Toward a theory-based specification of non-pharmacological treatments in aging and dementia: Focused reviews and methodological recommendations.

INTRODUCTION: Non-pharmacological treatments (NPTs) have the potential to improve meaningful outcomes for older people at risk of, or living with dementia, but research often lacks methodological rigor and continues to produce mixed results. METHODS: In the current position paper, experts in NPT research have specified treatment targets, aims, and ingredients using an umbrella framework, the Rehabilitation Treatment Specification System. RESULTS: Experts provided a snapshot and an authoritative summary of the evidence for different NPTs based on the best synthesis efforts, identified main gaps in knowledge and relevant barriers, and provided directions for future research. Experts in trial methodology provide best practice principles and recommendations for those working in this area, underscoring the importance of prespecified protocols. DISCUSSION: We conclude that the evidence strongly supports various NPTs in relation to their primary targets, and discuss opportunities and challenges associated with a unifying theoretical framework to guide future efforts in this area.

Brain γ-Tocopherol Levels Are Associated with Presynaptic Protein Levels in Elderly Human Midfrontal Cortex.

BACKGROUND: Higher vitamin E intake has been widely related to lower risks of cognitive decline and dementia. Animal models suggest that this relationship might be (partially) explained by the protection of vitamin E against presynaptic protein oxidation. OBJECTIVE: In this cross-sectional study, we aimed to examine the associations between brain tocopherols and presynaptic protein levels in elderly humans. METHODS: We examined associations of α- and γ-tocopherol brain levels with presynaptic protein levels in 113 deceased participants (age 88.5±6.0 years, 45 (40%) female) from the prospective Memory and Aging project. Three distinct presynaptic proteins, a SNARE protein composite, a synaptotagmin synaptophysin composite and the protein-protein interaction between synaptosomal-associated protein 25 (SNAP-25), and syntaxin were measured in two cortical brain regions. Linear regression models assessed associations of brain tocopherols with presynaptic protein levels. RESULTS: Higher brain γ-tocopherol levels were associated with higher levels of the SNARE protein composite, complexin-I, complexin-II, the synaptotagmin synaptophysin composite, and septin-5 in the midfrontal cortex (B(SE) = 0.272 to 0.412 (0.084 to 0.091), p < 0.001 to 0.003). When additionally adjusted for global Alzheimer's disease pathology, cerebral infarcts, and Lewy body disease pathology, these associations remained largely similar. No associations were found between α-tocopherol and presynaptic protein levels. CONCLUSION: In this cross-sectional study, we found higher brain γ-tocopherol levels were associated with presynaptic protein levels in the midfrontal cortex. These results are consistent with a proposed role of vitamin E to maintain presynaptic protein levels.

Recent Caffeine Drinking Associates with Cognitive Function in the UK Biobank.

Clinical evidence points to the premise that caffeine may benefit cognition, but whether these findings extend to real life settings and amidst factors that impact caffeine metabolism is unclear. The aim of this study was to investigate the impact of recent caffeine drinking on cognitive ability while additionally accounting for lifestyle and genetic factors that impact caffeine metabolism. We included up to 434,900 UK Biobank participants aged 37-73 years, recruited in 2006-2010, who provided biological samples and completed touchscreen questionnaires regarding sociodemographic factors, medical history, lifestyle, and diet. Recent caffeine drinking (yes/no in the last hour) was recorded during a physical assessment. Participants completed at least one of four self-administered cognitive function tests using the touchscreen system: prospective memory (PM), pairs matching (Pairs), fluid intelligence (FI), and reaction time (RT). Multivariable regressions were used to examine the association between recent caffeine drinking and cognition test scores. We also tested interactions between recent caffeine drinking and a genetic caffeine-metabolism score (CMS) on cognitive function. Among white participants, recent caffeine drinking was associated with higher performance on RT but lower performance on FI, Pairs, and PM (p ≤ 0.004). Similar directions of associations for FI (p = 0.09), Pairs (p = 0.03), and PM (p = 0.34) were observed among non-white participants. No significant and consistent effect modification by age, sex, smoking, test time, habitual caffeine intake, or CMS was observed. Caffeine consumed shortly before tasks requiring shorter reaction times may improve task performance. Potential impairments in memory and reasoning tasks with recent caffeine drinking warrant further study.

Caffeinated Coffee and Tea Consumption, Genetic Variation and Cognitive Function in the UK Biobank.

BACKGROUND: Coffee and tea are the major contributors of caffeine in the diet. Evidence points to the premise that caffeine may benefit cognition. OBJECTIVE: We examined the associations of habitual regular coffee or tea and caffeine intake with cognitive function whilst additionally accounting for genetic variation in caffeine metabolism. METHODS: We included white participants aged 37-73 y from the UK Biobank who provided biological samples and completed touchscreen questionnaires regarding sociodemographic factors, medical history, lifestyle, and diet. Habitual caffeine-containing coffee and tea intake was self-reported in cups/day and used to estimate caffeine intake. Between 97,369 and 445,786 participants with data also completed ≥1 of 7 self-administered cognitive functioning tests using a touchscreen system (2006-2010) or on home computers (2014). Multivariable regressions were used to examine the association between coffee, tea, or caffeine intake and cognition test scores. We also tested interactions between coffee, tea, or caffeine intake and a genetic-based caffeine-metabolism score (CMS) on cognitive function. RESULTS: After multivariable adjustment, reaction time, Pairs Matching, Trail Making test B, and symbol digit substitution, performance significantly decreased with consumption of 1 or more cups of coffee (all tests P-trend < 0.0001). Tea consumption was associated with poor performance on all tests (P-trend < 0.0001). No statistically significant CMS × tea, CMS × coffee, or CMS × caffeine interactions were observed. CONCLUSIONS: Our findings, based on the participants of the UK Biobank, provide little support for habitual consumption of regular coffee or tea and caffeine in improving cognitive function. On the contrary, we observed decrements in performance with intakes of these beverages which may be a result of confounding. Whether habitual caffeine intake affects cognitive function therefore remains to be tested.

Fish Intake, Genetic Predisposition to Alzheimer Disease, and Decline in Global Cognition and Memory in 5 Cohorts of Older Persons.

Fish are a primary source of long-chain omega-3 fatty acids, which may help delay cognitive aging. We pooled participants from the French Three-City study and 4 US cohorts (Nurses' Health Study, Women's Health Study, Chicago Health and Aging Project, and Rush Memory and Aging Project) for whom diet and cognitive data were available (n = 23,688 white persons, aged ≥65 years, 88% female, baseline year range of 1992-1999, and median follow-up range of 3.9-9.1 years) to investigate the relationship of fish intake to cognitive decline and examine interactions with genes related to Alzheimer disease. We estimated cohort-specific associations between fish and change in composite scores of global cognition and episodic memory using linear mixed models, and we pooled results using inverse-variance weighted meta-analysis. In multivariate analyses, higher fish intake was associated with slower decline in both global cognition and memory (P for trend ≤ 0.031). Consuming ≥4 servings/week versus <1 serving/week of fish was associated with a lower rate of memory decline: 0.018 (95% confidence interval: 0.004, 0.032) standard units, an effect estimate equivalent to that found for 4 years of age. For global cognition, no comparisons of higher versus low fish intake reached statistical significance. In this meta-analysis, higher fish intake was associated with a lower rate of memory decline. We found no evidence of effect modification by genes associated with Alzheimer disease.

Association of Seafood Consumption, Brain Mercury Level, and APOE ε4 Status With Brain Neuropathology in Older Adults.

IMPORTANCE: Seafood consumption is promoted for its many health benefits even though its contamination by mercury, a known neurotoxin, is a growing concern. OBJECTIVE: To determine whether seafood consumption is correlated with increased brain mercury levels and also whether seafood consumption or brain mercury levels are correlated with brain neuropathologies. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analyses of deceased participants in the Memory and Aging Project clinical neuropathological cohort study, 2004-2013. Participants resided in Chicago retirement communities and subsidized housing. The study included 286 autopsied brains of 554 deceased participants (51.6%). The mean (SD) age at death was 89.9 (6.1) years, 67% (193) were women, and the mean (SD) educational attainment was 14.6 (2.7) years. EXPOSURES: Seafood intake was first measured by a food frequency questionnaire at a mean of 4.5 years before death. MAIN OUTCOMES AND MEASURES: Dementia-related pathologies assessed were Alzheimer disease, Lewy bodies, and the number of macroinfarcts and microinfarcts. Dietary consumption of seafood and n-3 fatty acids was annually assessed by a food frequency questionnaire in the years before death. Tissue concentrations of mercury and selenium were measured using instrumental neutron activation analyses. RESULTS: Among the 286 autopsied brains of 544 participants, brain mercury levels were positively correlated with the number of seafood meals consumed per week (ρ = 0.16; P = .02). In models adjusted for age, sex, education, and total energy intake, seafood consumption (≥ 1 meal[s]/week) was significantly correlated with less Alzheimer disease pathology including lower density of neuritic plaques (ß = -0.69 score units [95% CI, -1.34 to -0.04]), less severe and widespread neurofibrillary tangles (ß = -0.77 score units [95% CI, -1.52 to -0.02]), and lower neuropathologically defined Alzheimer disease (ß = -0.53 score units [95% CI, -0.96 to -0.10]) but only among apolipoprotein E (APOE ε4) carriers. Higher intake levels of α-linolenic acid (18:3 n-3) were correlated with lower odds of cerebral macroinfarctions (odds ratio for tertiles 3 vs 1, 0.51 [95% CI, 0.27 to 0.94]). Fish oil supplementation had no statistically significant correlation with any neuropathologic marker. Higher brain concentrations of mercury were not significantly correlated with increased levels of brain neuropathology. CONCLUSIONS AND RELEVANCE: In cross-sectional analyses, moderate seafood consumption was correlated with lesser Alzheimer disease neuropathology. Although seafood consumption was also correlated with higher brain levels of mercury, these levels were not correlated with brain neuropathology.

Brain tocopherols related to Alzheimer's disease neuropathology in humans.

Randomized trials of α-tocopherol supplements on cognitive decline are negative, whereas studies of dietary tocopherols have shown benefit. We investigated these inconsistencies by analyzing the relations of α- and γ-tocopherol brain concentrations to Alzheimer's disease (AD) neuropathology among 115 deceased participants of the prospective Rush Memory and Aging Project. Associations of amyloid load and neurofibrillary tangle severity with brain tocopherol concentrations were examined in separate adjusted linear regression models. γ-Tocopherol concentrations were associated with lower amyloid load (ß = -2.10, P = .002) and lower neurofibrillary tangle severity (ß = -1.16, P = .02). Concentrations of α-tocopherol were not associated with AD neuropathology, except as modified by γ-tocopherol: high α-tocopherol was associated with higher amyloid load when γ-tocopherol levels were low and with lower amyloid levels when γ-tocopherol levels were high (P for interaction = 0.03). Brain concentrations of γ- and α-tocopherols may be associated with AD neuropathology in interrelated, complex ways. Randomized trials should consider the contribution of γ-tocopherol.

Consideration of nutrient levels in studies of cognitive decline.

Epidemiological studies suggest that certain micronutrients may improve or maintain cognitive function. Consistent demonstration of benefits in intervention trials has been elusive, possibly because most intervention trials do not select subjects on the basis of nutrient status and/or intake. The objective of this review was to identify levels of intake or markers of nutrient insufficiency that define at-risk older adult populations to determine whether these populations will benefit from nutritional intervention. This review examines evidence from interventional and prospective observational studies that evaluated the effects of folate, vitamin B12 , and vitamin E on cognitive decline in older populations. The studies suggest that supplementation may protect against cognitive decline when serum folate is <12 nmol/L or vitamin E intake is <6.1 mg/day. The literature is inadequate to define a level for vitamin B12 . Epidemiological studies investigating the relations of nutrients to cognitive decline should consider nutrient status in the reporting and interpretation of results. Randomized trials should design inclusion and exclusion criteria to select individuals with low intake and to disallow multivitamin intake. These recommendations may be useful for the design of valid trials and to advance the current understanding of nutrition and neurological diseases.

Dietary fat composition and dementia risk.

This is a qualitative review of the evidence linking dietary fat composition to the risk of developing dementia. The review considers laboratory and animal studies that identify underlying mechanisms as well as prospective epidemiologic studies linking biochemical or dietary fatty acids to cognitive decline or incident dementia. Several lines of evidence provide support for the hypothesis that high saturated or trans fatty acids increase the risk of dementia and high polyunsaturated or monounsaturated fatty acids decrease risk. Dietary fat composition is an important factor in blood-brain barrier function and the blood cholesterol profile. Cholesterol and blood-brain barrier function are involved in the neuropathology of Alzheimer's disease, and the primary genetic risk factor for Alzheimer's disease, apolipoprotein E-ε4, is involved in cholesterol transport. The epidemiologic literature is seemingly inconsistent on this topic, but many studies are difficult to interpret because of analytical techniques that ignored negative confounding by other fatty acids, which likely resulted in null findings. The studies that appropriately adjust for confounding by other fats support the dietary fat composition hypothesis.

Plasma and brain fatty acid profiles in mild cognitive impairment and Alzheimer's disease.

Alzheimer's disease (AD) is generally associated with lower omega-3 fatty acid intake from fish but despite numerous studies, it is still unclear whether there are differences in omega-3 fatty acids in plasma or brain. In matched plasma and brain samples provided by the Memory and Aging Project, fatty acid profiles were quantified in several plasma lipid classes and in three brain cortical regions. Fatty acid data were expressed as % composition and as concentrations (mg/dL for plasma or mg/g for brain). Differences in plasma fatty acid profiles between AD, mild cognitive impairment (MCI), and those with no cognitive impairment (NCI) were most apparent in the plasma free fatty acids (lower oleic acid isomers and omega-6 fatty acids in AD) and phospholipids (lower omega-3 fatty acids in AD). In brain, % DHA was lower only in phosphatidylserine of mid-frontal cortex and superior temporal cortex in AD compared to NCI (-14% and -12%, respectively; both p < 0.05). The only significant correlation between plasma and brain fatty acids was between % DHA in plasma total lipids and % DHA in phosphatidylethanolamine of the angular gyrus, but only in the NCI group (+0.77, p < 0.05). We conclude that AD is associated with altered plasma status of both DHA and other fatty acids unrelated to DHA, and that the lipid class-dependent nature of these differences reflects a combination of differences in intake and metabolism.

Longitudinal association of vitamin B-6, folate, and vitamin B-12 with depressive symptoms among older adults over time.

BACKGROUND: B-vitamin deficiencies have been associated with depression; however, there is very little prospective evidence from population-based studies of older adults. OBJECTIVE: We examined whether dietary intakes of vitamins B-6, folate, or vitamin B-12 were predictive of depressive symptoms over an average of 7.2 y in a community-based population of older adults. DESIGN: The study sample consisted of 3503 adults from the Chicago Health and Aging project, an ongoing, population-based, biracial (59% African American) study in adults aged > or =65 y. Dietary assessment was made by food-frequency questionnaire. Incident depression was measured by the presence of > or =4 depressive symptoms from the 10-item version of the Center for Epidemiologic Studies Depression scale. RESULTS: The logistic regression models, which used generalized estimating equations, showed that higher total intakes, which included supplementation, of vitamins B-6 and B-12 were associated with a decreased likelihood of incident depression for up to 12 y of follow-up, after adjustment for age, sex, race, education, income, and antidepressant medication use. For example, each 10 additional milligrams of vitamin B-6 and 10 additional micrograms of vitamin B-12 were associated with 2% lower odds of depressive symptoms per year. There was no association between depressive symptoms and food intakes of these vitamins or folate. These associations remained after adjustment for smoking, alcohol use, widowhood, caregiving status, cognitive function, physical disability, and medical conditions. CONCLUSION: Our results support the hypotheses that high total intakes of vitamins B-6 and B-12 are protective of depressive symptoms over time in community-residing older adults.

Biochemical indicators of vitamin B12 and folate insufficiency and cognitive decline.

BACKGROUND: In some prospective studies, associations of serum vitamin B(12) and homocysteine concentrations with cognitive decline have been reported but few have examined the role of methylmalonic acid, a more specific marker of vitamin B(12) deficiency than homocysteine. OBJECTIVE: The aim of the study was to determine whether serum concentrations of vitamin B(12) or selected metabolites are related to cognitive decline. METHODS: A total of 516 subjects were selected in a stratified random sampling design from among Chicago Health and Aging Project participants for clinical evaluation. We used linear mixed models to examine the association of blood markers of vitamin B(12) status to change in cognitive scores over 6 years. Cognitive function was assessed every 3 years and measured as the sum of standardized scores on four tests. RESULTS: Probable vitamin B(12) deficiency was observed in 14.2% of the sample. Elevated serum concentrations of homocysteine were present in 19.2% of subjects, and of methylmalonic acid, in 36.4%. Higher serum methylmalonic acid concentrations were predictive of faster rates of cognitive decline (beta = -0.00016, SE = 0.0001, p = 0.004) and higher serum vitamin B(12) concentrations were associated with slower rates of cognitive decline (beta = +0.00013, SE < 0.0001, p = 0.005) in multivariable adjusted mixed models. Serum concentrations of homocysteine had no relationship to cognitive decline. CONCLUSIONS: Serum methylmalonic acid and vitamin B(12) concentrations may be the more important risk factors for cognitive decline when compared to serum homocysteine concentrations, particularly in older populations exposed to food fortification and possible supplements containing folic acid.

Thoughts on B-vitamins and dementia.

The B-vitamins, including vitamins B12, B6, B1, B2, niacin (B3) and folate (B9), have been implicated as protective risk factors against cognitive decline and Alzheimer's disease. This commentary reviews the evidence to support protective relations of these vitamins, including consideration of known vitamin deficiency syndromes, theories of underlying biologic mechanisms, and the epidemiologic evidence. We also comment on the potential benefits and harms of vitamin supplementation as well as make recommendations for the direction of future studies.

Dietary folate and vitamins B-12 and B-6 not associated with incident Alzheimer's disease.

CONTEXT: It is currently not known whether dietary intakes of folate and vitamins B12 and B6, co-factors in the methylation of homocysteine, protect against Alzheimer's disease. OBJECTIVE: To examine the association between risk of incident Alzheimer's disease and dietary intakes of folate, vitamin B-12, and vitamin B-6. DESIGN: Prospective cohort study. SETTING: Geographically defined biracial Chicago community. PARTICIPANTS: 1,041 residents, aged 65 years and older, initially free of Alzheimer's disease and followed a median 3.9 years for the development of incident disease. MAIN OUTCOME MEASURE: Probable Alzheimer's disease identified through structured clinical neurological evaluation using standardized criteria. RESULTS: A total of 162 persons developed incident Alzheimer's disease during follow-up. In logistic regression models adjusted for age, sex, race, education, cognitive activities, APOE-epsilon4, and dietary intakes of vitamin E in food and total niacin, there was no association between risk of developing Alzheimer's disease and quintiles of folate intake or of vitamin B-12 intake. The adjusted odds ratio was 1.6 (95% confidence interval: 0.5, 5.2) for persons in the highest quintile of total folate intake (median of 752.7 microg/d) compared with persons in the lowest quintile of intake (median, 202.8 microg/d). Compared with persons in the first quintile of total vitamin B-12 intake (median, 3.1 microg/d) the odds ratio was 0.6 (95% confidence interval: 0.2, 1.6) for persons in the fifth quintile of intake (median, 20.6 microg/d). Intake of vitamin B-6 was not associated with incident Alzheimer's disease after control for dietary intakes of vitamin E and total niacin. CONCLUSION: Dietary intakes of folate, vitamin B-12, or vitamin B-6 do not appear to be associated with the development of Alzheimer's disease.

Dietary copper and high saturated and trans fat intakes associated with cognitive decline.

BACKGROUND: Evidence from prospective epidemiologic studies and animal models suggests that intakes of dietary fats and copper may be associated with neurodegenerative diseases. OBJECTIVE: To examine whether high dietary copper intake is associated with increased cognitive decline among persons who also consume a diet high in saturated and trans fats. DESIGN: Community-based prospective study. SETTING: Chicago, Ill. Patients Chicago residents 65 years and older. MAIN OUTCOME MEASURES: Cognitive function was assessed using 4 cognitive tests administered during in-home interviews at 3-year intervals for 6 years. Dietary assessment was performed with a food frequency questionnaire. Dietary intakes of copper and fats were related to change in global cognitive score (the mean of the 4 tests) among 3718 participants. RESULTS: Among persons whose diets were high in saturated and trans fats, higher copper intake was associated with a faster rate of cognitive decline. In multiple-adjusted mixed models, the difference in rates for persons in the highest (median, 2.75 mg/d) vs lowest (median, 0.88 mg/d) quintiles of total copper intake was -6.14 standardized units per year (P<.001) or the equivalent of 19 more years of age. There was also a marginally statistically significant association (P = .07) with the highest quintile of food intake of copper (median, 1.51 mg/d) and a strong dose-response association with higher copper dose in vitamin supplements. Copper intake was not associated with cognitive change among persons whose diets were not high in these fats. CONCLUSION: These data suggest that high dietary intake of copper in conjunction with a diet high in saturated and trans fats may be associated with accelerated cognitive decline.

Folic acid and cognition in older persons.

Folic acid supplementation has drawn much attention in recent years for the prevention of Alzheimer's disease and cognitive decline. In this review, the authors describe how current evidence does not support the use of folic acid supplements to protect against cognitive decline. Although a few studies suggest that folic acid supplementation may provide neuroprotection among persons who are folate deficient, there is also data to indicate that supplementation in persons without folate deficiency may pose a risk to neurological function. Vitamin B12 deficiency is common in old age and may not be easy to recognise. Folic acid supplementation may mask the anaemia associated with vitamin B12 deficiency and, therefore, may delay treatment while allowing progression of neurological symptoms. Whether or not folic acid supplementation exacerbates neurological symptoms of vitamin B12 deficiency is not clear. Further studies are needed to determine the possible risks and benefits of folic acid supplementation in older persons.

Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons.

BACKGROUND: Deficiencies in folate and vitamin B12 have been associated with neurodegenerative disease. OBJECTIVE: To examine the association between rates of age-related cognitive change and dietary intakes of folate and vitamin B12. DESIGN: Prospective study performed from 1993 to 2002. SETTING: Geographically defined biracial community in Chicago, Ill. PARTICIPANTS: A total of 3718 residents, 65 years and older, who completed 2 to 3 cognitive assessments and a food frequency questionnaire. MAIN OUTCOME MEASURE: Change in cognitive function measured at baseline and 3-year and 6-year follow-ups, using the average z score of 4 tests: the East Boston Tests of immediate and delayed recall, the Mini-Mental State Examination, and the Symbol Digit Modalities Test. RESULTS: High folate intake was associated with a faster rate of cognitive decline in mixed models adjusted for multiple risk factors. The rate of cognitive decline among persons in the top fifth of total folate intake (median, 742 microg/d) was more than twice that of those in the lowest fifth of intake (median, 186 microg/d), a statistically significant difference of 0.02 standardized unit per year (P = .002). A faster rate of cognitive decline was also associated with high folate intake from food (P for trend = .04) and with folate vitamin supplementation of more than 400 microg/d compared with nonusers (beta = -.03, P<.001). High total B12 intake was associated with slower cognitive decline only among the oldest participants. CONCLUSIONS: High intake of folate may be associated with cognitive decline in older persons. These unexpected findings call for further study of the cognitive implications of high levels of dietary folate in older populations.

Relation of the tocopherol forms to incident Alzheimer disease and to cognitive change.

BACKGROUND: High intake of vitamin E from food (tocopherol), but not from supplements (which usually contain alpha-tocopherol), is inversely associated with Alzheimer disease. OBJECTIVE: We examined whether food intakes of vitamin E, alpha-tocopherol equivalents (a measure of the relative biologic activity of tocopherols and tocotrienols), or individual tocopherols would protect against incident Alzheimer disease and cognitive decline over 6 y in participants of the Chicago Health and Aging Project. DESIGN: The 1993-2002 study of community residents aged >or=65 y included the administration of 4 cognitive tests and clinical evaluations for Alzheimer disease. Dietary assessment was by food-frequency questionnaire. RESULTS: Tocopherol intake from food was related to the 4-y incidence of Alzheimer disease determined by logistic regression in 1041 participants who were clinically evaluated (n=162 incident cases) and to change in a global cognitive score determined by mixed models in 3718 participants. Higher intakes of vitamin E (relative risk: 0.74 per 5 mg/d increase; 95% CI: 0.62, 0.88) and alpha-tocopherol equivalents (relative risk: 0.56 per 5 mg/d increase; 95% CI: 0.32, 0.98) were associated with a reduced incidence of Alzheimer disease in separate multiple-adjusted models that included intakes of saturated and trans fats and docosahexaenoic acid. alpha- and gamma-Tocopherol had independent associations. In separate mixed models, a slower rate of cognitive decline was associated with intakes of vitamin E, alpha-tocopherol equivalents, and alpha- and gamma-tocopherols. CONCLUSION: The results suggest that various tocopherol forms rather than alpha- tocopherol alone may be important in the vitamin E protective association with Alzheimer disease.