Higher Folate Intake is Related to Lower Risk of Alzheimer's Disease in the Elderly

The prevalence of Alzheimer' disease (AD) is expected to quadruple by the year 2047 in the United States. Delaying theonset by a few years would decrease its prevalence and public health burden. Elevated plasma homocysteine levels, a novel risk factor for cardiovascular disease and stroke, may also be related to a higher risk of AD (1). Deficiencies of folate, and the B vitamins cobalamin (B12), and pyridoxine (B6), result in increased levels of homocysteine through diverse pathways. Thus, high dietary intake or supplementation of folate, B6 andB12 may decrease the risk of cardiovascular disease, stroke, and dementia by reducing homocysteine. This article is a summary of our study relating intake of folate and vitamins B6and B12 to the risk of AD in a prospective study of aging in Northern New York City (2).

Methods

Participants and Setting. Participants were enrolled in a longitudinal cohort study by a random sampling of Medicare recipients 65 years or older residing in northern Manhattan(Washington Heights, Hamilton Heights, Inwood). Complete data on intakes of folate, B6, and B12 were available in 965persons who comprise the final sample for this study.

Diet assessment

Assessment of daily dietary intake was made with a 61-itemsemi-quantitative food frequency questionnaire (SFFQ, Channing laboratory, Cambridge, MA). Information on daily dietary, supplement, and total intake of folate, and B6 and B12vitamins were estimated from the SFFQ. We adjusted the daily dietary and total intake of these vitamins for daily energy intake using the residuals method. The residuals represent the nutrient intake that is independent of total caloric intake.

Diagnosis of Dementia

Diagnosis of dementia and assignment of specific cause wasmade by consensus of 2 neurologists, 1 psychiatrist, and 2 neuropsychologists based on baseline and follow-up information. The diagnosis of dementia was based on DSM-IV criteria. Diagnosis of AD was based on the NINCDS-ADRDA criteria.

Covariates

In addition to demographic variables (age, gender, ethnic group, years of education), we included as covariates variables that are associated with a higher risk of AD in our cohort, diabetes mellitus, hypertension, heart disease, current smoking, and stroke, all defined by self report. Heart disease included a history of atrial fibrillation and other arrhythmias, congestive heart failure, myocardial infarction, and angina pectoris. We classified persons as homozygeous or heterozygeous for the APOE ε4 allele or not having any ε4 allele.

Statistical Methods

Daily intake of calories, folate, B6, and B12 required logarithmic transformation to resemble a normal distribution. Cox proportional hazards regression models were used in multivariable analyses exploring the association of intakes of folate, vitamin B6, and vitamin B12 to incident AD. The time-to-event variable was time from the dietary interview to incident AD; individuals who did not develop dementia were censored at the last time of follow-up. In the main analysis we related total intake of each nutrient to AD. We conducted secondary analyses relating supplement and non-supplement nutrient intake to AD.

Results

There were 192 cases of AD in 5,902 person-years of observation (mean follow-up = 6.1±3.3 years). The mean age was 75.8±5.8 years, 70.2% of the sample were women, 32.6%were African American, 45.3% were Hispanic, and 22.1% were White; 29.2% were homozygous or heterozygous for theAPOE-ε4 allele, 19.3% had diabetes, 60.3% had hypertension,27.8% had heart disease, and 10.3% had stroke. The mean total intake of folate was 446 ± 226.8 μg, B12 was 12.6 ± 18.8 μg, and B6 was 7.1 ± 17.3 mg.

Persons who developed AD during follow-up were older and had less years of education, a higher proportion of Hispanics and lower proportion of Whites, a higher proportion of APOEε4, and a higher prevalence of diabetes, hypertension, heart disease, and stroke. There were no differences between persons with and without incident AD in the energy adjusted intake ofB6, B12, or in the use of supplements. Compared to those without AD, persons with AD had a lower energy-adjusted total intake of folate that was close to statistical significance (383.8.1 vs. 40.7.5 μg; p=0.09).

The risk of AD decreased with increasing quartile of total folate intake (Table 1) and this association was statistically significant after adjustment for B6 and B12. The association between dietary (non-supplement) folate intake and AD was not statistically significant; the HR for the 4th quartile of dietary folate intake was 0.8 (95% CI = 0.5,1.2; p for trend =0.25) in the full model adjusting for other vitamins. Folate supplement intake alone was not related to the risk of AD (HR = 1.0; 95% CI: 0.7,1.4). When only high doses of folate supplement intake were considered (400 μg or more), the association between folate and AD remained non-significant(HR = 0.7; 95% CI: 0.5,1.2) but in a direction suggesting a lower risk of AD. Total intakes of B6 and B12 were not related to the risk of AD in any of the models. We conducted secondary analyses stratifying by gender, age categorized by the median, APOE-ε4, and history of diabetes and there was no evidence of interaction.

Table 1.

Hazard ratios and 95% confidence intervals relating quartiles ofenergy-adjusted total folate intake to incident Alzheimer'sDisease. Model 1 is adjusted for age and gender. Model 2 isadjusted also for ethnic group, education, and APOE-ε4 allele, history of diabetes, hypertension, current smoking, heartdisease, stroke, and intake of vitamins B6 and B12.

Folate quartiles (μg)	At risk	Cases (Rate per 100 person-years)	Model 1	Model 2
1 (≤ 292.9)	241	54 (3.7)	1.0	1.0
2 (293.0 - 365.0)	241	52 (3.4)	1.1 (0.7, 1.6)	0.9 (0.6,1.3)
3 (365.1 – 487.8)	241	49 (3.2)	0.9 (0.6,1.3)	0.7 (0.5,1.1)
4 (≥ 487.9)	242	37 (2.6)	0.7 (0.5,1.1)	0.5 (0.3,0.9)
P for trend			0.13	0.02

Discussion

We found that total folate intake was related to a lower risk of AD independent of other risk factors, heart disease, stroke, and intake of vitamins B6 and B12 in a largely Hispanic and Black cohort of elderly persons followed for 6.1 ± 3.3 years. B6and B12 intake were not related to the risk of AD.

The putative culprit of AD is the abnormal accumulation of intra and extra-cellular amyloid beta (Aβ) in the brain. In vitro, homocysteine has the ability to potentiate the effects of Aβ on calcium influx and apoptosis. Animal models show that homocysteine and folic acid deficiency impair DNA repair in hippocampal neurons and makes them susceptible to toxicity from Aβ. Another potentially important pathway for the pathogenesis of AD is cerebrovascular disease. Elevated homocysteine levels may be a risk factor for cerebrovascular disease. Higher intake of folate is related to a lower risk of stroke, presumably by decreasing homocysteine levels.

There are conflicting cross-sectional and prospective data on the association of intake and levels of B vitamins and folate to dementia and cognition. Homocysteine levels over 14micromol per liter doubled the risk of AD in the Framingham study (1), but there was no relation between the plasma levels of folate, B6 and B12 to the risk of AD. We found that the association between elevated homocysteine levels and AD was confounded by age (3), and there was no association between a level of homocysteine over 14 micromol/lt and risk of AD. We replicated those results in the sample for this study. Others have reported that elevated homocysteine levels are related to cognitive decline and a higher risk of dementia but not consistently. One implication of the apparent inconsistency between our results for homocysteine and folate is that folate may be related to AD through mechanisms that are independent of homocysteine.

Since 1998 cereal-grain products in the USA have been fortified with folic acid. This supplementation has been accompanied by decreases in homocysteine levels in the general population. Folic acid fortification in women of childbearing age has resulted in a decrease in the incidence of neural tube defects, an important public health success. However, the effects of folic acid fortification for the population at large remain to be determined. There is concern that folic acid fortification may improve anemia in elderly persons with B12 deficiency but could exacerbate neuropsychiatric complications, either because of masking ofB12 deficiency, or other mechanisms. A recent cross-sectional analysis of the National Health and Nutrition Examination Survey (NHANES) data showed that in elderly people with low serum B12, high folate levels were related to cognitive impairment and anemia (4).

There are few trials studying the cognitive effects of homocysteine lowering with vitamins. A two-year, double-blind, placebo-controlled, randomized clinical trial of homocysteine-lowering treatment with folate B6, and B12 supplements in 276 participants, 65 years of age or older, with plasma homocysteine concentrations of at least 13 micromol per liter found a lower homocysteine level in the treatment group, but no differences in cognition at 2 years (5). A secondary analysis with a composite measure of cognition revealed a higher risk of cognitive decline of borderline statistical significance.

folate, vitamin B12, and B6, it seems reasonable at this time to state that supplementation of these vitamins should be reserved for the treatment of documented deficiency states, but not expressly for the prevention or treatment of cognitive disorders including AD. Our results for folate are encouraging, but are in conflict with other evidence suggesting no benefit or potential harm. Thus, we must be conservative in our recommendations. Clinicians often make recommendations of vitamin supplementation based on the premise that while they may not be helpful, they are not harmful, assuming a favorable risk benefit ratio. However, at least one observational study and oneclinical trial found an association between homocysteine relatedvitamin intake and cognitive decline, and this finding needs tobe clarified. In addition, purchasing vitamin supplements with uncertain benefits (beyond food fortification) and possibleadverse effects could be an additional financial burden for seniors who may live on a modest fixed income.