent safety of this intervention, further research is merited. The results of two large ongoing prevention trials (203, 204) will provide important data.

Hypertension

Meta-analyses or reviews. A comprehensive review (205) concluded that available longitudinal evidence suggests that high blood pressure in midlife is a risk factor for cognitive impairment and dementia/Alzheimer disease in late life, but that results are inconsistent for the effects of late-life blood pressure.

A Cochrane meta-analysis (206) assessed the effects of three blood pressure-lowering interventions of at least 6 months' duration on cognition in individuals without prior cerebrovascular disease. No significant effect on cognitive function or the incidence of dementia was detected, but there was heterogeneity between trials. Two other meta-analyses (207, 208) with much less stringent inclusion/exclusion criteria noted modest or borderline protective effects of antihypertensive treatment on dementia or certain cognitive domains.

Prospective longitudinal studies. Late-life blood pressure. Fourteen studies found increased late-life blood pressure to be associated with increased dementia (107, 209–212), mild cognitive impairment (213), or cognitive impairment/decline (83, 214–220), although in some cases the association was restricted to a certain age group (209), either systolic (209, 215, 220) or diastolic (217) blood pressure only, medicated hypertension (218), or vascular dementia but not Alzheimer disease (107, 210, 212).

Four studies, however, suggested that higher late-life blood pressure is associated with a decreased risk of dementia (221–223) or impaired cognitive function (224), and other studies have found U-shaped (225–227) or other (228, 229) relations.

Seven studies found no association between late-life blood pressure and dementia (104, 230–233) or cognition (234, 235).

Midlife blood pressure. Eleven studies found midlife hypertension to be associated with an increased risk of dementia (122, 236–239) or cognitive decline (240–245) during late life, although the relation was sometimes restricted to a certain type of dementia (vascular dementia not Alzheimer disease) (122), either systolic or diastolic blood pressure (241, 243–245), untreated hypertension (237), or older participants (242). One study (246) found no association between midlife blood pressure and late-life cognition.

Antihypertensive treatment. Three studies found use or increased duration of use of antihypertensive treatment to be associated with a decreased dementia/Alzheimer disease risk (228, 247, 248). One study found that antihypertensive treatment was associated with a decreased risk of vascular dementia but not Alzheimer disease (249), while three found no association with dementia (104, 221, 250).

Experimental studies (table 8). Five large-scale (≥2,500 subjects) randomized controlled trials (251–255) examined the effects of antihypertensive treatment on dementia or cognitive decline in elderly subjects for at least 3 years, although not as a primary outcome. Two studies (251, 252) found that treatment reduced the risk of dementia although, in one case (251), it was associated with only reduced risks of recurrent stroke-associated dementia and cognitive decline. The other three studies found no effect on dementia or cognition.


View this table:
[in this window]
[in a new window]

  		TABLE 8. Randomized controlled prevention trials of antihypertensive treatments

 
Limitations. Consistent longitudinal evidence points to raised midlife blood pressure as a risk factor for dementia/Alzheimer disease or cognitive decline, but experimental studies of antihypertensive treatment were carried out in late life, perhaps missing the ideal window of exposure. Longitudinal studies present an unclear picture of the effects of late-life blood pressure. Furthermore, follow-up in the randomized controlled trials may have been too short to demonstrate an effect.

Of five randomized controlled trials, two (251, 252) were positive, but in the Perindopril Protection against Recurrent Stroke Study (PROGRESS), treatment was linked to a lower risk of only recurrent stroke-related dementia, and in the Systolic Hypertension in Europe (Syst-Eur) trial, the relation was borderline significant (256). Other randomized controlled trials failed to demonstrate any protective effects.

In the Study on Cognition and Prognosis in the Elderly (SCOPE) trial, because of ethical reasons, experimental treatment was compared with usual treatment rather than placebo as originally planned, which probably reduced the detectable between-group effects.

Different types of antihypertensive treatments may have different effects on dementia or cognition. Specifically, calcium channel blockers and angiotensin-converting enzyme inhibitors may have the greatest effects, which may be brought about through mechanisms other than blood pressure lowering (257, 258).

There is relatively strong evidence that hypertension in midlife is a risk factor for dementia or cognitive decline, but associations with late-life blood pressure remain unclear. There is little evidence to suggest that antihypertensive treatment in late life reduces risks of dementia or cognitive decline. Initiation of antihypertensive treatment in midlife needs to be assessed in future randomized controlled trials.

Diabetes

Meta-analyses or reviews.. Two reviews (259, 260) studied the relation between diabetes and cognitive decline and concluded that, compared with people without diabetes, people with diabetes have a 1.5-fold greater risk of cognitive decline.

A review of 14 longitudinal based studies (261) compared the incident risk of dementia (Alzheimer disease, vascular dementia, and mixed dementia) in diabetic and nondiabetic subjects. They concluded that there is convincing evidence that shows an increased risk of dementia in people with diabetes, but there are few details on the modulating and mediating effects of glycemic control, other vascular risk factors, and microvascular complications.

In addition, a Cochrane review (262) of the effect of type 2 diabetes treatment on cognitive decline was unable to carry out a meta-analysis of randomized controlled trials because of a lack of studies of suitable quality.

Prospective longitudinal studies.. Sixteen studies (215, 218, 242, 263–275) have explored the link between diabetes and cognitive decline. All but two (218, 272) found that diabetic adults have more cognitive decline compared with nondiabetic adults; psychomotor efficiency, executive function, and learning and memory skills are often the most affected domains.

Seventeen studies (107, 122, 231, 263, 270, 276–286) have examined the association between diabetes and Alzheimer disease incidence. The risk of Alzheimer disease tended to be largest in the three (122, 277, 285) studies that measured the risk factor in midlife and had a long follow-up period. However, one study (277) found no association between diabetes in midlife and risk of Alzheimer disease, and six studies (107, 270, 278, 282, 286, 287) found no association between diabetes in late life and risk of Alzheimer disease. Diabetes treatment might also be a relevant factor. Two studies indicate that the risk of dementia is higher in diabetic subjects treated with insulin (282, 283).

Experimental studies.. Five randomized controlled trials (288–292) evaluating the effect of diabetes treatment on cognitive function over short durations (<1 year) or with questionable methodology (lack of double blinding) have reported contradictory results.

There are currently no intervention trials of high methodological quality assessing cognitive decline. The Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes (ACCORD-MIND) Study (293) was testing the effects of long-term glycemic control on cognitive decline and structural brain changes in patients with type 2 diabetes, but treatment has been stopped because of safety concerns (294).

Limitations.. There is consistent longitudinal evidence to suggest that diabetes is associated with dementia and cognitive decline, although nine studies were negative. In one of these studies, subjects were 85 or more years (272). There may be a "survivor effect," where individuals who reach old age, despite having multiple vascular risk factors, are survivors and might be less susceptible to the adverse effects of these risk factors.

Of the six studies finding no effect of diabetes on Alzheimer disease, five distinguished between vascular dementia and Alzheimer disease. The boundary between vascular dementia and Alzheimer disease remains controversial, so the possibility of misdiagnosis must be considered and might explain some of the negative results.

An increased risk of Alzheimer disease was seen in diabetic subjects treated by insulin (282, 283); whether these results show the severity of diabetes or an effect of insulin treatment itself is unknown.

In conclusion, diabetes is a risk factor for cognitive decline and dementia, but at this time, there are no high quality intervention studies examining the effect of metabolic control on cognition.


   COMMON METHODOLOGICAL ISSUES
TOP
 ABSTRACT
 INTRODUCTION
 SEARCH STRATEGY
 SUMMARY OF FINDINGS FROM...
 COMMON METHODOLOGICAL ISSUES
MULTIPLE EXPOSURE AND...
 CONCLUSION
 REFERENCES
 
Some common methodological limits could apply to various domains. The measurement of some exposures can suffer from a lack of precision: Self- or proxy-report rather than objective measures can lead to misclassification. In two studies (218, 277), diabetes was assessed only through declarative data, which may have led to an underestimation of the effect.

In longitudinal studies, exposure is often measured at one time point, and exposure variations over time are not considered. For example, few studies assessed changes in social interactions or activity participation over time, which may be especially important around the time of retirement.

The window of exposure might also be important, as some interventions may have differential effects according to the time of exposure. It has been suggested that hormone replacement therapy needs to be started around the immediate postmenopausal period for a beneficial effect (143, 168, 170, 295–297) but that randomized controlled trial participants were perhaps too old. Subjects included in nutritional randomized controlled trials were generally aged over 60 years, but nutrients may affect the neurodegenerative process at an early stage (7). One successful nutritional trial (63) was conducted in a slightly younger population, aged 50–70 years.

Observational studies often fail to take into account all potential confounding factors, such as depression or baseline cognitive performance. From this review, we can see the importance of adjusting for the presence of APOE*E4, but many studies did not consider this factor. We suggest that a minimum set of confounders including age, education, and baseline cognitive performance should be considered, but some studies did not adjust for all of the these factors simultaneously. Furthermore, recorded exposure variables could be a marker of unrecorded characteristics. For example, a healthy diet or use of vitamin supplements could reflect overall healthier behavior, leading to "healthy user" bias (298). In addition, postmenopausal treated women may have fewer hormone replacement therapy contraindications (hypertension, diabetes, history of stroke). Controlling for such confounders diminished the effect of hormone replacement therapy on cognition (138, 153, 159). Social engagement or activity participation could also be an indicator of previous life experiences (299), such as education or socioeconomic status, but generally only education was controlled for (73).

Protopathic bias is important. A low level of exposure (e.g., social engagement or activity participation) may be indicative of a neurodegenerative process that is not yet clinically apparent. However, in several domains, all observed associations remained after controlling for baseline cognitive function or after sensitivity analysis, excluding persons who developed dementia or cognitive decline soon after exposure measurement.

Outcome definition is variable. Some studies evaluated dementia incidence (assessed using standard international criteria with or without independent validation committees). Other studies considered different aspects of cognition by using a variety of cognitive tests and definitions of impairment or decline. Thus, the comparison of studies is difficult, and some authors questionably assume that cognitive decline is a validated surrogate marker of dementia. Furthermore, the clinical relevance of cognitive decline is rarely mentioned (300). Furthermore, some hypertension studies assessed all-cause dementia, including vascular forms, and therefore were more likely to be related to hypertension or an antihypertensive drug, while others specifically assessed Alzheimer disease.

Insufficient statistical power is a frequent limitation. For example, of the 10 nutritional randomized controlled trials, only two were large scale (68, 69). Given that interventions may have relatively modest effects, randomized controlled trials need sufficient power to detect small changes on cognitive outcome measures. Ancillary studies initially designed for noncognitive outcomes could be underpowered for cognitive outcome, since dementia/Alzheimer disease incidence remains relatively low.

Attrition rates are rarely considered. In nutritional intervention, the trial with the lowest attrition rate was the only trial able to demonstrate significant benefits of supplementation (63). In the Systolic Hypertension in the Elderly Program (SHEP) Study, which found no effect of antihypertensive treatment on cognitive decline or dementia, sensitivity analyses suggested that differential dropout may have obscured potential treatment effects (301). Some other trials of antihypertensives reported high rates of dropout (255) or discontinuation of study medication (251), which could have affected results.

Concerning statistical analysis, few studies used methods that took into account variation of covariates with time, which is important with many years of follow-up. Furthermore, it is difficult to compare longitudinal studies analyzing only subjects followed for the entire study period (e.g., excluding deaths and dropouts) and studies considering unequal durations of follow-up (i.e., survival analysis) or missing value(s) (i.e., mixed models).


   MULTIPLE EXPOSURE AND MULTIDOMAIN INTERVENTIONS
TOP
 ABSTRACT
 INTRODUCTION
 SEARCH STRATEGY
 SUMMARY OF FINDINGS FROM...
 COMMON METHODOLOGICAL ISSUES
 MULTIPLE EXPOSURE AND...
CONCLUSION
 REFERENCES
 
Because of the multifactorial nature of Alzheimer disease, it would seem logical to initiate multidomain interventions designed to examine not only the individual effects of each intervention but also any potential synergistic effects. Several intervention trials of this nature are currently underway (302, 303).

Some specific challenges need to be underlined in designing trials involving multidomain interventions. First, surrounding the specific selection of subjects, we can imagine that subjects who agree to modify multiple lifestyle domains are likely to have a higher level of education and better overall health, meaning that it may be difficult to demonstrate an effect of the intervention. Observance in multidomain trials is difficult to assess if the intervention combines different lifestyle factors. If the intervention is based on lifestyle recommendations, it will be difficult to evaluate actual behavioral modifications precisely. In these interventions, it is impossible to maintain double-blind conditions and difficult to define an adequate control group, especially for physical exercise interventions. It is also difficult to identify the independent effects of each factor, because they may act through common mechanisms (e.g., via cardiovascular mechanisms), and there may be between-group contamination.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 SEARCH STRATEGY
 SUMMARY OF FINDINGS FROM...
 COMMON METHODOLOGICAL ISSUES
 MULTIPLE EXPOSURE AND...
 CONCLUSION
REFERENCES
 
In this review, many methodological explanations for divergent observational and experimental results for dementia prevention were identified.

The evidence for preventive strategies for neurodegenerative dementia remains inconsistent, especially because of the lack of randomized controlled trials assessing dementia incidence as a primary outcome. At present, it is not possible to determine any specific recommendations for pharmacologic strategies or lifestyle changes. Future epidemiologic studies must attempt as much as possible to minimize bias and confounding, in order to generate reliable hypotheses on which to base randomized controlled trials.

If it existed, a preventive strategy based on the use of a pharmacologic treatment would seem to be a relatively simple method of preventing dementia/Alzheimer disease. A good risk-benefit ratio would be imperative because of the number of subjects who will be exposed to the intervention without ever developing the disease. In the absence of such a treatment, even if it is difficult to change lifestyle habits, lifestyle factors (diet, social engagement, cognitive stimulation, physical exercise) seem the most reasonable candidates for prevention trials at the current time, in particular because of their safety. As a result of the difficulties in conducting a multidomain intervention, randomized controlled trials may not represent the "gold standard" in this field, and large public health interventions at the population level could be required. However, such interventions would have to be feasible, cost effective, and easily transferable in order to have a real public health impact.


   ACKNOWLEDGMENTS
 
Nicola Coley is supported by a CIFRE PhD studentship, which is jointly funded by the French National Association for Technical Research and Beaufour Ipsen Pharma.

Conflict of interest: none declared.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SEARCH STRATEGY
 SUMMARY OF FINDINGS FROM...
 COMMON METHODOLOGICAL ISSUES
 MULTIPLE EXPOSURE AND...
 CONCLUSION
 REFERENCES
 

  1. Ferri CP, Prince M, Brayne C, et al. Global prevalence of dementia: a Delphi consensus study. Lancet (2005) 366:2112–17.[CrossRef][Web of Science][Medline]
  2. Brookmeyer R, Johnson E, Ziegler G, et al. Forecasting the global burden of Alzheimer's disease. Alzheimers Dement (2007) 3:186–91.[CrossRef]
  3. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health (1998) 88:1337–42.[Abstract/Free Full Text]
  4. Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA (2004) 291:2947–58.[Abstract/Free Full Text]
  5. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA (2003) 289:2651–62.[Abstract/Free Full Text]
  6. Gillette Guyonnet S, Abellan Van Kan G, Andrieu S, et al. IANA task force on nutrition and cognitive decline with aging. J Nutr Health Aging (2007) 11:132–52.[Web of Science][Medline]
  7. Luchsinger JA, Mayeux R. Dietary factors and Alzheimer's disease. Lancet Neurol (2004) 3:579–87.[CrossRef][Web of Science][Medline]
  8. Malouf M, Grimley EJ, Areosa SA. Folic acid with or without vitamin B12 for cognition and dementia. Cochrane Database Syst Rev (2003) (4). CD004514.
  9. Malouf R, Grimley Evans J. The effect of vitamin B6 on cognition. Cochrane Database Syst Rev (2003) (4). CD004393.
  10. Bjelakovic G, Nikolova D, Gluud LL, et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA (2007) 297:842–57.[Abstract/Free Full Text]
  11. Haan MN, Miller JW, Aiello AE, et al. Homocysteine, B vitamins, and the incidence of dementia and cognitive impairment: results from the Sacramento Area Latino Study on Aging. Am J Clin Nutr (2007) 85:511–17.[Abstract/Free Full Text]
  12. Ravaglia G, Forti P, Maioli F, et al. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr (2005) 82:636–43.[Abstract/Free Full Text]
  13. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med (2002) 346:476–83.[Abstract/Free Full Text]
  14. Dufouil C, Alperovitch A, Ducros V, et al. Homocysteine, white matter hyperintensities, and cognition in healthy elderly people. Ann Neurol (2003) 53:214–21.[CrossRef][Web of Science][Medline]
  15. McCaddon A, Hudson P, Davies G, et al. Homocysteine and cognitive decline in healthy elderly. Dement Geriatr Cogn Disord (2001) 12:309–13.[CrossRef][Web of Science][Medline]
  16. Tucker KL, Qiao N, Scott T, et al. High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. Am J Clin Nutr (2005) 82:627–35.[Abstract/Free Full Text]
  17. Luchsinger JA, Tang MX, Shea S, et al. Plasma homocysteine levels and risk of Alzheimer disease. Neurology (2004) 62:1972–6.[Abstract/Free Full Text]
  18. Kalmijn S, Launer LJ, Lindemans J, et al. Total homocysteine and cognitive decline in a community-based sample of elderly subjects: the Rotterdam Study. Am J Epidemiol (1999) 150:283–9.[Abstract/Free Full Text]
  19. Mooijaart SP, Gussekloo J, Frolich M, et al. Homocysteine, vitamin B-12, and folic acid and the risk of cognitive decline in old age: the Leiden 85-Plus study. Am J Clin Nutr (2005) 82:866–71.[Abstract/Free Full Text]
  20. Teunissen CE, Blom AH, Van Boxtel MP, et al. Homocysteine: a marker for cognitive performance? A longitudinal follow-up study. J Nutr Health Aging (2003) 7:153–9.[Medline]
  21. Clarke R, Birks J, Nexo E, et al. Low vitamin B-12 status and risk of cognitive decline in older adults. Am J Clin Nutr (2007) 86:1384–91.[Abstract/Free Full Text]
  22. Corrada M, Kawas C, Hallfrisch J, et al. Reduced risk of Alzheimer's disease with high folate intake: the Baltimore Longitudinal Study of Aging. Alzheimers Dement (2005) 1:11–18.
  23. Wang HX, Wahlin A, Basun H, et al. Vitamin B(12) and folate in relation to the development of Alzheimer's disease. Neurology (2001) 56:1188–94.[Abstract/Free Full Text]
  24. Morris MC, Evans DA, Bienias JL, et al. Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Arch Neurol (2005) 62:641–5.[Abstract/Free Full Text]
  25. Kado DM, Karlamangla AS, Huang MH, et al. Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging. Am J Med (2005) 118:161–7.[CrossRef][Web of Science][Medline]
  26. Luchsinger JA, Tang MX, Miller J, et al. Relation of higher folate intake to lower risk of Alzheimer disease in the elderly. Arch Neurol (2007) 64:86–92.[Abstract/Free Full Text]
  27. Morris MC, Evans DA, Schneider JA, et al. Dietary folate and vitamins B-12 and B-6 not associated with incident Alzheimer's disease. J Alzheimers Dis (2006) 9:435–43.[Web of Science][Medline]
  28. Crystal HA, Ortof E, Frishman WH, et al. Serum vitamin B12 levels and incidence of dementia in a healthy elderly population: a report from the Bronx Longitudinal Aging Study. J Am Geriatr Soc (1994) 42:933–6.[Web of Science][Medline]
  29. Kang JH, Irizarry MC, Grodstein F. Prospective study of plasma folate, vitamin B12, and cognitive function and decline. Epidemiology (2006) 17:650–7.[CrossRef][Web of Science][Medline]
  30. Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Dietary intake of antioxidants and risk of Alzheimer disease. JAMA (2002) 287:3223–9.[Abstract/Free Full Text]
  31. Morris MC, Evans DA, Bienias JL, et al. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA (2002) 287:3230–7.[Abstract/Free Full Text]
  32. Morris MC, Evans DA, Tangney CC, et al. Relation of the tocopherol forms to incident Alzheimer disease and to cognitive change. Am J Clin Nutr (2005) 81:508–14.[Abstract/Free Full Text]
  33. Wengreen HJ, Munger RG, Corcoran CD, et al. Antioxidant intake and cognitive function of elderly men and women: the Cache County Study. J Nutr Health Aging (2007) 11:230–7.[Web of Science][Medline]
  34. Grodstein F, Chen J, Willett WC. High-dose antioxidant supplements and cognitive function in community-dwelling elderly women. Am J Clin Nutr (2003) 77:975–84.[Abstract/Free Full Text]
  35. Maxwell CJ, Hicks MS, Hogan DB, et al. Supplemental use of antioxidant vitamins and subsequent risk of cognitive decline and dementia. Dement Geriatr Cogn Disord (2005) 20:45–51.[CrossRef][Web of Science][Medline]
  36. Masaki KH, Losonczy KG, Izmirlian G, et al. Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology (2000) 54:1265–72.[Abstract/Free Full Text]
  37. Zandi PP, Anthony JC, Khachaturian AS, et al. Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch Neurol (2004) 61:82–8.[Abstract/Free Full Text]
  38. Commenges D, Scotet V, Renaud S, et al. Intake of flavonoids and risk of dementia. Eur J Epidemiol (2000) 16:357–63.[CrossRef][Web of Science][Medline]
  39. Letenneur L, Proust-Lima C, Le Gouge A, et al. Flavonoid intake and cognitive decline over a 10-year period. Am J Epidemiol (2007) 165:1364–71.[Abstract/Free Full Text]
  40. Hu P, Bretsky P, Crimmins EM, et al. Association between serum beta-carotene levels and decline of cognitive function in high-functioning older persons with or without apolipoprotein E 4 alleles: MacArthur studies of successful aging. J Gerontol A Biol Sci Med Sci (2006) 61:616–20.[Abstract/Free Full Text]
  41. Gray SL, Hanlon JT, Landerman LR, et al. Is antioxidant use protective of cognitive function in the community-dwelling elderly? Am J Geriatr Pharmacother (2003) 1:3–10.[CrossRef][Medline]
  42. Akbaraly NT, Hininger-Favier I, Carriere I, et al. Plasma selenium over time and cognitive decline in the elderly. Epidemiology (2007) 18:52–8.[CrossRef][Web of Science][Medline]
  43. Berr C, Balansard B, Arnaud J, et al. Cognitive decline is associated with systemic oxidative stress: the EVA study. Etude du Vieillissement Arteriel. J Am Geriatr Soc (2000) 48:1285–91.[Web of Science][Medline]
  44. Laurin D, Masaki KH, Foley DJ, et al. Midlife dietary intake of antioxidants and risk of late-life incident dementia: the Honolulu-Asia Aging Study. Am J Epidemiol (2004) 159:959–67.[Abstract/Free Full Text]
  45. Luchsinger JA, Tang MX, Shea S, et al. Antioxidant vitamin intake and risk of Alzheimer disease. Arch Neurol (2003) 60:203–8.[Abstract/Free Full Text]
  46. Kang JH, Grodstein F. Plasma carotenoids and tocopherols and cognitive function: a prospective study. Neurobiol Aging (2008) 29:1394–403.[CrossRef][Web of Science][Medline]
  47. Laitinen MH, Ngandu T, Rovio S, et al. Fat intake at midlife and risk of dementia and Alzheimer's disease: a population-based study. Dement Geriatr Cogn Disord (2006) 22:99–107.[CrossRef][Web of Science][Medline]
  48. Solfrizzi V, Colacicco AM, D'Introno A, et al. Dietary intake of unsaturated fatty acids and age-related cognitive decline: a 8.5-year follow-up of the Italian Longitudinal Study on Aging. Neurobiol Aging (2006) 27:1694–704.[CrossRef][Web of Science][Medline]
  49. Morris MC, Evans DA, Bienias JL, et al. Dietary fats and the risk of incident Alzheimer disease. Arch Neurol (2003) 60:194–200.[Abstract/Free Full Text]
  50. Solfrizzi V, Colacicco AM, D'Introno A, et al. Dietary fatty acids intakes and rate of mild cognitive impairment. The Italian Longitudinal Study on Aging. Exp Gerontol (2006) 41:619–27.[CrossRef][Web of Science][Medline]
  51. Engelhart MJ, Geerlings MI, Ruitenberg A, et al. Diet and risk of dementia: does fat matter? The Rotterdam Study. Neurology (2002) 59:1915–21.[Abstract/Free Full Text]
  52. Schaefer EJ, Bongard V, Beiser AS, et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol (2006) 63:1545–50.[Abstract/Free Full Text]
  53. Beydoun MA, Kaufman JS, Satia JA, et al. Plasma n-3 fatty acids and the risk of cognitive decline in older adults: the Atherosclerosis Risk in Communities Study. Am J Clin Nutr (2007) 85:1103–11.[Abstract/Free Full Text]
  54. Dullemeijer C, Durga J, Brouwer IA, et al. n 3 fatty acid proportions in plasma and cognitive performance in older adults. Am J Clin Nutr (2007) 86:1479–85.[Abstract/Free Full Text]
  55. Barberger-Gateau P, Raffaitin C, Letenneur L, et al. Dietary patterns and risk of dementia: the Three-City Cohort Study. Neurology (2007) 69:1921–30.[Abstract/Free Full Text]
  56. Scarmeas N, Stern Y, Tang MX, et al. Mediterranean diet and risk for Alzheimer's disease. Ann Neurol (2006) 59:912–21.[CrossRef][Web of Science][Medline]
  57. Barberger-Gateau P, Letenneur L, Deschamps V, et al. Fish, meat, and risk of dementia: cohort study. BMJ (2002) 325:932–3.[Free Full Text]
  58. Kalmijn S, Launer LJ, Ott A, et al. Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol (1997) 42:776–82.[CrossRef][Web of Science][Medline]
  59. Morris MC, Evans DA, Bienias JL, et al. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol (2003) 60:940–6.[Abstract/Free Full Text]
  60. Morris MC, Evans DA, Tangney CC, et al. Fish consumption and cognitive decline with age in a large community study. Arch Neurol (2005) 62:1849–53.[Abstract/Free Full Text]
  61. van Gelder BM, Tijhuis M, Kalmijn S, et al. Fish consumption, n-3 fatty acids, and subsequent 5-y cognitive decline in elderly men: the Zutphen Elderly Study. Am J Clin Nutr (2007) 85:1142–7.[Abstract/Free Full Text]
  62. Bryan J, Calvaresi E, Hughes D. Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr (2002) 132:1345–56.[Abstract/Free Full Text]
  63. Durga J, van Boxtel MP, Schouten EG, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet (2007) 369:208–16.[CrossRef][Web of Science][Medline]
  64. Eussen SJ, de Groot LC, Joosten LW, et al. Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. Am J Clin Nutr (2006) 84:361–70.[Abstract/Free Full Text]
  65. Lewerin C, Matousek M, Steen G, et al. Significant correlations of plasma homocysteine and serum methylmalonic acid with movement and cognitive performance in elderly subjects but no improvement from short-term vitamin therapy: a placebo-controlled randomized study. Am J Clin Nutr (2005) 81:1155–62.[Abstract/Free Full Text]
  66. McMahon JA, Green TJ, Skeaff CM, et al. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med (2006) 354:2764–72.[Abstract/Free Full Text]
  67. Stott DJ, MacIntosh G, Lowe GD, et al. Randomized controlled trial of homocysteine-lowering vitamin treatment in elderly patients with vascular disease. Am J Clin Nutr (2005) 82:1320–6.[Abstract/Free Full Text]
  68. Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA (2004) 291:565–75.[Abstract/Free Full Text]
  69. Kang JH, Cook N, Manson J, et al. A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med (2006) 166:2462–8.[Abstract/Free Full Text]
  70. McNeill G, Avenell A, Campbell MK, et al. Effect of multivitamin and multimineral supplementation on cognitive function in men and women aged 65 years and over: a randomised controlled trial. (Electronic article). Nutr J (2007) 6:10.[CrossRef][Medline]
  71. Wolters M, Hickstein M, Flintermann A, et al. Cognitive performance in relation to vitamin status in healthy elderly German women—the effect of 6-month multivitamin supplementation. Prev Med (2005) 41:253–9.[CrossRef][Web of Science][Medline]
  72. Green RC, Dekosky ST. Primary prevention trials in Alzheimer disease. Neurology (2006) 67(suppl 3):S2–5.[Abstract/Free Full Text]
  73. Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol (2004) 3:343–53.[CrossRef][Web of Science][Medline]
  74. Lautenschlager NT, Almeida OP. Physical activity and cognition in old age. Curr Opin Psychiatry (2006) 19:190–3.[Web of Science][Medline]
  75. Rolland Y, Abellan van Kan G, Vellas B. Physical activity and Alzheimer's disease: from prevention to therapeutic perspectives. J Am Med Dir Assoc (2008) 9:390–405.[CrossRef][Web of Science][Medline]
  76. Karp A, Paillard-Borg S, Wang HX, et al. Mental, physical and social components in leisure activities equally contribute to decrease dementia risk. Dement Geriatr Cogn Disord (2006) 21:65–73.[Web of Science][Medline]
  77. Scarmeas N, Levy G, Tang MX, et al. Influence of leisure activity on the incidence of Alzheimer's disease. Neurology (2001) 57:2236–42.[Abstract/Free Full Text]
  78. Wang HX, Karp A, Winblad B, et al. Late-life engagement in social and leisure activities is associated with a decreased risk of dementia: a longitudinal study from the Kungsholmen Project. Am J Epidemiol (2002) 155:1081–7.[Abstract/Free Full Text]
  79. Bickel H, Cooper B. Incidence and relative risk of dementia in an urban elderly population: findings of a prospective field study. Psychol Med (1994) 24:179–92.[Web of Science][Medline]
  80. Fratiglioni L, Wang HX, Ericsson K, et al. Influence of social network on occurrence of dementia: a community-based longitudinal study. Lancet (2000) 355:1315–19.[CrossRef][Web of Science][Medline]
  81. Helmer C, Damon D, Letenneur L, et al. Marital status and risk of Alzheimer's disease: a French population-based cohort study. Neurology (1999) 53:1953–8.[Abstract/Free Full Text]
  82. Saczynski JS, Pfeifer LA, Masaki K, et al. The effect of social engagement on incident dementia: the Honolulu-Asia Aging Study. Am J Epidemiol (2006) 163:433–40.[Abstract/Free Full Text]
  83. Barnes DE, Cauley JA, Lui LY, et al. Women who maintain optimal cognitive function into old age. J Am Geriatr Soc (2007) 55:259–64.[CrossRef][Medline]
  84. Barnes LL, Mendes de Leon CF, Wilson RS, et al. Social resources and cognitive decline in a population of older African Americans and whites. Neurology (2004) 63:2322–6.[Abstract/Free Full Text]
  85. Bassuk SS, Glass TA, Berkman LF. Social disengagement and incident cognitive decline in community-dwelling elderly persons. Ann Intern Med (1999) 131:165–73.[Abstract/Free Full Text]
  86. Beland F, Zunzunegui MV, Alvarado B, et al. Trajectories of cognitive decline and social relations. J Gerontol B Psychol Sci Soc Sci (2005) 60:P320–30.[Abstract/Free Full Text]
  87. Bosma H, van Boxtel MP, Ponds RW, et al. Engaged lifestyle and cognitive function in middle and old-aged, non-demented persons: a reciprocal association? Z Gerontol Geriatr (2002) 35:575–81.[CrossRef][Web of Science][Medline]
  88. Holtzman RE, Rebok GW, Saczynski JS, et al. Social network characteristics and cognition in middle-aged and older adults. J Gerontol B Psychol Sci Soc Sci (2004) 59:P278–84.[Abstract/Free Full Text]
  89. Zunzunegui MV, Alvarado BE, Del Ser T, et al. J Gerontol B Psychol Sci Soc Sci. (2003) 58:S93–100.
  90. Seeman TE, Lusignolo TM, Albert M, et al. Social relationships, social support, and patterns of cognitive aging in healthy, high-functioning older adults: MacArthur studies of successful aging. Health Psychol (2001) 20:243–55.[CrossRef][Web of Science][Medline]
  91. Glei DA, Landau DA, Goldman N, et al. Participating in social activities helps preserve cognitive function: an analysis of a longitudinal, population-based study of the elderly. Int J Epidemiol (2005) 34:864–71.[Abstract/Free Full Text]
  92. Hultsch DF, Hertzog C, Small BJ, et al. Use it or lose it: engaged lifestyle as a buffer of cognitive decline in aging? Psychol Aging (1999) 14:245–63.[CrossRef][Web of Science][Medline]
  93. Wang JY, Zhou DH, Li J, et al. Leisure activity and risk of cognitive impairment: the Chongqing Aging Study. Neurology (2006) 66:911–13.[Abstract/Free Full Text]
  94. Menec VH. The relation between everyday activities and successful aging: a 6-year longitudinal study. J Gerontol B Psychol Sci Soc Sci (2003) 58:S74–82.[Abstract/Free Full Text]
  95. Verghese J, Lipton RB, Katz MJ, et al. Leisure activities and the risk of dementia in the elderly. N Engl J Med (2003) 348:2508–16.[Abstract/Free Full Text]
  96. Wilson RS, Bennett DA, Bienias JL, et al. Cognitive activity and incident AD in a population-based sample of older persons. Neurology (2002) 59:1910–14.[Abstract/Free Full Text]
  97. Wilson RS, Mendes De Leon CF, Barnes LL, et al. Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA (2002) 287:742–8.[Abstract/Free Full Text]
  98. Wilson RS, Scherr PA, Schneider JA, et al. Relation of cognitive activity to risk of developing Alzheimer disease. Neurology (2007) 69:1911–20.[Abstract/Free Full Text]
  99. Verghese J, LeValley A, Derby C, et al. Leisure activities and the risk of amnestic mild cognitive impairment in the elderly. Neurology (2006) 66:821–7.[Abstract/Free Full Text]
  100. Wilson RS, Bennett DA, Bienias JL, et al. Cognitive activity and cognitive decline in a biracial community population. Neurology (2003) 61:812–16.[Abstract/Free Full Text]
  101. Abbott RD, White LR, Ross GW, et al. Walking and dementia in physically capable elderly men. JAMA (2004) 292:1447–53.[Abstract/Free Full Text]
  102. Larson EB, Wang L, Bowen JD, et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med (2006) 144:73–81.[Abstract/Free Full Text]
  103. Laurin D, Verreault R, Lindsay J, et al. Physical activity and risk of cognitive impairment and dementia in elderly persons. Arch Neurol (2001) 58:498–504.[Abstract/Free Full Text]
  104. Lindsay J, Laurin D, Verreault R, et al. Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging. Am J Epidemiol (2002) 156:445–53.[Abstract/Free Full Text]
  105. Podewils LJ, Guallar E, Kuller LH, et al. Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study. Am J Epidemiol (2005) 161:639–51.[Abstract/Free Full Text]
  106. van Gelder BM, Tijhuis MA, Kalmijn S, et al. Physical activity in relation to cognitive decline in elderly men: the FINE Study. Neurology (2004) 63:2316–21.[Abstract/Free Full Text]
  107. Yoshitake T, Kiyohara Y, Kato I, et al. Incidence and risk factors of vascular dementia and Alzheimer's disease in a defined elderly Japanese population: the Hisayama Study. Neurology (1995) 45:1161–8.[Abstract/Free Full Text]
  108. Albert MS, Jones K, Savage CR, et al. Predictors of cognitive change in older persons: MacArthur studies of successful aging. Psychol Aging (1995) 10:578–89.[CrossRef][Web of Science][Medline]
  109. Carmelli D, Swan GE, LaRue A, et al. Correlates of change in cognitive function in survivors from the Western Collaborative Group Study. Neuroepidemiology (1997) 16:285–95.[Web of Science][Medline]
  110. Lytle ME, Vander Bilt J, Pandav RS, et al. Exercise level and cognitive decline: the MoVIES project. Alzheimer Dis Assoc Disord (2004) 18:57–64.[CrossRef][Web of Science][Medline]
  111. Richards M, Hardy R, Wadsworth ME. Does active leisure protect cognition? Evidence from a national birth cohort. Soc Sci Med (2003) 56:785–92.[CrossRef][Web of Science][Medline]
  112. Schuit AJ, Feskens EJ, Launer LJ, et al. Physical activity and cognitive decline, the role of the apolipoprotein e4 allele. Med Sci Sports Exerc (2001) 33:772–7.[CrossRef][Web of Science][Medline]
  113. Sumic A, Michael YL, Carlson NE, et al. Physical activity and the risk of dementia in oldest old. J Aging Health (2007) 19:242–59.[Abstract/Free Full Text]
  114. Weuve J, Kang JH, Manson JE, et al. Physical activity, including walking, and cognitive function in older women. JAMA (2004) 292:1454–61.[Abstract/Free Full Text]
  115. Yaffe K, Barnes D, Nevitt M, et al. A prospective study of physical activity and cognitive decline in elderly women: women who walk. Arch Intern Med (2001) 161:1703–8.[Abstract/Free Full Text]
  116. Broe GA, Creasey H, Jorm AF, et al. Health habits and risk of cognitive impairment and dementia in old age: a prospective study on the effects of exercise, smoking and alcohol consumption. Aust N Z J Public Health (1998) 22:621–3.[Web of Science][Medline]
  117. Fabrigoule C, Letenneur L, Dartigues JF, et al. Social and leisure activities and risk of dementia: a prospective longitudinal study. J Am Geriatr Soc (1995) 43:485–90.[Web of Science][Medline]
  118. Barnes DE, Yaffe K, Satariano WA, et al. A longitudinal study of cardiorespiratory fitness and cognitive function in healthy older adults. J Am Geriatr Soc (2003) 51:459–65.[CrossRef][Web of Science][Medline]
  119. Ho SC, Woo J, Sham A, et al. A 3-year follow-up study of social, lifestyle and health predictors of cognitive impairment in a Chinese older cohort. Int J Epidemiol (2001) 30:1389–96.[Abstract/Free Full Text]
  120. Sturman MT, Morris MC, Mendes de Leon CF, et al. Physical activity, cognitive activity, and cognitive decline in a biracial community population. Arch Neurol (2005) 62:1750–4.[Abstract/Free Full Text]
  121. Rovio S, Kareholt I, Helkala EL, et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease. Lancet Neurol (2005) 4:705–11.[CrossRef][Web of Science][Medline]
  122. Yamada M, Kasagi F, Sasaki H, et al. Association between dementia and midlife risk factors: the Radiation Effects Research Foundation Adult Health Study. J Am Geriatr Soc (2003) 51:410–14.[CrossRef][Web of Science][Medline]
  123. Ghisletta P, Bickel JF, Lovden M. Does activity engagement protect against cognitive decline in old age? Methodological and analytical considerations. J Gerontol B Psychol Sci Soc Sci (2006) 61:P253–61.[Abstract/Free Full Text]
  124. Arbuckle TY, Maag U, Pushkar D, et al. Individual differences in trajectory of intellectual development over 45 years of adulthood. Psychol Aging (1998) 13:663–75.[CrossRef][Web of Science][Medline]
  125. Aartsen MJ, Smits CH, van Tilburg T, et al. Activity in older adults: cause or consequence of cognitive functioning? A longitudinal study on everyday activities and cognitive performance in older adults. J Gerontol B Psychol Sci Soc Sci (2002) 57:P153–62.[Abstract/Free Full Text]
  126. Calero MD, Navarro E. Cognitive plasticity as a modulating variable on the effects of memory training in elderly persons. Arch Clin Neuropsychol (2007) 22:63–72.[Abstract]
  127. Willis S, Nesselroade C. Long-term effects of fluid ability training in old-old age. Dev Psychol (1990) 26:905–10.[CrossRef][Web of Science]
  128. Neely AS, Backman L. Effects of multifactorial memory training in old age: generalizability across tasks and individuals. J Gerontol B Psychol Sci Soc Sci (1995) 50:P134–40.[Abstract]
  129. Xeno-Rasmusson D, Rebok G, Bylsma F, et al. Effects of three types of memory training in normal elderly. Aging Neuropsychol Cogn (1999) 6:56–66.[CrossRef]
  130. Edwards JD, Wadley VG, Myers RS, et al. Transfer of a speed of processing intervention to near and far cognitive functions. Gerontology (2002) 48:329–40.[CrossRef][Web of Science][Medline]
  131. Mahncke HW, Connor BB, Appelman J, et al. Memory enhancement in healthy older adults using a brain plasticity-based training program: a randomized, controlled study. Proc Natl Acad Sci U S A (2006) 103:12523–8.[Abstract/Free Full Text]
  132. Willis SL, Tennstedt SL, Marsiske M, et al. Long-term effects of cognitive training on everyday functional outcomes in older adults. JAMA (2006) 296:2805–14.[Abstract/Free Full Text]
  133. Valentijn SA, van Hooren SA, Bosma H, et al. The effect of two types of memory training on subjective and objective memory performance in healthy individuals aged 55 years and older: a randomized controlled trial. Patient Educ Couns (2005) 57:106–14.[CrossRef][Web of Science][Medline]
  134. Teri L, Gibbons LE, McCurry SM, et al. Exercise plus behavioral management in patients with Alzheimer disease: a randomized controlled trial. JAMA (2003) 290:2015–22.[Abstract/Free Full Text]
  135. Oken BS, Zajdel D, Kishiyama S, et al. Randomized, controlled, six-month trial of yoga in healthy seniors: effects on cognition and quality of life. Altern Ther Health Med (2006) 12:40–7.[Web of Science][Medline]
  136. Kramer AF, Hahn S, Cohen NJ, et al. Ageing, fitness and neurocognitive function. Nature (1999) 400:418–19.[CrossRef][Web of Science][Medline]
  137. Kramer AF, Erickson KI. Capitalizing on cortical plasticity: influence of physical activity on cognition and brain function. Trends Cogn Sci (2007) 11:342–8.[CrossRef][Web of Science][Medline]
  138. Hogervorst E, Williams J, Budge M, et al. The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis. Neuroscience (2000) 101:485–512.[CrossRef][Web of Science][Medline]
  139. LeBlanc ES, Janowsky J, Chan BK, et al. Hormone replacement therapy and cognition: systematic review and meta-analysis. JAMA (2001) 285:1489–99.[Abstract/Free Full Text]
  140. Lethaby A, Hogervorst E, Richards M, et al. Hormone replacement therapy for cognitive function in postmenopausal women. Cochrane Database Syst Rev (2008) 1. CD003122.
  141. Low LF, Anstey KJ. Hormone replacement therapy and cognitive performance in postmenopausal women—a review by cognitive domain. Neurosci Biobehav Rev (2006) 30:66–84.[CrossRef][Web of Science][Medline]
  142. Maki P, Hogervorst E. The menopause and HRT. HRT and cognitive decline. Best Pract Res Clin Endocrinol Metab (2003) 17:105–22.[CrossRef][Medline]
  143. Sherwin BB. Estrogen and cognitive functioning in women. Endocr Rev (2003) 24:133–51.[Abstract/Free Full Text]
  144. Yaffe K, Sawaya G, Lieberburg I, et al. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA (1998) 279:688–95.[Abstract/Free Full Text]
  145. Zec RF, Trivedi MA. The effects of estrogen replacement therapy on neuropsychological functioning in postmenopausal women with and without dementia: a critical and theoretical review. Neuropsychol Rev (2002) 12:65–109.[CrossRef][Web of Science][Medline]
  146. Kawas C, Resnick S, Morrison A, et al. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology (1997) 48:1517–21.[Abstract/Free Full Text]
  147. Tang MX, Jacobs D, Stern Y, et al. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet (1996) 348:429–32.[CrossRef][Web of Science][Medline]
  148. Paganini-Hill A, Henderson VW. Estrogen deficiency and risk of Alzheimer's disease in women. Am J Epidemiol (1994) 140:256–61.[Abstract/Free Full Text]
  149. Matthews K, Cauley J, Yaffe K, et al. Estrogen replacement therapy and cognitive decline in older community women. J Am Geriatr Soc (1999) 47:518–23.[Web of Science][Medline]
  150. Rice MM, Graves AB, McCurry SM, et al. Postmenopausal estrogen and estrogen-progestin use and 2-year rate of cognitive change in a cohort of older Japanese American women: the Kame Project. Arch Intern Med (2000) 160:1641–9.[Abstract/Free Full Text]
  151. Yaffe K, Haan M, Byers A, et al. Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction. Neurology (2000) 54:1949–54.[Abstract/Free Full Text]
  152. Grodstein F, Chen J, Pollen DA, et al. Postmenopausal hormone therapy and cognitive function in healthy older women. J Am Geriatr Soc (2000) 48:746–52.[Web of Science][Medline]
  153. Kang JH, Weuve J, Grodstein F. Postmenopausal hormone therapy and risk of cognitive decline in community-dwelling aging women. Neurology (2004) 63:101–7.[Abstract/Free Full Text]
  154. Zandi PP, Carlson MC, Plassman BL, et al. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA (2002) 288:2123–9.[Abstract/Free Full Text]
  155. Carlson MC, Zandi PP, Plassman BL, et al. Hormone replacement therapy and reduced cognitive decline in older women: the Cache County Study. Neurology (2001) 57:2210–16.[Abstract/Free Full Text]
  156. Lokkegaard E, Pedersen AT, Laursen P, et al. The influence of hormone replacement therapy on the aging-related change in cognitive performance. Analysis based on a Danish cohort study. Maturitas (2002) 42:209–18.[CrossRef][Web of Science][Medline]
  157. Barrett-Connor E, Kritz-Silverstein D. Estrogen replacement therapy and cognitive function in older women. JAMA (1993) 269:2637–41.[Abstract/Free Full Text]
  158. de Moraes SA, Szklo M, Knopman D, et al. Prospective assessment of estrogen replacement therapy and cognitive functioning: Atherosclerosis Risk in Communities Study. Am J Epidemiol (2001) 154:733–9.[Abstract/Free Full Text]
  159. Fillenbaum GG, Hanlon JT, Landerman LR, et al. Impact of estrogen use on decline in cognitive function in a representative sample of older community-resident women. Am J Epidemiol (2001) 153:137–44.[Abstract/Free Full Text]
  160. Yaffe K, Grady D, Pressman A, et al. Serum estrogen levels, cognitive performance, and risk of cognitive decline in older community women. J Am Geriatr Soc (1998) 46:816–21.[Web of Science][Medline]
  161. Almeida OP, Lautenschlager NT, Vasikaran S, et al. A 20-week randomized controlled trial of estradiol replacement therapy for women aged 70 years and older: effect on mood, cognition and quality of life. Neurobiol Aging (2006) 27:141–9.[CrossRef][Web of Science][Medline]
  162. Binder EF, Schechtman KB, Birge SJ, et al. Effects of hormone replacement therapy on cognitive performance in elderly women. Maturitas (2001) 38:137–46.[CrossRef][Web of Science][Medline]
  163. Polo-Kantola P, Portin R, Polo O, et al. The effect of short-term estrogen replacement therapy on cognition: a randomized, double-blind, cross-over trial in postmenopausal women. Obstet Gynecol (1998) 91:459–66.[CrossRef][Web of Science][Medline]
  164. Viscoli CM, Brass LM, Kernan WN, et al. Estrogen therapy and risk of cognitive decline: results from the Women's Estrogen for Stroke Trial (WEST). Am J Obstet Gynecol (2005) 192:387–93.[CrossRef][Web of Science][Medline]
  165. Resnick SM, Maki PM, Rapp SR, et al. Effects of combination estrogen plus progestin hormone treatment on cognition and affect. J Clin Endocrinol Metab (2006) 91:1802–10.[Abstract/Free Full Text]
  166. Greenspan SL, Resnick NM, Parker RA. The effect of hormone replacement on physical performance in community-dwelling elderly women. Am J Med (2005) 118:1232–9.[CrossRef][Web of Science][Medline]
  167. Yaffe K, Vittinghoff E, Ensrud KE, et al. Effects of ultra-low-dose transdermal estradiol on cognition and health-related quality of life. Arch Neurol (2006) 63:945–50.[Abstract/Free Full Text]
  168. Henderson VW. Estrogen-containing hormone therapy and Alzheimer's disease risk: understanding discrepant inferences from observational and experimental research. Neuroscience (2006) 138:1031–9.[CrossRef][Web of Science][Medline]
  169. Almeida OP, Flicker L. Association between hormone replacement therapy and dementia: is it time to forget? Int Psychogeriatr (2005) 17:155–64.[CrossRef][Web of Science][Medline]
  170. Maki PM. Hormone therapy and cognitive function: is there a critical period for benefit? Neuroscience (2006) 138:1027–30.[CrossRef][Web of Science][Medline]
  171. Sherwin BB. The critical period hypothesis: can it explain discrepancies in the oestrogen-cognition literature? J Neuroendocrinol (2007) 19:77–81.[CrossRef][Web of Science][Medline]
  172. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA (2002) 288:321–33.[Abstract/Free Full Text]
  173. de Craen AJ, Gussekloo J, Vrijsen B, et al. Meta-analysis of nonsteroidal antiinflammatory drug use and risk of dementia. Am J Epidemiol (2005) 161:114–20.[Abstract/Free Full Text]
  174. Etminan M, Gill S, Samii A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer's disease: systematic review and meta-analysis of observational studies. (Electronic article). BMJ (2003) 327:128.[Abstract/Free Full Text]
  175. Szekely CA, Thorne JE, Zandi PP, et al. Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer's disease: a systematic review. Neuroepidemiology (2004) 23:159–69.[CrossRef][Web of Science][Medline]
  176. Robertson M. Effect of NSAIDs on risk of Alzheimer's disease: confounding factors were not discussed. BMJ (2003) 327. 751; author reply 751–2.
  177. McGeer PL, McGeer EG. NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies. Neurobiol Aging (2007) 28:639–47.[CrossRef][Web of Science][Medline]
  178. Zandi PP, Anthony JC, Hayden KM, et al. Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study. Neurology (2002) 59:880–6.[Abstract/Free Full Text]
  179. Szekely CA, Breitner JC, Fitzpatrick AL, et al. NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type. Neurology (2008) 70:17–24.[Abstract/Free Full Text]
  180. Jonker C, Comijs HC, Smit JH. Does aspirin or other NSAIDs reduce the risk of cognitive decline in elderly persons? Results from a population-based study. Neurobiol Aging (2003) 24:583–8.[CrossRef][Web of Science][Medline]
  181. Fourrier A, Letenneur L, Begaud B, et al. Nonsteroidal antiinflammatory drug use and cognitive function in the elderly: inconclusive results from a population-based cohort study. J Clin Epidemiol (1996) 49:1201.[CrossRef][Web of Science][Medline]
  182. Henderson AS, Jorm AF, Christensen H, et al. Aspirin, anti-inflammatory drugs and risk of dementia. Int J Geriatr Psychiatry (1997) 12:926–30.[CrossRef][Web of Science][Medline]
  183. Hanlon JT, Schmader KE, Landerman LR, et al. Relation of prescription nonsteroidal antiinflammatory drug use to cognitive function among community-dwelling elderly. Ann Epidemiol (1997) 7:87–94.[CrossRef][Web of Science][Medline]
  184. Hee Kang J, Grodstein F. Regular use of nonsteroidal anti-inflammatory drugs and cognitive function in aging women. Neurology (2003) 60:1591–7.[Abstract/Free Full Text]
  185. Sturmer T, Glynn RJ, Field TS, et al. Aspirin use and cognitive function in the elderly. Am J Epidemiol (1996) 143:683–91.[Abstract/Free Full Text]
  186. Stewart WF, Kawas C, Corrada M, et al. Risk of Alzheimer's disease and duration of NSAID use. Neurology (1997) 48:626–32.[Abstract/Free Full Text]
  187. in ‘t Veld BA, Ruitenberg A, Hofman A, et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med (2001) 345:1515–21.[Abstract/Free Full Text]
  188. Cornelius C, Fastbom J, Winblad B, et al. Aspirin, NSAIDs, risk of dementia, and influence of the apolipoprotein E epsilon 4 allele in an elderly population. Neuroepidemiology (2004) 23:135–43.[CrossRef][Web of Science][Medline]
  189. Hayden KM, Zandi PP, Khachaturian AS, et al. Does NSAID use modify cognitive trajectories in the elderly? The Cache County Study. Neurology (2007) 69:275–82.[Abstract/Free Full Text]
  190. Lyketsos CG, Breitner JC, et al, ADAPT Research Group. Naproxen and celecoxib do not prevent AD in early results from a randomized controlled trial. Neurology (2007) 68:1800–8.[Abstract/Free Full Text]
  191. Kang JH, Cook N, Manson J, et al. Low dose aspirin and cognitive function in the Women's Health Study cognitive cohort. (Electronic article). BMJ (2007) 334:987.[Abstract/Free Full Text]
  192. Farrell MJ, Katz B, Helme RD. The impact of dementia on the pain experience. Pain (1996) 67:7–15.[CrossRef][Web of Science][Medline]
  193. Szekely CA, Breitner JC, Zandi PP. Prevention of Alzheimer's disease. Int Rev Psychiatry (2007) 19:693–706.[CrossRef][Web of Science][Medline]
  194. Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature (2001) 414:212–16.[CrossRef][Web of Science][Medline]
  195. Eriksen JL, Sagi SA, Smith TE, et al. NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Aβ42 in vivo. J Clin Invest (2003) 112:440–9.[CrossRef][Web of Science][Medline]
  196. Birks J, Evans J Grimley. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev (2007) (2). CD003120.
  197. in ‘t Veld BA, Launer LJ, Breteler MM, et al. Pharmacologic agents associated with a preventive effect on Alzheimer’s disease: a review of the epidemiologic evidence. Epidemiol Rev (2002) 24:248–68.[Free Full Text]
  198. Andrieu S, Gillette S, Amouyal K, et al. Association of Alzheimer's disease onset with Ginkgo biloba and other symptomatic cognitive treatments in a population of women aged 75 years and older from the EPIDOS study. J Gerontol A Biol Sci Med Sci (2003) 58:372–7.[Web of Science][Medline]
  199. Dartigues JF, Carcaillon L, Helmer C, et al. Vasodilators and nootropics as predictors of dementia and mortality in the PAQUID cohort. J Am Geriatr Soc (2007) 55:395–9.[CrossRef][Web of Science][Medline]
  200. Wesnes KA, Ward T, McGinty A, et al. The memory enhancing effects of a Ginkgo biloba/Panax ginseng combination in healthy middle-aged volunteers. Psychopharmacology (Berl) (2000) 152:353–61.[CrossRef][Medline]
  201. Carlson JJ, Farquhar JW, DiNucci E, et al. Safety and efficacy of a Ginkgo biloba-containing dietary supplement on cognitive function, quality of life, and platelet function in healthy, cognitively intact older adults. J Am Diet Assoc (2007) 107:422–32.[CrossRef][Web of Science][Medline]
  202. Dodge HH, Zitzelberger T, Oken BS, et al. A randomized placebo-controlled trial of Ginkgo biloba for the prevention of cognitive decline. Neurology (2008) 70((pt 2)):1809–17.[Abstract/Free Full Text]
  203. DeKosky ST, Fitzpatrick A, Ives DG, et al. The Ginkgo Evaluation of Memory (GEM) Study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia. Contemp Clin Trials (2006) 27:238–53.[CrossRef][Web of Science][Medline]
  204. Vellas B, Andrieu S, Ousset PJ, et al. The GuidAge Study: methodological issues. A 5-year double-blind randomized trial of the efficacy of EGb 761 for prevention of Alzheimer disease in patients over 70 with a memory complaint. Neurology (2006) 67((suppl 3)):S6–11.[Abstract/Free Full Text]
  205. Qiu C, Winblad B, Fratiglioni L. The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol (2005) 4:487–99.[CrossRef][Web of Science][Medline]
  206. McGuinness B, Todd S, Passmore P, et al. The effects of blood pressure lowering on development of cognitive impairment and dementia in patients without apparent prior cerebrovascular disease. Cochrane Database Syst Rev (2006) (2). CD004034.
  207. Birns J, Morris R, Donaldson N, et al. The effects of blood pressure reduction on cognitive function: a review of effects based on pooled data from clinical trials. J Hypertens (2006) 24:1907–14.[Web of Science][Medline]
  208. Feigin V, Ratnasabapathy Y, Anderson C. Does blood pressure lowering treatment prevent dementia or cognitive decline in patients with cardiovascular and cerebrovascular disease? J Neurol Sci (2005) 229–230:151–5.
  209. Li G, Rhew IC, Shofer JB, et al. Age-varying association between blood pressure and risk of dementia in those aged 65 and older: a community-based prospective cohort study. J Am Geriatr Soc (2007) 55:1161–7.[CrossRef][Web of Science][Medline]
  210. Posner HB, Tang MX, Luchsinger J, et al. The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function. Neurology (2002) 58:1175–81.[Web of Science][Medline]
  211. Skoog I, Lernfelt B, Landahl S, et al. 15-year longitudinal study of blood pressure and dementia. Lancet (1996) 347:1141–5.[CrossRef][Web of Science][Medline]
  212. Hayden KM, Zandi PP, Lyketsos CG, et al. Vascular risk factors for incident Alzheimer disease and vascular dementia: the Cache County Study. Alzheimer Dis Assoc Disord (2006) 20:93–100.[CrossRef][Web of Science][Medline]
  213. Reitz C, Tang MX, Manly J, et al. Hypertension and the risk of mild cognitive impairment. Arch Neurol (2007) 64:1734–40.[Abstract/Free Full Text]
  214. Elias MF, Elias PK, Sullivan LM, et al. Lower cognitive function in the presence of obesity and hypertension: the Framingham Heart Study. Int J Obes Relat Metab Disord (2003) 27:260–8.[CrossRef][Web of Science][Medline]
  215. Haan MN, Shemanski L, Jagust WJ, et al. The role of APOE {varepsilon}4 in modulating effects of other risk factors for cognitive decline in elderly persons. JAMA (1999) 282:40–6.[Abstract/Free Full Text]
  216. Piguet O, Grayson DA, Creasey H, et al. Vascular risk factors, cognition and dementia incidence over 6 years in the Sydney Older Persons Study. Neuroepidemiology (2003) 22:165–71.[CrossRef][Web of Science][Medline]
  217. Reinprecht F, Elmstahl S, Janzon L, et al. Hypertension and changes of cognitive function in 81-year-old men: a 13-year follow-up of the population study "Men born in 1914, " Sweden. J Hypertens (2003) 21:57–66.[CrossRef][Web of Science][Medline]
  218. Tervo S, Kivipelto M, Hanninen T, et al. Incidence and risk factors for mild cognitive impairment: a population-based three-year follow-up study of cognitively healthy elderly subjects. Dement Geriatr Cogn Disord (2004) 17:196–203.[CrossRef][Web of Science][Medline]
  219. Tzourio C, Dufouil C, Ducimetiere P, et al. Cognitive decline in individuals with high blood pressure: a longitudinal study in the elderly. EVA Study Group. Epidemiology of Vascular Aging. Neurology (1999) 53:1948–52.[Abstract/Free Full Text]
  220. Waldstein SR, Giggey PP, Thayer JF, et al. Nonlinear relations of blood pressure to cognitive function: the Baltimore Longitudinal Study of Aging. Hypertension (2005) 45:374–9.[Abstract/Free Full Text]
  221. Morris MC, Scherr PA, Hebert LE, et al. Association of incident Alzheimer disease and blood pressure measured from 13 years before to 2 years after diagnosis in a large community study. Arch Neurol (2001) 58:1640–6.[Abstract/Free Full Text]
  222. Ruitenberg A, Skoog I, Ott A, et al. Blood pressure and risk of dementia: results from the Rotterdam Study and the Gothenburg H-70 Study. Dement Geriatr Cogn Disord (2001) 12:33–9.[CrossRef][Web of Science][Medline]
  223. Rastas S, Pirttilä T, Mattila K, et al. Vascular risk factors and dementia in the general population aged >85 years: prospective population-based study. Neurobiol Aging. (doi: 10.1016/j.neurobiolaging. 2008. 02.020).
  224. Nilsson SE, Read S, Berg S, et al. Low systolic blood pressure is associated with impaired cognitive function in the oldest old: longitudinal observations in a population-based sample 80 years and older. Aging Clin Exp Res (2007) 19:41–7.[Web of Science][Medline]
  225. Bohannon AD, Fillenbaum GG, Pieper CF, et al. Relationship of race/ethnicity and blood pressure to change in cognitive function. J Am Geriatr Soc (2002) 50:424–9.[CrossRef][Web of Science][Medline]
  226. Glynn RJ, Beckett LA, Hebert LE, et al. Current and remote blood pressure and cognitive decline. JAMA (1999) 281:438–45.[Abstract/Free Full Text]
  227. Guo Z, Fratiglioni L, Winblad B, et al. Blood pressure and performance on the Mini-Mental State Examination in the very old. Cross-sectional and longitudinal data from the Kungsholmen Project. Am J Epidemiol (1997) 145:1106–13.[Abstract/Free Full Text]
  228. Qiu C, von Strauss E, Fastbom J, et al. Low blood pressure and risk of dementia in the Kungsholmen Project: a 6-year follow-up study. Arch Neurol (2003) 60:223–38.[Abstract/Free Full Text]
  229. Verghese J, Lipton RB, Hall CB, et al. Low blood pressure and the risk of dementia in very old individuals. Neurology (2003) 61:1667–72.[Abstract/Free Full Text]
  230. Borenstein AR, Wu Y, Mortimer JA, et al. Developmental and vascular risk factors for Alzheimer's disease. Neurobiol Aging (2005) 26:325–34.[CrossRef][Web of Science][Medline]
  231. Brayne C, Gill C, Huppert FA, et al. Vascular risks and incident dementia: results from a cohort study of the very old. Dement Geriatr Cogn Disord (1998) 9:175–80.[CrossRef][Web of Science][Medline]
  232. Kuller LH, Lopez OL, Newman A, et al. Risk factors for dementia in the Cardiovascular Health Cognition Study. Neuroepidemiology (2003) 22:13–22.[CrossRef][Web of Science][Medline]
  233. Tyas SL, Manfreda J, Strain LA, et al. Risk factors for Alzheimer's disease: a population-based, longitudinal study in Manitoba, Canada. Int J Epidemiol (2001) 30:590–7.[Abstract/Free Full Text]
  234. Hebert LE, Scherr PA, Bennett DA, et al. Blood pressure and late-life cognitive function change: a biracial longitudinal population study. Neurology (2004) 62:2021–4.[Abstract/Free Full Text]
  235. Solfrizzi V, Panza F, Colacicco AM, et al. Vascular risk factors, incidence of MCI, and rates of progression to dementia. Neurology (2004) 63:1882–91.[Abstract/Free Full Text]
  236. Kivipelto M, Helkala EL, Laakso MP, et al. Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. BMJ (2001) 322:1447–51.[Abstract/Free Full Text]
  237. Launer LJ, Ross GW, Petrovitch H, et al. Midlife blood pressure and dementia: the Honolulu-Asia Aging Study. Neurobiol Aging (2000) 21:49–55.[Web of Science][Medline]
  238. Whitmer RA, Sidney S, Selby J, et al. Midlife cardiovascular risk factors and risk of dementia in late life. Neurology (2005) 64:277–81.[Abstract/Free Full Text]
  239. Wu C, Zhou D, Wen C, et al. Relationship between blood pressure and Alzheimer's disease in Linxian County, China. Life Sci (2003) 72:1125–33.[CrossRef][Web of Science][Medline]
  240. Elias MF, Wolf PA, D'Agostino RB, et al. Untreated blood pressure level is inversely related to cognitive functioning: the Framingham Study. Am J Epidemiol (1993) 138:353–64.[Abstract/Free Full Text]
  241. Kilander L, Nyman H, Boberg M, et al. The association between low diastolic blood pressure in middle age and cognitive function in old age. A population-based study. Age Ageing (2000) 29:243–8.[Abstract/Free Full Text]
  242. Knopman D, Boland LL, Mosley T, et al. Cardiovascular risk factors and cognitive decline in middle-aged adults. Neurology (2001) 56:42–8.[Abstract/Free Full Text]
  243. Launer LJ, Masaki K, Petrovitch H, et al. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. JAMA (1995) 274:1846–51.[Abstract/Free Full Text]
  244. Swan GE, Carmelli D, Larue A. Systolic blood pressure tracking over 25 to 30 years and cognitive performance in older adults. Stroke (1998) 29:2334–40.[Abstract/Free Full Text]
  245. Kilander L, Nyman H, Boberg M, et al. Hypertension is related to cognitive impairment: a 20-year follow-up of 999 men. Hypertension (1998) 31:780–6.[Abstract/Free Full Text]
  246. Kivipelto M, Helkala EL, Hanninen T, et al. Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study. Neurology (2001) 56:1683–9.[Abstract/Free Full Text]
  247. Khachaturian AS, Zandi PP, Lyketsos CG, et al. Antihypertensive medication use and incident Alzheimer disease: the Cache County Study. Arch Neurol (2006) 63:686–92.[Abstract/Free Full Text]
  248. Peila R, White LR, Masaki K, et al. Reducing the risk of dementia: efficacy of long-term treatment of hypertension. Stroke (2006) 37:1165–70.[Abstract/Free Full Text]
  249. in 't Veld BA, Ruitenberg A, Hofman A, et al. Antihypertensive drugs and incidence of dementia: the Rotterdam Study. Neurobiol Aging (2001) 22:407–12.[CrossRef][Web of Science][Medline]
  250. Yasar S, Corrada M, Brookmeyer R, et al. Calcium channel blockers and risk of AD: the Baltimore Longitudinal Study of Aging. Neurobiol Aging (2005) 26:157–63.[CrossRef][Web of Science][Medline]
  251. Tzourio C, Anderson C, Chapman N, et al. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med (2003) 163:1069–75.[Abstract/Free Full Text]
  252. Forette F, Seux ML, Staessen JA, et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet (1998) 352:1347–51.[CrossRef][Web of Science][Medline]
  253. Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens (2003) 21:875–86.[CrossRef][Web of Science][Medline]
  254. Applegate WB, Pressel S, Wittes J, et al. Impact of the treatment of isolated systolic hypertension on behavioral variables. Results from the Systolic Hypertension in the Elderly Program. Arch Intern Med (1994) 154:2154–60.[Abstract/Free Full Text]
  255. Prince MJ, Bird AS, Blizard RA, et al. Is the cognitive function of older patients affected by antihypertensive treatment? Results from 54 months of the Medical Research Council's trial of hypertension in older adults. BMJ (1996) 312:801–5.[Abstract/Free Full Text]
  256. Collins R, MacMahon S. Reliable assessment of the effects of treatment on mortality and major morbidity, I: clinical trials. Lancet (2001) 357:373–80.[CrossRef][Web of Science][Medline]
  257. Amenta F, Mignini F, Rabbia F, et al. Protective effect of anti-hypertensive treatment on cognitive function in essential hypertension: analysis of published clinical data. J Neurol Sci (2002) 203–204:147–51.
  258. Poon IO. Effects of antihypertensive drug treatment on the risk of dementia and cognitive impairment. Pharmacotherapy (2008) 28:366–75.[CrossRef][Web of Science][Medline]
  259. Allen KV, Frier BM, Strachan MW. The relationship between type 2 diabetes and cognitive dysfunction: longitudinal studies and their methodological limitations. Eur J Pharmacol (2004) 490:169–75.[CrossRef][Web of Science][Medline]
  260. Cukierman T, Gerstein HC, Williamson JD. Cognitive decline and dementia in diabetes—systematic overview of prospective observational studies. Diabetologia (2005) 48:2460–9.[CrossRef][Web of Science][Medline]
  261. Biessels GJ, Staekenborg S, Brunner E, et al. Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol (2006) 5:64–74.[CrossRef][Web of Science][Medline]
  262. Areosa SA, Grimley EV. Effect of the treatment of type II diabetes mellitus on the development of cognitive impairment and dementia. Cochrane Database Syst Rev (2002) (4). CD003804.
  263. Arvanitakis Z, Wilson RS, Bienias JL, et al. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol (2004) 61:661–6.[Abstract/Free Full Text]
  264. Elias PK, Elias MF, D'Agostino RB, et al. NIDDM and blood pressure as risk factors for poor cognitive performance. The Framingham Study. Diabetes Care (1997) 20:1388–95.[Abstract]
  265. Fontbonne A, Berr C, Ducimetiere P, et al. Changes in cognitive abilities over a 4-year period are unfavorably affected in elderly diabetic subjects: results of the Epidemiology of Vascular Aging Study. Diabetes Care (2001) 24:366–70.[Abstract/Free Full Text]
  266. Gregg EW, Yaffe K, Cauley JA, et al. Is diabetes associated with cognitive impairment and cognitive decline among older women? Study of Osteoporotic Fractures Research Group. Arch Intern Med (2000) 160:174–80.[Abstract/Free Full Text]
  267. Hassing LB, Hofer SM, Nilsson SE, et al. Comorbid type 2 diabetes mellitus and hypertension exacerbates cognitive decline: evidence from a longitudinal study. Age Ageing (2004) 33:355–61.[Abstract/Free Full Text]
  268. Kanaya AM, Barrett-Connor E, Gildengorin G, et al. Change in cognitive function by glucose tolerance status in older adults: a 4-year prospective study of the Rancho Bernardo Study cohort. Arch Intern Med (2004) 164:1327–33.[Abstract/Free Full Text]
  269. Logroscino G, Kang JH, Grodstein F. Prospective study of type 2 diabetes and cognitive decline in women aged 70–81 years. (Electronic article). BMJ (2004) 328:548.[Abstract/Free Full Text]
  270. MacKnight C, Rockwood K, Awalt E, et al. Diabetes mellitus and the risk of dementia, Alzheimer's disease and vascular cognitive impairment in the Canadian Study of Health and Aging. Dement Geriatr Cogn Disord (2002) 14:77–83.[Web of Science][Medline]
  271. Stewart R, Prince M, Mann A. Age, vascular risk, and cognitive decline in an older, British, African-Caribbean population. J Am Geriatr Soc (2003) 51:1547–53.[CrossRef][Web of Science][Medline]
  272. van den Berg E, de Craen AJ, Biessels GJ, et al. The impact of diabetes mellitus on cognitive decline in the oldest of the old: a prospective population-based study. Diabetologia (2006) 49:2015–23.[CrossRef][Web of Science][Medline]
  273. Xiong GL, Plassman BL, Helms MJ, et al. Vascular risk factors and cognitive decline among elderly male twins. Neurology (2006) 67:1586–91.[Abstract/Free Full Text]
  274. Yaffe K, Blackwell T, Kanaya AM, et al. Diabetes, impaired fasting glucose, and development of cognitive impairment in older women. Neurology (2004) 63:658–63.[Abstract/Free Full Text]
  275. Wu JH, Haan MN, Liang J, et al. Impact of antidiabetic medications on physical and cognitive functioning of older Mexican Americans with diabetes mellitus: a population-based cohort study. Ann Epidemiol (2003) 13:369–76.[CrossRef][Web of Science][Medline]
  276. Akomolafe A, Beiser A, Meigs JB, et al. Diabetes mellitus and risk of developing Alzheimer disease: results from the Framingham Study. Arch Neurol (2006) 63:1551–5.[Abstract/Free Full Text]
  277. Curb JD, Rodriguez BL, Abbott RD, et al. Longitudinal association of vascular and Alzheimer's dementias, diabetes, and glucose tolerance. Neurology (1999) 52:971–5.[Abstract/Free Full Text]
  278. Hassing LB, Johansson B, Nilsson SE, et al. Diabetes mellitus is a risk factor for vascular dementia, but not for Alzheimer's disease: a population-based study of the oldest old. Int Psychogeriatr (2002) 14:239–48.[CrossRef][Web of Science][Medline]
  279. Irie F, Fitzpatrick AL, Lopez OL, et al. Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE {varepsilon}4: the Cardiovascular Health Study Cognition Study. Arch Neurol (2008) 65:89–93.[Abstract/Free Full Text]
  280. Leibson CL, Rocca WA, Hanson VA, et al. Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol (1997) 145:301–8.[Abstract/Free Full Text]
  281. Luchsinger JA, Reitz C, Honig LS, et al. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology (2005) 65:545–51.[Abstract/Free Full Text]
  282. Luchsinger JA, Tang MX, Stern Y, et al. Diabetes mellitus and risk of Alzheimer's disease and dementia with stroke in a multiethnic cohort. Am J Epidemiol (2001) 154:635–41.[Abstract/Free Full Text]
  283. Ott A, Stolk RP, van Harskamp F, et al. Diabetes mellitus and the risk of dementia: the Rotterdam Study. Neurology (1999) 53:1937–42.[Abstract/Free Full Text]
  284. Peila R, Rodriguez BL, Launer LJ. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: the Honolulu-Asia Aging Study. Diabetes (2002) 51:1256–62.[Abstract/Free Full Text]
  285. Schnaider Beeri M, Goldbourt U, Silverman JM, et al. Diabetes mellitus in midlife and the risk of dementia three decades later. Neurology (2004) 63:1902–7.[Abstract/Free Full Text]
  286. Xu WL, Qiu CX, Wahlin A, et al. Diabetes mellitus and risk of dementia in the Kungsholmen Project: a 6-year follow-up study. Neurology (2004) 63:1181–6.[Abstract/Free Full Text]
  287. Katzman R, Kang D, Thomas R. Interaction of apolipoprotein E epsilon 4 with other genetic and non-genetic risk factors in late onset Alzheimer disease: problems facing the investigator. Neurochem Res (1998) 23:369–76.[CrossRef][Web of Science][Medline]
  288. Naor M, Steingruber HJ, Westhoff K, et al. Cognitive function in elderly non-insulin-dependent diabetic patients before and after inpatient treatment for metabolic control. J Diabetes Complicat (1997) 11:40–6.[CrossRef][Web of Science][Medline]
  289. Ryan CM, Freed MI, Rood JA, et al. Improving metabolic control leads to better working memory in adults with type 2 diabetes. Diabetes Care (2006) 29:345–51.[Abstract/Free Full Text]
  290. Testa MA, Simonson DC. Health economic benefits and quality of life during improved glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled, double-blind trial. JAMA (1998) 280:1490–6.[Abstract/Free Full Text]
  291. Tovi J, Engfeldt P. Well-being and symptoms in the elderly type 2 diabetes with poor metabolic control: effect of insulin treatment. Pract Diabetes Int (1998) 15:73–7.[CrossRef]
  292. Quality of life in type 2 diabetic patients is affected by complications but not by intensive policies to improve blood glucose or blood pressure control (UKPDS 37). U.K. Prospective Diabetes Study Group. Diabetes Care (1999) 22:1125–36.[Abstract/Free Full Text]
  293. Williamson JD, Miller ME, Bryan RN, et al. The Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes Study (ACCORD-MIND): rationale, design, and methods. Am J Cardiol (2007) 99:112i–22i.[CrossRef][Web of Science][Medline]
  294. Questions and answers: Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial. (2008) Bethesda, MD: National Heart, Lung, and Blood Institute. (http://www.nhlbi.nih.gov/health/prof/heart/other/accord/q_a.htm). (Accessed April 29, 2008).
  295. Henderson VW. Hormone therapy and Alzheimer's disease: benefit or harm? Expert Opin Pharmacother (2004) 5:389–406.[Web of Science][Medline]
  296. Gibbs RB. Estrogen replacement enhances acquisition of a spatial memory task and reduces deficits associated with hippocampal muscarinic receptor inhibition. Horm Behav (1999) 36:222–33.[CrossRef][Medline]
  297. Rapp PR, Morrison JH, Roberts JA. Cyclic estrogen replacement improves cognitive function in aged ovariectomized rhesus monkeys. J Neurosci (2003) 23:5708–14.[Abstract/Free Full Text]
  298. Egeland GM, Kuller LH, Matthews KA, et al. Premenopausal determinants of menopausal estrogen use. Prev Med (1991) 20:343–9.[CrossRef][Web of Science][Medline]
  299. Gold D, Andres D, Etezadi J, et al. Structural equation model of intellectual change and continuity and predictors of intelligence in older men. Psychol Aging (1995) 10:294–303.[CrossRef][Web of Science][Medline]
  300. Vellas B, Andrieu S, Sampaio C, et al. Endpoints for trials in Alzheimer's disease: a European task force consensus. Lancet Neurol (2008) 7:436–50.[CrossRef][Web of Science][Medline]
  301. Di Bari M, Pahor M, Franse LV, et al. Dementia and disability outcomes in large hypertension trials: lessons learned from the Systolic Hypertension in the Elderly Program (SHEP) Trial. Am J Epidemiol (2001) 153:72–8.[Abstract/Free Full Text]
  302. Barnes D. The Mental Activity and eXercise Trial for seniors (MAX). (2008) San Francisco, CA: University of California. (ClinicalTrials.gov identifier: NCT00522899). (http://clinicaltrials.gov/ct2/show/NCT00522899?term=NCT00522899&rank=1).
  303. Heuser I. Prevention of the age-related cognitive impairment by exercise and mental activity—Berlin Bleibt Fit. (2008) Berlin, Germany: Charite University. (ClinicalTrials.gov identifier: NCT00629174). (http://clinicaltrials.gov/ct2/show/NCT00629174?term=NCT00629174&rank=1).

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 NeurologyHome page
C. Sanz, S. Andrieu, A. Sinclair, H. Hanaire, B. Vellas, and For the REAL.FR Study Group
Diabetes is associated with a slower rate of cognitive decline in Alzheimer disease
Neurology, October 27, 2009; 73(17): 1359 - 1366.
[Abstract] [Full Text] [PDF]

Home page
 BMJHome page
Y. Doyle, M. McKee, B. Rechel, and E. Grundy
Meeting the challenge of population ageing
BMJ, October 5, 2009; 339(oct05_1): b3926 - b3926.
[Full Text]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
30/1/35    most recent
mxn010v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Coley, N.
Right arrow Articles by Grand, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Coley, N.
Right arrow Articles by Grand, A.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?