Apolipoprotein E and Its Association With Cognitive Change and Modification of Treatment Effects of Vitamin D3 and Omega-3s on Cognitive Change: Results From the In-Clinic Subset of a Randomized Clinical Trial.

BACKGROUND: Apolipoprotein E (APOE)-ε4 allele is associated with cognitive decline; however, its potential to modify effects of vitamin D3 and omega-3s supplementation on later-life cognition is unclear. Our objectives were to estimate among the in-clinic subset of a randomized trial: (1) associations between APOE-ε4 and global and domain-specific cognitive change, with exploration of potential sex and race differences; and (2) modification by APOE-ε4 of effects of vitamin D3 and omega-3s supplementation on cognitive change. METHODS: From an ancillary study of depression prevention within a completed 2 × 2 factorial trial testing vitamin D3 (2 000 IU per day), omega-3s (1 g per day), and/or placebos, we included 743 older adults with baseline in-person neuropsychiatric assessments and APOE genotyping data. The primary outcome was change in global cognition (averaging z-scores of 9 tests) over 2 years. Secondarily, episodic memory and executive function/attention z-scores were examined. General linear models of response profiles with multiplicative interaction terms were constructed; stratified results were reported. RESULTS: Mean age (standard deviation) was 67.1 (5.3) years; 50.6% were females; 24.9% were APOE-ε4 carriers. Compared to noncarriers, APOE-ε4 carriers had worse 2-year change in global cognition and episodic memory; differences were more apparent among females than males. There was no variation by race in APOE-ε4 associations with cognition. APOE-ε4 did not significantly modify effects of vitamin D3 or omega-3s, compared to placebo, on change in global cognition, episodic memory, or executive function/attention. CONCLUSIONS: APOE-ε4 was associated with worse cognition but did not modify overall effects of vitamin D3 or omega-3 supplementation on cognition over 2 years.

Marine n-3 Fatty Acids and Prevention of Cardiovascular Disease: A Novel Analysis of the VITAL Trial Using Win Ratio and Hierarchical Composite Outcomes.

This study aimed to investigate whether n-3 fatty acid supplementation reduced cardiovascular disease (CVD) events in a novel analysis using hierarchical composite CVD outcomes based on win ratio in the VITamin D and OmegA-3 TriaL (VITAL). This was a secondary analysis of our VITAL randomized trial, which assessed the effects of marine n-3 fatty acids (1 g/day) and vitamin D3 on incident CVD and cancer among healthy older adults (n = 25,871). The primary analysis estimated win ratios of a composite of major CVD outcomes prioritized as fatal coronary heart disease, other fatal CVD including stroke, non-fatal myocardial infarction (MI), and non-fatal stroke, comparing n-3 fatty acids to placebo. The primary result was a nonsignificant benefit of this supplementation for the prioritized primary CVD outcome (reciprocal win ratio [95% confidence interval]: 0.90 [0.78-1.04]), similar to the 0.92 (0.80-1.06) hazard ratio in our original time-to-first event analysis without outcome prioritization. Its benefits came from reducing MI (0.71 [0.57-0.88]) but not stroke (1.01 [0.80 to 1.28]) components. For the primary CVD outcome, participants with low fish consumption at baseline benefited (0.79 [0.65-0.96]) more than those with high consumption (1.05 [0.85-1.30]). These results are consistent with, but slightly stronger than, those without outcome prioritization.

Effects of Vitamin D3 and Marine Omega-3 Fatty Acids Supplementation on Indicated and Selective Prevention of Depression in Older Adults: Results From the Clinical Center Sub-Cohort of the VITamin D and OmegA-3 TriaL (VITAL).

Objective: To test vitamin D3 and omega-3 fatty acids (omega-3s) for late-life depression prevention under the National Academy of Medicine framework for indicated (targeting subthreshold depression) and selective (targeting presence of high-risk factors) prevention.Methods: The VITamin D and OmegA-3 TriaL (VITAL) is a 2 × 2 factorial trial of vitamin D3 (2,000 IU/d) and/or omega-3s (1 g/d) for cardiovascular and cancer prevention (enrollment: November 2011-March 2014; end date: December 31, 2017). In this targeted prevention study, we included 720 VITAL clinical sub-cohort participants who completed neurobehavioral assessments at baseline and 2 years (91.9% retention). High-risk factors were subthreshold or clinical anxiety, impaired activities of daily living, physical/functional limitation, medical comorbidity, cognitive impairment, caregiving burden, problem drinking, and low psychosocial support. Coprimary outcomes were incident major depressive disorder (MDD), adjudicated using DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), and change in mood (Patient Health Questionnaire-9 [PHQ-9]). We used exact tests to determine treatment effects on MDD incidence and repeated-measures models to determine treatment effects on PHQ-9.Results: A total of 11.1% had subthreshold depression, 60.8% had ≥ 1 high-risk factor, MDD incidence was 4.7% (5.1% among completers), and mean PHQ-9 score change was 0.02 points. Among those with subthreshold depression, the MDD risk ratio (95% confidence interval) was 0.36 (0.06 to 1.28) for vitamin D3 and 0.85 (0.25 to 2.92) for omega-3s, compared to placebo; results were also null among those with ≥ 1 high-risk factor (vitamin D3 vs placebo: 0.63 [0.25 to 1.53]; omega-3s vs placebo: 1.08 [0.46 to 2.71]). There were no significant differences in PHQ-9 score change comparing either supplement with placebo.Conclusions: Neither vitamin D3 nor omega-3s showed benefits for indicated and selective prevention of late-life depression; statistical power was limited.Trial Registration: ClinicalTrials.gov identifier: NCT01696435.

Marine n-3 fatty acids and cognitive change among older adults in the VITAL randomized trial.

Introduction: : Few large, randomized trials have evaluated marine n-3 supplements and cognition in healthy older adults. Methods: : Healthy community-dwelling participants aged 60+ years (mean [standard deviation] = 70.9 [5.8] years) in VITAL (randomized trial of n-3 fats [1 g/day, including 840 mg of eicosapentaenoic acid + docosahexaenoic acid] and vitamin D) were included: 3424 whose cognition was assessed by phone (VITAL-Cog; eight neuropsychological tests; 2.8 years) and 794 evaluated in person (CTSC-Cog; nine tests; 2.0 years). The primary outcome was a global score (average of test z-scores) of change over two assessments. We used multivariable-adjusted linear mixed models; substudy-specific results were meta-analyzed. Results: : We observed no significant effect of n-3 supplementation: the mean difference in annual rate of cognitive change for the n-3 versus placebo group was -0.01 standard units (95% confidence interval [CI]: -0.02, 0.003) in VITAL-Cog and -0.002 (95% CI: -0.04, 0.03) in CTSC-Cog; the pooled difference was -0.01 (95% CI: -0.02, 0.003; P = .15). Discussion: : Marine n-3 supplementation (1 g/day) did not confer cognitive benefits over 2 to 3 years in community-dwelling older adults.

Effect of vitamin D on cognitive decline: results from two ancillary studies of the VITAL randomized trial.

Low vitamin D levels have been associated with cognitive decline; however, few randomized trials have been conducted. In a trial, we evaluated vitamin D3 supplementation on cognitive decline. We included participants aged 60+ years (mean[SD] = 70.9[5.8] years) free of cardiovascular disease and cancer in two substudies in the VITAL 2 × 2 randomized trial of vitamin D3 (2000 IU/day of cholecalciferol) and fish oil supplements: 3424 had cognitive assessments by phone (eight neuropsychologic tests; 2.8 years follow-up) and 794 had in-person assessments (nine tests; 2.0 years follow-up). The primary, pre-specified outcome was decline over two assessments in global composite score (average z-scores of all tests); substudy-specific results were meta-analyzed. The pooled mean difference in annual rate of decline (MD) for vitamin D3 versus placebo was 0.01 (95% CI - 0.01, 0.02; p = 0.39). We observed no interaction with baseline 25-hydroxyvitamin-D levels (p-interaction = 0.84) and a significant interaction with self-reported race (p-interaction = 0.01). Among Black participants (19%), those assigned vitamin D3 versus placebo had better cognitive maintenance (MD = 0.04, 95% CI 0.01, 0.08, similar to that observed for Black participants 1.2 years apart in age). Thus, vitamin D3 (2000 IU/day cholecalciferol) supplementation was not associated with cognitive decline over 2-3 years among community-dwelling older participants but may provide modest cognitive benefits in older Black adults, although these results need confirmation.Trial registration ClinicalTrials.gov; VITAL (NCT01169259), VITAL-DEP (NCT01696435) and VITAL-Cog (NCT01669915); the date the registration for the parent trial (NCT01169259) was submitted to the registry: 7/26/2010 and the date of first patient enrollment in either of the ancillary studies for cognitive function in a subset of eligible VITAL participants: 9/14/2011.

Habitual consumption of long-chain n-3 PUFAs and fish attenuates genetically associated long-term weight gain.

BACKGROUND: A growing amount of data suggests that n-3 (ω-3) polyunsaturated fatty acid (PUFA) intake may modify the genetic association with weight change. OBJECTIVES: We aimed to prospectively test interactions of habitual consumption of n-3 PUFAs or fish, the major food source, with overall genetic susceptibility on long-term weight change. DESIGN: Gene-diet interactions were examined in 11,330 women from the Nurses' Health Study (NHS), 6773 men from the Health Professionals Follow-Up Study (HPFS), and 6254 women from the Women's Health Initiative (WHI). RESULTS: In the NHS and HPFS cohorts, food-sourced long-chain n-3 PUFA intake showed directionally consistent interactions with genetic risk score on long-term changes in BMI (P-interaction = 0.01 in the HPFS, 0.15 in the NHS, and 0.01 in both cohorts combined). Such interactions were successfully replicated in the WHI, an independent cohort (P-interaction = 0.02 in the WHI and 0.01 in the combined 3 cohorts). The genetic associations with changes in BMI (in kg/m2) consistently decreased (0.15, 0.10, 0.07, and -0.14 per 10 BMI-increasing alleles) across the quartiles of long-chain n-3 PUFAs in the combined cohorts. In addition, high fish intake also attenuated the genetic associations with long-term changes in BMI in the HPFS (P-interaction = 0.01), NHS (P-interaction = 0.03), WHI (P-interaction = 0.10), and the combined cohorts (P-interaction = 0.01); and the differences in BMI changes per 10 BMI-increasing alleles were 0.16, 0.06, -0.08, and -0.18, respectively, across the categories (≤1, 1∼4, 4∼6, and ≥7 servings/wk) of total fish intake. Similar interactions on body weight were observed for fish intake (P-interaction = 0.003) and long-chain n-3 PUFA intake (P-interaction = 0.12). CONCLUSION: Our study provides replicable evidence to show that high intakes of fish and long-chain n-3 PUFAs are associated with an attenuation of the genetic association with long-term weight gain based on results from 3 prospective cohorts of Caucasians.

Habitual coffee consumption and genetic predisposition to obesity: gene-diet interaction analyses in three US prospective studies.

BACKGROUND: Whether habitual coffee consumption interacts with the genetic predisposition to obesity in relation to body mass index (BMI) and obesity is unknown. METHODS: We analyzed the interactions between genetic predisposition and habitual coffee consumption in relation to BMI and obesity risk in 5116 men from the Health Professionals Follow-up Study (HPFS), in 9841 women from the Nurses' Health Study (NHS), and in 5648 women from the Women's Health Initiative (WHI). The genetic risk score was calculated based on 77 BMI-associated loci. Coffee consumption was examined prospectively in relation to BMI. RESULTS: The genetic association with BMI was attenuated among participants with higher consumption of coffee than among those with lower consumption in the HPFS (P interaction = 0.023) and NHS (P interaction = 0.039); similar results were replicated in the WHI (P interaction = 0.044). In the combined data of all cohorts, differences in BMI per increment of 10-risk allele were 1.38 (standard error (SE), 0.28), 1.02 (SE, 0.10), and 0.95 (SE, 0.12) kg/m2 for coffee consumption of < 1, 1-3 and > 3 cup(s)/day, respectively (P interaction < 0.001). Such interaction was partly due to slightly higher BMI with higher coffee consumption among participants at lower genetic risk and slightly lower BMI with higher coffee consumption among those at higher genetic risk. Each increment of 10-risk allele was associated with 78% (95% confidence interval (CI), 59-99%), 48% (95% CI, 36-62%), and 43% (95% CI, 28-59%) increased risk for obesity across these subgroups of coffee consumption (P interaction = 0.008). From another perspective, differences in BMI per increment of 1 cup/day coffee consumption were 0.02 (SE, 0.09), -0.02 (SE, 0.04), and -0.14 (SE, 0.04) kg/m2 across tertiles of the genetic risk score. CONCLUSIONS: Higher coffee consumption might attenuate the genetic associations with BMI and obesity risk, and individuals with greater genetic predisposition to obesity appeared to have lower BMI associated with higher coffee consumption.

DNA Methylation Variants at HIF3A Locus, B-Vitamin Intake, and Long-term Weight Change: Gene-Diet Interactions in Two U.S. Cohorts.

The first epigenome-wide association study of BMI identified DNA methylation at an HIF3A locus associated with BMI. We tested the hypothesis that DNA methylation variants are associated with BMI according to intake of B vitamins. In two large cohorts, we found significant interactions between the DNA methylation-associated HIF3A single nucleotide polymorphism (SNP) rs3826795 and intake of B vitamins on 10-year changes in BMI. The association between rs3826795 and BMI changes consistently increased across the tertiles of total vitamin B2 and B12 intake (all P for interaction <0.01). The differences in the BMI changes per increment of minor allele were -0.10 (SE 0.06), -0.01 (SE 0.06), and 0.12 (SE 0.07) within subgroups defined by increasing tertiles of total vitamin B2 intake and -0.10 (SE 0.06), -0.01 (SE 0.06), and 0.10 (SE 0.07) within subgroups defined by increasing tertiles of total vitamin B12 intake. In two independent cohorts, a DNA methylation variant in HIF3A was associated with BMI changes through interactions with total or supplemental vitamin B2, vitamin B12, and folate. These findings suggest a potential causal relation between DNA methylation and adiposity.

Folate, vitamin B-6, and vitamin B-12 intake and mild cognitive impairment and probable dementia in the Women's Health Initiative Memory Study.

BACKGROUND: Whether higher B vitamin intake (ie, B-6, B-12, and folate) is protective against cognitive decline in later life remains uncertain. Several prospective, observational studies find higher B vitamin intake to be associated with lower risk of dementia; other studies, including most trials of B vitamin supplementation, have observed no effect on cognition. We examined this question in a large population of older women carefully monitored for development of mild cognitive impairment (MCI) and probable dementia. OBJECTIVE: To determine whether baseline folate, vitamin B-6, and/or vitamin B-12 intake, alone or in combination, are associated with incident MCI/probable dementia among older women. DESIGN: Prospective, longitudinal cohort study. Participants were enrolled between 1993 and 1998, and B vitamin intake was self-reported using a food frequency questionnaire administered at baseline. PARTICIPANTS/SETTING: Postmenopausal women (N=7,030) free of MCI/probable dementia at baseline in the Women's Health Initiative Memory Study. MAIN OUTCOME MEASURES: Over a mean follow-up of 5.0 years, 238 cases of incident MCI and 69 cases of probable dementia were identified through rigorous screening and expert adjudication. STATISTICAL ANALYSES: Cox proportional hazard models adjusting for sociodemographic and lifestyle factors examined the association of B vitamin intake above and below the Recommended Daily Allowance and incident MCI/probable dementia. RESULTS: Folate intake below the Recommended Daily Allowance at study baseline was associated with increased risk of incident MCI/probable dementia (hazard ratio 2.0, 95% CI 1.3 to 2.9), after controlling for multiple confounders. There were no significant associations between vitamins B-6 or B-12 and MCI/probable dementia, nor any evidence of an interaction between these vitamins and folate intake. CONCLUSIONS: Folate intake below the Recommended Daily Allowance may increase risk for MCI/probable dementia in later life. Future research should include long-term trials of folic acid supplementation to examine whether folate may impart a protective effect on cognition in later life.

Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process.

Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important disease-related optic nerve parameter. In 21,094 individuals of European ancestry and 6,784 individuals of Asian ancestry, we identify 10 new loci associated with variation in VCDR. In a separate risk-score analysis of five case-control studies, Caucasians in the highest quintile have a 2.5-fold increased risk of primary open-angle glaucoma as compared with those in the lowest quintile. This study has more than doubled the known loci associated with optic disc cupping and will allow greater understanding of mechanisms involved in this common blinding condition.

A prospective study of folate, vitamin B6, and vitamin B12 intake in relation to exfoliation glaucoma or suspected exfoliation glaucoma.

IMPORTANCE: Effective strategies for primary prevention are lacking for exfoliation glaucoma (EG), which is the most common type of secondary glaucoma. OBJECTIVE: To examine the association between B vitamin intake and EG or suspected EG (EG/SEG) risk. DESIGN, SETTING, AND PARTICIPANTS: National prospective cohort study using more than 20 years of follow-up data from the Nurses' Health Study (all female registered nurses) and the Health Professionals Follow-up Study (all male health professionals) from June 1, 1980, to May 31, 2010 (Nurses' Health Study) and January 1, 1986, to December 31, 2010 (Health Professionals Follow-up Study). We included a subset of 78,980 Nurses' Health Study women and 41,221 Health Professionals Follow-up Study men who were 40 years or older, free of glaucoma, had completed diet questionnaires, and reported eye examinations (follow-up rate, >85%). EXPOSURES: Cumulatively updated intake of B vitamins (folate, vitamin B6, and vitamin B12) as ascertained by repeated administration of validated questionnaires. MAIN OUTCOMES AND MEASURES: Incident cases of EG/SEG, totaling 399 (329 women and 70 men), were first identified with the questionnaires and were subsequently confirmed with medical records. Multivariable relative risks for EG/SEG were calculated in each cohort and then pooled with meta-analysis. RESULTS: Vitamin B6 and vitamin B12 intake was not associated with EG/SEG risk in pooled analyses (P = .52 and P = .99 for linear trend, respectively). However, a suggestive trend of a reduced risk was observed with higher intake of folate: compared with the lowest quintile of cumulatively averaged updated total folate intake, the multivariable relative risk for EG/SEG for the highest quintile (≥654 µg/d) was 0.75 (95% CI, 0.54-1.04; P = .02 for linear trend). These results were not materially altered after adjustment for vitamin B6 and vitamin B12 intake. An association was observed for supplemental folate intake but not for dietary folate only (P = .03 and P = .64 for linear trend, respectively). Greater frequency of multivitamin use showed a modest suggestive inverse association (current multivitamin use of ≥6 times per week vs nonuse multivariable relative risk, 0.84; 95% CI, 0.64-1.11; P = .06 for linear trend). CONCLUSIONS AND RELEVANCE: Higher total folate intake was associated with a suggestive lower risk for EG/SEG, supporting a possible causal role of homocysteine in EG/SEG.

Caffeine and cognitive decline in elderly women at high vascular risk.

BACKGROUND: Persons with vascular disorders are at higher risk of cognitive decline. OBJECTIVE: To determine whether caffeine may be associated with cognitive decline reduction in elderly at high vascular risk. METHODS: We included 2,475 women aged 65+ years in the Women's Antioxidant Cardiovascular Study, a randomized trial of antioxidants and B vitamins for cardiovascular disease secondary prevention. We ascertained regular caffeine intake at baseline (1995-1996) using a validated 116 item-food frequency questionnaire. From 1998-2000 to 2005-2006, we administered four telephone cognitive assessments at two-year intervals evaluating global cognition, verbal memory, and category fluency. The primary outcome was the change in global cognitive score, which was the average of the z-scores of all tests. We used generalized linear models for repeated measures that were adjusted for various sociodemographic, health, and lifestyle factors to evaluate the difference in cognitive decline rates across quintiles of caffeine intake. RESULTS: We observed significantly slower rates of cognitive decline with increasing caffeine intake (p-trend = 0.02). The rate difference between the highest and lowest quintiles of usual caffeine intake (>371 versus <30 mg/day) was equivalent to that observed between those who were 7 years apart in age (p = 0.006). Consumption of caffeinated coffee was significantly related to slower cognitive decline (p-trend = 0.05), but not other caffeinated products (e.g., decaf, tea, cola, chocolate). We conducted interaction analyses and observed stronger associations in women assigned to vitamin B supplementation (p-interaction = 0.02). CONCLUSIONS: Caffeine intake was related to moderately better cognitive maintenance over 5 years in older women with vascular disorders.

The Relationship between caffeine and coffee consumption and exfoliation glaucoma or glaucoma suspect: a prospective study in two cohorts.

PURPOSE: We examined the association between caffeine and caffeinated beverage consumption in relation to the risk of exfoliation glaucoma or exfoliation glaucoma suspect (EG/EGS). METHODS: We followed 78,977 women from the Nurses' Health Study (NHS) and 41,202 men from the Health Professionals Follow-up Study (HPFS) who were at least 40 years of age, did not have glaucoma, and reported undergoing eye examinations from 1980 (NHS) or 1986 (HPFS) to 2008. Information on consumption of caffeine-containing beverages and potential confounders were repeatedly ascertained in validated follow-up questionnaires. Confirmation with medical record review revealed 360 incident EG/EGS cases. Multivariate rate ratios (RRs) for EG/EGS were calculated in each cohort and then pooled using meta-analytic techniques. RESULTS: Compared with participants whose cumulatively updated total caffeine consumption was <125 mg/day, participants who consumed ≥ 500 mg/day had a trend toward increased risk of EG/EGS that was not statistically significant (RR = 1.43; 95% confidence interval [CI], 0.98-2.08); P trend = 0.06). Compared to abstainers, those who drank ≥ 3 cups of caffeinated coffee daily were at increased risk of EG/EGS (RR = 1.66; 95% CI, 1.09-2.54; P trend = 0.02). These results were not materially altered after adjustment for total fluid intake. Associations were stronger among women with a family history of glaucoma (P interaction = 0.06 for coffee; P interaction = 0.03 for caffeine). We did not find associations with consumption of other caffeinated products (caffeinated soda, caffeinated tea, decaffeinated coffee or chocolate) and risk of EG/EGS (P trend ≥ 0.31). CONCLUSIONS: We observed a positive association between heavier coffee consumption with risk of EG/EGS in this large prospective study.

Physical activity and cognition in women with vascular conditions.

BACKGROUND: Individuals with vascular disease or risk factors have substantially higher rates of cognitive decline, yet little is known about means of maintaining cognition in this group. METHODS: We examined the relation between physical activity and cognitive decline in participants of the Women's Antioxidant Cardiovascular Study, a cohort of women with prevalent vascular disease or at least 3 coronary risk factors. Recreational physical activity was assessed at baseline (October 1995 through June 1996) and every 2 years thereafter. Between December 1998 and July 2000, a total of 2809 women 65 years or older underwent a cognitive battery by telephone interview, including 5 tests of global cognition, verbal memory, and category fluency. Tests were administered 3 additional times over 5.4 years. We used multivariable-adjusted general linear models for repeated measures to compare the annual rates of cognitive score changes across levels of total physical activity and energy expended in walking, as assessed at Women's Antioxidant Cardiovascular Study baseline. RESULTS: We found a significant trend (P < .001 for trend) toward decreasing rates of cognitive decline with increasing energy expenditure. Compared with the bottom quintile of total physical activity, significant differences in rates of cognitive decline were observed from the fourth quintile (P = .04 for the fourth quintile and P < .001 for the fifth quintile), or the equivalent of daily 30-minute walks at a brisk pace. This was equivalent to the difference in cognitive decline observed for women who were 5 to 7 years younger. Regularly walking for exercise was strongly related to slower rates of cognitive decline (P = .003 for trend). CONCLUSION: Regular physical activity, including walking, was associated with better preservation of cognitive function in older women with vascular disease or risk factors.

A randomized trial of beta carotene supplementation and cognitive function in men: the Physicians' Health Study II.

BACKGROUND: Oxidative stress contributes to brain aging. Antioxidant treatment, especially over the long term, might confer cognitive benefits. METHODS: We added cognitive testing to the Physicians' Health Study II (PHSII), a randomized trial of beta carotene and other vitamin supplements for chronic disease prevention. The PHSII is a continuation of the Physicians' Health Study (PHS), which had randomized male participants to low-dose aspirin and beta carotene. Participants include those continuing their original beta carotene assignment from the PHS, begun in 1982, and newer recruits randomized as of 1998. The beta carotene arm (50 mg, alternate days) was terminated; follow-up is ongoing for the remaining arms. Near the close of the beta carotene arm, we interviewed 5956 participants older than 65 years to assess general cognition, verbal memory, and category fluency. The primary end point was a global score averaging all tests (using z scores); the secondary end point was a verbal memory score combining results of 4 tests. We compared mean cognition among those assigned to beta carotene vs placebo. We separately examined new recruits and continuing participants. RESULTS: Among 1904 newly recruited subjects (mean treatment duration, 1 year), cognition was similar across treatment assignments. Among 4052 continuing participants from the PHS (mean treatment duration, 18 years), the mean global score was significantly higher in the beta carotene group than in the placebo group (mean difference in z scores, 0.047 standard units; P = .03). On verbal memory, men receiving long-term beta carotene supplementation also performed significantly better than the placebo group (mean difference in z scores, 0.063; P = .007). CONCLUSION: We did not find an impact of short-term beta carotene supplementation on cognitive performance, but long-term supplementation may provide cognitive benefits.

Dietary fat consumption and primary open-angle glaucoma.

BACKGROUND: Prostaglandin F(2alpha) analogues are effective intraocular-pressure-lowering drugs. Dietary fatty acids affect endogenous prostaglandin F(2alpha) concentrations and may thus influence intraocular pressure. OBJECTIVE: We prospectively examined dietary fat consumption in relation to primary open-angle glaucoma (POAG). DESIGN: Women (n = 76 199 in the Nurses' Health Study) and men (n = 40 306 in the Health Professionals Follow-Up Study) free of POAG in 1980 and 1986, respectively, were followed until 1996 if they were > or =40 y old and reported receiving eye exams during follow-up. Potential confounders were assessed on biennial questionnaires, and energy-adjusted cumulative averaged fat intakes were measured by using validated food-frequency questionnaires. We analyzed 474 self-reported POAG cases confirmed by medical chart review. Cohort-specific multivariate rate ratios (RRs) were obtained by using proportional hazards models and were then pooled. RESULTS: Major fats and fat subtypes were not independently associated with POAG risk. Pooled multivariate RRs (95% CI) for POAG comparing the highest with the lowest quintile of fat intake were as follows: 0.90 (0.67, 1.21) for total fat, 1.03 (0.77, 1.38) for saturated fat, 0.76 (0.56, 1.03) for monounsaturated fat, and 0.87 (0.66, 1.16) for polyunsaturated fat, none of which were statistically significant. We found a suggestive positive association between a higher ratio of n-3 to n-6 polyunsaturated fat and risk of POAG [RR = 1.49 (1.11, 2.01); P for trend = 0.10], which was stronger for high-tension POAG [RR = 1.68 (1.18, 2.39); P for trend = 0.009]. CONCLUSION: A high ratio of n-3 to n-6 polyunsaturated fat appears to increase the risk of POAG, particularly high-tension POAG. Further studies are needed.

Antioxidant intake and primary open-angle glaucoma: a prospective study.

The relation between dietary antioxidant intake and primary open-angle glaucoma risk was examined in participants aged over 40 years in the Nurses' Health Study (n = 76,200) and the Health Professionals Follow-up Study (n = 40,284). They were followed biennially from 1980 and 1986, respectively, to 1996, during periods when they received an eye examination. Dietary intakes were measured repeatedly from 1980 in the Nurses' Health Study and from 1986 in the Health Professionals Follow-up Study using validated food frequency questionnaires. The authors analyzed 474 self-reported glaucoma cases confirmed by medical chart review to have primary open-angle glaucoma with visual field loss. The authors used Cox proportional hazards models for cohort-specific multivariate analyses, and results were pooled using random effects models. The pooled multivariate rate ratios for primary open-angle glaucoma comparing the highest versus lowest quintile of cumulative updated intake were 1.17 (95% confidence interval (CI): 0.87, 1.58) for alpha-carotene, 1.10 (95% CI: 0.82, 1.48) for beta-carotene, 0.95 (95% CI: 0.70, 1.29) for beta-cryptoxanthin, 0.82 (95% CI: 0.60, 1.12) for lycopene, 0.92 (95% CI: 0.69, 1.24) for lutein/zeaxanthin, 1.05 (95% CI: 0.59, 1.89) for vitamin C, 0.97 (95% CI: 0.62, 1.52) for vitamin E, and 1.11 (95% CI: 0.82, 1.51) for vitamin A. In conclusion, the authors did not observe any strong associations between antioxidant consumption and the risk of primary open-angle glaucoma.