Christine C. Tangney

Associations of vegetable and fruit consumption with age-related cognitive change.

Objective: To examine the association between rates of cognitive change and dietary consumption of fruits and vegetables among older persons. Methods: The authors conducted a prospective cohort study of 3,718 participants, aged 65 years and older of the Chicago Health and Aging Project. Participants completed a food frequency questionnaire and were administered at least two of three cognitive assessments at baseline, 3-year, and 6-year follow-ups. Cognitive function was measured using the average z-score of four tests: the East Boston Tests of immediate memory and delayed recall, the Mini-Mental State Examination, and the Symbol Digit Modalities Test. Results: The mean cognitive score at baseline for the analyzed cohort was 0.18 (range: –3.5 to 1.6), and the overall mean change in score per year was a decline of 0.04 standardized units. In mixed effects models adjusted for age, sex, race, and education, compared with the rate of cognitive decline among persons in the lowest quintile of vegetable intake (median of 0.9 servings/day), the rate for persons in the fourth quintile (median, 2.8 servings/day) was slower by 0.019 standardized units per year (p = 0.01), a 40% decrease, and by 0.018 standardized units per year (p = 0.02) for the fifth quintile (median, 4.1 servings/day), or a 38% decrease in rates. The association remained significant (p for linear trend = 0.02) with further control of cardiovascular-related conditions and risk factors. Fruit consumption was not associated with cognitive change. Conclusion: High vegetable but not fruit consumption may be associated with slower rate of cognitive decline with older age.

Adherence to a Mediterranean-type dietary pattern and cognitive decline in a community population–

BACKGROUND Many of the foods abundant in the traditional Mediterranean diet, such as vegetables and fish, have been associated with slower cognitive decline. OBJECTIVE We investigated whether adherence to a Mediterranean dietary pattern or to the Healthy Eating Index-2005 (HEI-2005) is associated with cognitive change in older adults. DESIGN This article is based on analyses of data from an ongoing longitudinal study in adults aged ≥65 y known as the Chicago Health and Aging Project (CHAP). CHAP participants (2280 blacks and 1510 whites) with ≥2 cognitive assessments were evaluated for adherence to 1) the Mediterranean dietary pattern (MedDiet; maximum score: 55) and 2) the HEI-2005 (maximum score: 100). For both scoring systems, higher scores connote greater adherence. Cognitive function was assessed at 3-y intervals on the basis of a composite measure of global cognition. Linear mixed models were used to examine the association of dietary scores to change in cognitive function. Mean follow-up time was 7.6 y. RESULTS Mean (±SD) scores for participants were 28.2 ± 0.1 for the MedDiet and 61.2 ± 9.6 for the HEI-2005. White participants had higher energy-adjusted MedDiet scores but lower HEI-2005 scores than did black participants. Higher MedDiet scores were associated with slower rates of cognitive decline (β = +0.0014 per 1-point increase, SEE = 0.0004, P = 0.0004) after adjustment for age, sex, race, education, participation in cognitive activities, and energy. No such associations were observed for HEI-2005 scores. CONCLUSION The Mediterranean dietary pattern as captured by the MedDiet scoring system may reduce the rate of cognitive decline with older age.

Dietary fat intake and 6-year cognitive change in an older biracial community population

Objective: To examine whether consumption of different types of fat is associated with age-related change in cognition. Methods: The authors related fat consumption to 6-year change in cognitive function among 2,560 participants of the Chicago Health and Aging Project, ages 65 and older, with no history of heart attack, stroke, or diabetes at baseline. Fat intake was measured by food frequency questionnaire. Cognitive function was measured at baseline and 3-year and 6-year follow-ups, using the average z score of four cognitive tests: the East Boston Tests of Immediate and Delayed Recall, the Mini-Mental State Examination, and the Symbol Digit Modalities Test. Results: In separate mixed models adjusted for demographic and cardiovascular risk factors and intakes of antioxidant nutrients and other dietary fats, higher intakes of saturated fat (p for trend = 0.04) and trans-unsaturated fat (p for trend = 0.07) were linearly associated with greater decline in cognitive score over 6 years. These associations became stronger in analyses that eliminated persons whose fat intake changed in recent years or whose baseline cognitive scores were in the lowest 15%. Inverse associations with cognitive decline were observed in these latter restricted analyses for high intake of monounsaturated fat and a high ratio of polyunsaturated to saturated fat intake. Intakes of total fat, vegetable and animal fats, and cholesterol were not associated with cognitive change. Conclusion: A diet high in saturated or trans-unsaturated fat or low in nonhydrogenated unsaturated fats may be associated with cognitive decline among older persons.

Dietary niacin and the risk of incident Alzheimer’s disease and of cognitive decline

Background: Dementia can be caused by severe niacin insufficiency, but it is unknown whether variation in intake of niacin in the usual diet is linked to neurodegenerative decline. We examined whether dietary intake of niacin was associated with incident Alzheimer’s disease (AD) and cognitive decline in a large, prospective study. Methods: This study was conducted in 1993–2002 in a geographically defined Chicago community of 6158 residents aged 65 years and older. Nutrient intake was determined by food frequency questionnaire. Four cognitive tests were administered to all study participants at 3 year intervals in a 6 year follow up. A total of 3718 participants had dietary data and at least two cognitive assessments for analyses of cognitive change over a median 5.5 years. Clinical evaluations were performed on a stratified random sample of 815 participants initially unaffected by AD, and 131 participants were diagnosed with 4 year incident AD by standardised criteria. Results: Energy adjusted niacin intake had a protective effect on development of AD and cognitive decline. In a logistic regression model, relative risks (95% confidence intervals) for incident AD from lowest to highest quintiles of total niacin intake were: 1.0 (referent) 0.3 (0.1 to 0.6), 0.3 (0.1 to 0.7), 0.6 (0.3 to 1.3), and 0.3 (0.1 to 0.7) adjusted for age, sex, race, education, and ApoE e4 status. Niacin intake from foods was also inversely associated with AD (p for linear trend = 0.002 in the adjusted model). In an adjusted random effects model, higher food intake of niacin was associated with a slower annual rate of cognitive decline, by 0.019 standardised units (SU) per natural log increase in intake (mg) (p = 0.05). Stronger associations were observed in analyses that excluded participants with a history of cardiovascular disease (β = 0.028 SU/year; p = 0.008), those with low baseline cognitive scores (β = 0.023 SU/year; p = 0.02), or those with fewer than 12 years’ education (β = 0.035 SU/year; p = 0.002) Conclusion: Dietary niacin may protect against AD and age related cognitive decline.

Plasma and Brain Fatty Acid Profiles in Mild Cognitive Impairment and Alzheimer's Disease

Alzheimers 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.

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 Alzheimers disease. OBJECTIVE To examine the association between risk of incident Alzheimers 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 Alzheimers disease and followed a median 3.9 years for the development of incident disease. MAIN OUTCOME MEASURE Probable Alzheimers disease identified through structured clinical neurological evaluation using standardized criteria. RESULTS A total of 162 persons developed incident Alzheimers 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 Alzheimers 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 Alzheimers 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 Alzheimers disease.

A Potential Design Flaw of Randomized Trials of Vitamin Supplements

What are scientists, physicians, and the general public to make of the many null findings from randomized controlled trials (RCTs) of vitamin supplements? These trials are usually conducted on the basis of positive findings from prospective epidemiological studies and laboratory evidence of biological mechanisms. A common view is that the negative findings from the RCTs offer incontrovertible evidence that the nutrient is unrelated to disease and that the epidemiological studies are biased. An alternative explanation is that most RCTs of vitamin supplements are designed to test the hypothesis that supplementation, no matter the nutrient status, is protective. Vitamin treatment may not be effective in these trials because nutrient intake among the participants is already at optimum levels. To specify, examples are provided from the field of dementia and investigations of 3 dietary components: vitamin E, B vitamins, and docosahexaenoic acid. A basic principle of nutrition is that most nutrients have a nonlinear, inverted U-shaped association with optimum physiological function (Figure). Very low nutrient levels in diet or tissues result in poor function or even death. As the nutrient level increases, function also increases. Optimal functioning occurs over a fairly wide range of nutrient levels but at some point, higher levels become toxic and result in suboptimum function. Figure Relationship Between Level of Nutrient Status and Physiological Function Consideration of nutrient level is critically important in the assessment of the epidemiological evidence. For example, among the first 3 prospective epidemiological studies1–3 reporting on the association of dietary antioxidants and the risk of Alzheimer disease, 2 studies found inverse associations with vitamin E from food sources1,2 and 1 found no association.3 Close examination of the reported intake levels of these study populations revealed that vitamin E intake was very low in the study with null findings, and the median intake level of the highest quartile of 4.7 mg per day was in the lowest categories of intake in the other 2 studies (lowest tertile <10.5 mg/d1 and quintile median of 4.2 mg/d2). Thus, a plausible explanation for the null association is that the range of vitamin intake in this study population was below the level of protective benefit to observe an association. Nutrient levels are rarely considered in trial inclusion criteria. Further, trial volunteers are typically healthy behavior–seeking individuals and are unlikely to have low nutrient intake. More probably, intake levels are already at the level for optimal functioning (Figure, point a) and further supplementation provides no additional benefit (Figure, point b). Three RCTs examining the effect of vitamin E supplementation on cognition have been published and all have null results.4–6 Of note, none of these trials targeted individuals who had low dietary intake. Post hoc analyses reported in 2 of the trials suggested that this could have accounted for the absence of effect. In the Women’s Health Study, among women whose vitamin E consumption at baseline was less than the median intake of 6.1 mg per day, vitamin E treatment of 435 mg every other day significantly slowed the rate of cognitive decline compared with placebo (rate difference=0.05), whereas there was no effect among women whose baseline intake was greater than 6.1 mg per day (rate difference of −0.01; P value for interaction=.04).4 In a similar post hoc analysis for the Women’s Antioxidant and Cardiovascular Study (WACS), there was no significant effect of intake of 402 mg of vitamin E on alternate days among women whose baseline intake levels were less than the median of 15 mg per day, currently the recommended dietary allowance (RDA).5 This raises the question of whether 15 mg per day is already within the range of optimum cognitive health and thus too high for observing a protective effect with additional supplementation. To further complicate interpretation of these data, trial participants were allowed to take multivitamin supplements containing nutrient levels that were as high as RDA levels; thus reported baseline levels were likely higher during the course of the trial. The Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFCS) also tested effects on cognition of B-vitamin supplementation, including folic acid (2.5 mg/d), vitamin B12 (1 mg/d), and vitamin B6 (50 mg/d).7 Overall, there was no effect of B-vitamin supplementation on cognitive decline but protective effects were observed among women who had dietary folate intakes of less than 279 mg per day (mean difference of 1.24 in cognitive change scores for B-vitamin treatment vs placebo compared with −0.04 among women with intakes ≥279 mg/d; P value for interaction=.002); vitamin B12 intakes less than the RDA of 2.4 μg per day (mean difference of 1.35 vs 0.10 in individuals with intakes ≥2.4 μg/d; P value for interaction=.05); and low intakes of at least 1 of the B vitamins (mean difference of 0.74 vs −0.10 in individuals with adequate intakes, P value for interaction=.01). The Folic Acid Cognitive Intervention Trial (FACIT) is a rare example of a vitamin supplement trial that targeted individuals who were found to have insufficient folate nutriture based on a stringent set of biochemical criteria.8 Participants were randomized to receive 800 μg per day of folic acid or placebo for 3 years. During this period, folate levels among treated individuals increased from a median 12 nmol/L to 76 nmol/L and homocysteine concentrations decreased from a median 13.0 μmol/L to 10.1 μmol/L. The folic acid–treated participants had significantly slower rates of decline in cognitive function on multiple tests compared with the placebo group. Published and ongoing RCTs of the effect of docosahexaenoic acid, an omega-3 fatty acid in fish oil, on cognitive decline and dementia have the same design flaw. The published trials report null findings. The exclusion criteria for these trials at best omitted persons who consumed more than 3 fish meals per week.9,10 This is far above the level of just 1 fish meal per week observed to be inversely associated with dementia in the majority of prospective epidemiological studies. The epidemiological literature strongly supports exclusion of individuals from supplement trials who consume fish more than occasionally (eg, rarely or never). Clinical trials are both costly and important for substantiation of nutrient effects on health. The public health may be better served by initially conducting trials in individuals with insufficient nutriture and, if effective, further testing the effectiveness in those with adequate nutrient levels.

Biochemical indicators of vitamin B12 and folate insufficiency and cognitive decline

Background: In some prospective studies, associations of serum vitamin B12 and homocysteine concentrations with cognitive decline have been reported but few have examined the role of methylmalonic acid, a more specific marker of vitamin B12 deficiency than homocysteine. Objective: The aim of the study was to determine whether serum concentrations of vitamin B12 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 B12 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 B12 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 (β = −0.00016, SE = 0.0001, p = 0.004) and higher serum vitamin B12 concentrations were associated with slower rates of cognitive decline (β = +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 B12 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. CHAP = Chicago Health and Aging Project; CI = confidence interval; FFQ = food frequency questionnaire; NHANES = National Health and Nutrition Examination Survey; OR = odds ratio.

Alpha-tocopherol in the ventricular cerebrospinal fluid of Parkinson's disease patients: Dose-response study and correlations with plasma levels

Objective: To determine if ventricular cerebrospinal fluid (vCSF) alpha-tocopherol levels in Parkinsons disease (PD) patients can be increased by oral alpha-tocopherol supplementation and whether vCSF levels are linearly related to plasma alpha-tocopherol levels. Background: In spite of its putative neuroprotective properties, alpha-tocopherol has failed to alter PD clinical progression. However, the ability of supplemental alpha-tocopherol to affect brain or vCSF levels has never been assessed in humans nor has a dose-response curve for alpha-tocopherol in vCSF been established. Methods: Five PD patients with Ommaya catheters received oral dl-alpha-tocopherol over 5 months. Each patient ingested alpha-tocopherol daily with monthly dosage increases (400, 800, 1,600, 3,200, 4,000 IU/day). Plasma and vCSF samples were obtained at baseline and at the end of each month. Alpha-tocopherol levels were determined in triplicate by high-pressure liquid chromatography with fluorometric and electrochemical detection. Results: At baseline, endogenous alpha-tocopherol was detected in plasma and vCSF, with a greater than one-hundred-fold difference between the fluid compartments (mean plasma level 18.76 micro Meter/l (SD +/- 4.69) versus mean CSF level 0.114 micro Meter/l (SD +/- 0.084). A clear dose-response curve occurred in plasma, with statistically significant increases over baseline developing even with 400 IU/d. With higher doses, a significant increase continued without evidence of saturation. However, there was no significant increase in vCSF alpha-tocopherol levels at any dose, including the supraclinical (4,000 IU/d). There was no correlation between plasma and vCSF alpha-tocopherol levels. Conclusion: Oral alpha-tocopherol supplementation, even at supraclinical doses, fails to increase vCSF alpha-tocopherol levels. This lack of change may be due to limited passage across the blood-brain barrier or very rapid alpha-tocopherol metabolism. All prior negative studies on efficacy of alpha-tocopherol in PD may need reevaluation in light of these pharmacologic data. NEUROLOGY 1996;47: 1037-1042