Dietary intake of folate was not associated with risk for incident dementia or AD among men and women of the Cache Study on Memory, Health, and Aging after nine years of follow-up. In multivariable-adjusted models no associations were observed for either folate, vitamin B-6, or vitamin B-12 from foods or supplements or both combined.
Several plausible biological mechanisms link folate and other B-vitamins to AD risk. Deficiencies of B-vitamins have been known to raise levels of homocysteine as a consequence of disrupted one-carbon metabolism (4
). Elevated levels of homocysteine may induce oxidative stress and increase the neurotoxicity (20
). Damaged or altered environment in the brain may contribute to increased plaques and tangles observed in persons with AD. In addition to elevated homocysteine levels, other consequences of disturbed one-carbon metabolism include decreased levels of S-adenosyl-methionine (SAM), increased S-adenosylhomocysteine (SAH), and limitation of folate metabolites involved in nucleotide synthesis (4
). SAM is required for the methylation of DNA, RNA and neurotransmitters and inadequate levels of SAM may impair neurons and damage vital brain structures (4
). SAH, the precursor to homocysteine, has also been observed at irregular levels in individuals with AD similar to homocysteine, SAM and B-vitamins (23
) and is thought to increase as homocysteine metabolism is inhibited. Increases in SAH have been seen to inhibited normal functions of SAM in the brain (24
Vitamin B-12 is a cofactor for methionine synthase, the enzyme that transfers a methyl group from 5-methyl-THF to homocysteine to form methionine. The conversion of 5,10 methylene-THF to 5-methyl-THF requires the enzyme, methyltetrahydrofolate reductase. This reaction is irreversible, therefore deficiency of B-12, prevents 5-methyl-THF from being converted to 5,10 methylene-THF, essential for the synthesis of nucleotides. Low levels of nucleotides may result in misincorporation of neucleotides in DNA replication and chromosomal breaks which may facilitate neuronal damage common in patient’s brains (5
Homocysteine can be metabolized in an alternative pathway that requires B-6 as a cofactor in converting homocysteine to cystathione. Further, more glutathione is produced in a downstream reaction and is a key antioxidant for preventing lipid peroxidation and other oxidative damage. Therefore, disrupted brain function may also be related to the decreased production of glutathione via disordered metabolism of homocysteine to cystathione.
The prevalence of B-vitamin deficiencies, especially B-12, is highest among elderly persons. Gastritis and other conditions that inhibit vitamin B-12 absorption have been estimated to affect 20–50% of the elderly in the US. Depending on the diagnosis criteria, 24% of elders age 60–69 and 37% of those older than 80 were found to have gastritis in the Framingham Studies cohort (24
). Deficiency of folate is also suspected to be higher among the elderly and may increase with age due to decreased absorption caused by changes in the gastrointestinal tract. Studies examining folate intake post-fortification have also seen average intakes below recommendations among all age groups (25
Beginning in 1998, U.S. Federal law required that all cereal grain products to be fortified with folic acid in order to reduce the birth prevalence of neural tube defects. A standard level of 140 μ
g folic acid per 100 grams of grain was required (27
). Some have raised concern that the benefits may not reach all populations and may even be detrimental to subgroups (7
). High levels of folic acid may “mask” evidence of vitamin B-12 deficiency (28
). A prolonged B-12 deficiency has been associated with cognitive deficits that in certain cases, depending upon severity and duration of the deficiency, appear to be irreversible (25
Since folate fortification in the U.S., increases in average serum levels of folate have been observed indicating that though many products, like cereals, were already fortified with folic acid, the mandate did meet its goal of increasing average intakes of folic acid. The Framingham group observed a 38% increase of serum RBC folate among participants who did not consume supplements post-fortification; they also estimated that 3% less of their cohort were deficient in folate post-fortification compared to pre-fortification (29
). If folate was independently associated with increased risk for cognitive decline and AD, a decrease in incidence would have been expected. No such report or observation has been made. One study, by Morris et al. (8
) did report increased risk for anemia and cognitive decline among those with low serum B-12 and high serum folate. The study included 1459 senior participants in the 1999–2002 US National Health and Nutrition Examination Survey. Morris et al. (7
) also found high folate intake to be associated with faster cognitive decline among a group of elderly from the Chicago Health and Aging Project. These finding support concerns that high folate may be toxic in certain situations.
In 1995, the CCMS participants average intake of folate from food was below the RDA (400 μg/d) at 319 μg/d and 46.9 % received less than the RDA from food and supplements combined. This data was collected pre-folate fortification and folate intake would be expected to be higher post fortification. Associations between dietary intake and AD may be difficult to detect as dietary intake in elderly may not indicate actual nutriture. Increases in malabsorption related to gastritis or pernicious anemia contribute to the problem of using dietary data alone to assess possible associations between B-vitamins and AD.
It is not surprising that results from population-based prospective studies on B-vitamins and cognitive health vary significantly given the variation in study methods. Results from the CCMS study appear consistent with some (10
) but not all recently published data (6
) similar in design. There is little information on dietary intake of B-vitamins and risk of incident AD (6
). Corrado et al. (31
) found no independent relation between total B-12 with incident of AD in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is a population based cohort study of elderly men and women, although somewhat younger than the elderly of the Cache study, from the Baltimore area followed for 9.3 years. Higher folate was associated with decreased risk for incident AD (RR: 0.45; 95% CI: 0.2, 0.97) in a model that included age, gender, education, and caloric intake. Morris and colleagues conducted longitudinal assessment of incident AD across quintile of increasing folate consumption from the Chicago Health and Aging Project (CHAP) (10
). Of 1041 participants of the CHAP study, 162 developed incident AD after 3.9 years of follow-up. Higher B-vitamin intakes from food and food and supplement were not associated with incidence of AD. Average intake of total folate in the CHAP and the Cache study was similar CHAP: 338 μ
g/d and CCMS: 319 μ
g/d). The Washington Heights Inwood Columbia Aging Project (n=965) reported a higher incidence of AD than that reported in the Cache study (109 vs. 212, respectively) (30
). The highest quartile of folate (food and supplement) in the Washington Heights Study intake (>489.7 μ
g) (equivalent to quintile four in the CCMS) was related to a decrease risk for AD (HR: 0.5; 95% CI: 0.3, 0.9).
Among studies that explored serum biomarkers and incident dementia and AD the results also vary. Among studies that examined homocysteine two out of three found elevated homocysteine to be related to incident AD (32
). Wang et al. (35
) examined serum folate and B-12 in relation to incident AD and found nearly double the risk for AD among subjects deficient in folate or B-12. The Conselice Study of Brain Aging (CSBA) also found low serum folate to be related to increased risk for AD (6
Recently, a clinical trial involving 340 participants with mild to moderate AD administered B-vitamin supplements including 5 mg of folate, 25 mg of vitamin B6 and 1 mg of B12 a day for 18 months (36
). Although homocysteine levels were significantly decreased, there was no improvement or slowing of cognitive decline among the treatment groups compared to placebo. Supplemented groups experienced a high incidence of depression (36
). Another trial involving B-vitamins also reported no improvement in delay of decline with supplementation (37
The Cache County Study has many strengths including a large long-lived and homogenous population, lengthy follow-up time, high rates of participation and retention, a extensive set of demographic information, medical history, medication usage, detailed and repeated cognitive assessment, dietary intake, lifestyle, occupational history and environment information. A limitation of this study is a lack of biomarkers. The majority of the population is Caucasian and are members of The Church of Jesus Christ of Latter-day Saints, and consequently has low rates of alcohol and tobacco use. Participants also have about an 80% rate of having at least a high school education. Detailed clinical assessment was used to assign diagnosis.
In summary folate intake from food, supplements, or from combined sources was not associated with incident dementia or AD. In addition, this null association was not mediated by intakes of vitamin B6 or vitamin B12, cofactors of folate’s role in one-carbon metabolism. The observed average intake of folate from food in 1995 was less than RDAs; although average intake of folate from food and supplement combined exceeded the DRI. Further studies should be done using serum biomarkers to assess the influence and possible interactions of B-vitamin status in relation to incident dementia and AD. Based on results from this study, general recommendations to increase folate intake or other B-vitamin intake in attempt to reduce risk of dementia or AD is not supported. Studies that include examining dietary B-vitamins, associated serum biomarkers, and incident dementia/AD with adequate power and follow-up time would be valuable to clarifying relationships.