Total protein, animal protein and physical activity in relation to muscle mass in middle-aged and older Americans.

Resistance training is recognised as a good strategy for retarding age-related declines in muscle mass and strength. Recent studies have also highlighted the potential value of protein intakes in excess of present recommendations. The roles that leisure-time physical activity and protein quality play in the preservation of skeletal muscle during ageing, and how such influences interact in free-living people are unclear. We sought to clarify these issues using data collected on 2425 participants aged ≥ 50 years in the US National Health and Nutrition Examination Survey (2003-2006). We estimated subjects' usual intakes of total protein and beef from two 24 h diet recalls and computed the appendicular skeletal muscle mass index from anthropometric measures. Participants self-reported their physical activity levels. Analyses accounted for demographic factors and smoking. The association between muscle-strengthening activity and the appendicular skeletal muscle mass index varied with protein intake. Furthermore, among obese subjects with protein intakes < 70 g/d, those who performed such activities had a lower appendicular skeletal muscle mass index than those who were physically inactive. Protein intakes above the present recommendations were associated with benefits to obese subjects only. The appendicular skeletal muscle mass index of non-obese subjects who performed vigorous aerobic activities was consistently high; in obese subjects, it varied with protein intake. High-protein intake was associated with a modest increase in the appendicular skeletal muscle mass index in non-obese, physically inactive subjects. The present findings reinforce the idea that muscle-strengthening exercise preserves muscle when combined with adequate dietary protein. Vigorous aerobic activity may also help.

The role of B vitamins in preventing and treating cognitive impairment and decline.

Many epidemiologic studies have considered whether markers of B-vitamin status are associated with cognitive function and cognitive decline. This avenue of research was sparked by the homocysteine (Hcy) theory of cardiovascular disease, which was extended to Alzheimer's disease when a link between vascular dementia and Alzheimer's disease was discovered. Hcy could cause cognitive impairment via direct neurotoxicity. However, decreased remethylation of Hcy to methionine might also compromise cognitive function by means other than mere Hcy lowering. Folate and vitamin B-12 participate in Hcy remethylation and largely determine Hcy status. Consequently, much of the relevant research has focused on these 2 B vitamins. The many subtly different hypotheses that investigators have addressed by attempting to link several B-vitamin status indicators to diverse cognition-related outcomes have created a confusing body of conflicting studies that seems to defy summarization. Nevertheless, themes are discernible that aid interpretation, foster hypothesis generation, and inform future study design. For example, despite a shared metabolic pathway, Hcy, vitamin B-12, and folate are differently related to specific cognitive outcomes. Although consistency of findings across studies is often touted as essential to distinguishing causal from coincidental relationships, discrepancies among study findings can be even more informative.

Vitamin B-12 and folate status in relation to decline in scores on the mini-mental state examination in the framingham heart study.

OBJECTIVES: To investigate the cognitive significance of low to low-normal plasma vitamin B-12 concentrations and to shed light on the role that folate status plays in the association between vitamin B-12 status and cognitive decline. DESIGN: Associations between plasma vitamin B-12 and folate and 8-year cognitive decline were evaluated, and the effects of interactions between vitamin B-12 status and folate status and supplemental folate use on cognitive decline were assessed. SETTING: The Framingham Heart Study - a prospective epidemiological study. PARTICIPANTS: Five hundred forty-nine community-dwelling individuals aged 74.8 ± 4.6. MEASUREMENTS: Mini-Mental State Examination (MMSE), plasma folate, vitamin B-12, methylmalonic acid, homocysteine, demographic factors, and body mass index. RESULTS: MMSE scores declined by 0.24 points per year over the 8-year follow-up period. Decline was significantly faster in cohort members in the bottom two plasma vitamin B-12 quintile categories, and no apparent cognitive advantage was associated with plasma vitamin B-12 from 187 to 256.8 pmol/L over less than 186 pmol/L. In cohort members with plasma vitamin B-12 less than 258 pmol/L, having a plasma folate concentration greater than 20.2 nmol/L was associated with an approximate 1-point per year decline, as was use of supplemental folate. CONCLUSION: Plasma vitamin B-12 levels from 187 to 256.8 pmol/L predict cognitive decline. Furthermore, having plasma vitamin B-12 levels in this range or below in conjunction with high plasma folate or supplemental folate use predicts especially rapid cognitive decline.

Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors.

BACKGROUND: Folate deficiency has serious consequences for the fetus. Folic acid fortification of food addresses this problem. However, clinical consequences of vitamin B-12 deficiency may be worsened by high folic acid intakes, perhaps as a direct result of unmetabolized folic acid, which does not occur naturally in body tissues. OBJECTIVE: We attempted to attribute associations that we previously found between higher folate status and anemia and cognitive test performance to circulating unmetabolized folic acid or 5-methyltetrahydrofolate (5MeTHF). DESIGN: The subjects (n = 1858) were senior participants in the US National Health and Nutrition Examination Survey (1999-2002) who had normal renal function and reported no history of stroke, recent anemia therapy, or diseases of the liver, thyroid, or coronary arteries. Subjects had undergone a phlebotomy, a complete blood count, and cognitive and dietary assessments. RESULTS: Circulating unmetabolized folic acid was detected in approximately 33% of the subjects and was related to an increased odds of anemia in alcohol users. In seniors with a serum vitamin B-12 concentration <148 pmol/L or a plasma methylmalonic acid concentration > or =210 nmol/L, the presence compared with the absence of detectable circulating unmetabolized folic acid was related to lower cognitive test scores and lower mean cell volume. In the same subgroup, higher serum 5MeTHF was related to an increased odds of anemia and a marginally significantly decreased odds of macrocytosis. In seniors with a normal vitamin B-12 status, a higher serum 5MeTHF concentration was related to higher cognitive test scores. CONCLUSION: Results of this epidemiologic study were somewhat consistent with reports on the folic acid treatment of patients with pernicious anemia, but some findings were unexpected.

Vitamin B-6 intake is inversely related to, and the requirement is affected by, inflammation status.

Low circulating pyridoxal 5'-phosphate (PLP) concentrations have been linked to inflammatory markers and the occurrence of inflammatory diseases. However, the implications of these findings are unclear. The measurement of PLP and C-reactive protein (CRP) in blood samples collected from participants in the 2003-2004 NHANES afforded us the opportunity to investigate this relationship in the general U.S. population. Dietary and laboratory data were available for 3864 of 5041 interviewed adults, 2686 of whom were eligible (i.e. provided reliable dietary data and were not diabetic, pregnant, lactating, or taking hormones or steroidal antiinflammatory drugs). Vitamin B-6 intake was assessed using 2 24-h diet recalls and supplement use data. After multivariate adjustment for demographics, smoking, BMI, alcohol use, antioxidant vitamin status, intakes of protein and energy, and serum concentrations of creatinine and albumin, high vitamin B-6 intake was associated with protection against serum CRP concentrations >10 mg/L compared with < or =3 mg/L. However, plasma PLP > or =20 nmol/L compared with <20 nmol/L was inversely related to serum CRP independently of vitamin B-6 intake (P < 0.001). Among participants with vitamin B-6 intakes from 2 to 3 mg/d, the multivariate-adjusted prevalence of vitamin B-6 inadequacy was <10% in participants with serum CRP < or =3 mg/L but close to 50% in those with serum CRP > 10 mg/L (P < 0.001). In conclusion, higher vitamin B-6 intakes were linked to protection against inflammation and the vitamin B-6 intake associated with maximum protection against vitamin B-6 inadequacy was increased in the presence compared to absence of inflammation.

Folate-vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency.

Previous reports on pernicious anemia treatment suggested that high folic acid intake adversely influences the natural history of vitamin B-12 deficiency, which affects many elderly individuals. However, experimental investigation of this hypothesis is unethical, and the few existing observational data are inconclusive. With the use of data from the 1999-2002 National Health and Nutrition Examination Survey (NHANES), we evaluated the interaction between high serum folate and low vitamin B-12 status [ie, plasma vitamin B-12 < 148 pmol/L or methylmalonic acid (MMA) > 210 nmol/L] with respect to anemia and cognitive impairment. With subjects having both plasma folate < or = 59 nmol/L and normal vitamin B-12 status as the referent category, odds ratios for the prevalence of anemia compared with normal hemoglobin concentration and impaired compared with unimpaired cognitive function were 2.1 (95% CI: 1.1, 3.7) and 1.7 (95% CI: 1.01, 2.9), respectively, for those with low vitamin B-12 status but normal serum folate and 4.9 (95% CI: 2.3, 10.6) and 5.0 (95% CI: 2.7, 9.5), respectively, for those with low vitamin B-12 status and plasma folate >59 nmol/L. Among subjects with low vitamin B-12 status, mean circulating vitamin B-12 was 228 pmol/L for the normal-folate subgroup and 354 pmol/L for the high-folate subgroup. We subsequently showed increases in circulating homocysteine and MMA concentrations with increasing serum folate among NHANES participants with serum vitamin B-12 < 148 pmol/L, whereas the opposite trends occurred among subjects with serum vitamin B-12 > or = 148 pmol/L. These interactions, which were not seen in NHANES III before fortification, imply that, in vitamin B-12 deficiency, high folate status is associated with impaired activity of the 2 vitamin B-12-dependent enzymes, methionine synthase and MMA-coenzyme A mutase.

Plasma pyridoxal 5'-phosphate in the US population: the National Health and Nutrition Examination Survey, 2003-2004.

BACKGROUND: No large-scale, population-based study has considered the descriptive epidemiology of vitamin B-6 status with use of plasma pyridoxal 5'-phosphate (PLP), the indicator of vitamin B-6 adequacy used to set the current Recommended Dietary Allowance, which is < or = 2 mg/d for all subgroups. OBJECTIVES: We sought to examine the epidemiology of vitamin B-6 status in the US population. METHODS: In > 6000 participants aged > or = 1 y in the National Health and Nutrition Examination Survey (2003-2004), we considered relations between plasma PLP and various subject characteristics and examined trends in plasma PLP and homocysteine with vitamin B-6 intake, both overall and in selected subgroups. RESULTS: In males, plasma PLP decreased with age after adolescence only in nonusers of supplemental vitamin B-6. Regardless of supplement use, plasma PLP concentrations of women of childbearing age were significantly lower than those of comparably aged men, and most oral contraceptive users had plasma PLP < 20 nmol/L. The prevalence of low plasma PLP was significantly > 3% at vitamin B-6 intakes from 2 to 2.9 mg/d in all subgroups and at intakes from 3 to 4.9 mg/d in smokers, the elderly, non-Hispanic blacks, and current and former oral contraceptive users. Intakes from 3 to 4.9 mg/d compared with < 2 mg/d were associated with significant protection from low plasma PLP in most subgroups and from hyperhomocysteinemia in the elderly. CONCLUSIONS: Vitamin B-6 intakes of 3 to 4.9 mg/d appear consistent with the definition of a Recommended Dietary Allowance for most Americans. However, at that intake level, substantial proportions of some population subgroups may not meet accepted criteria for adequate vitamin B-6 status.

In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations.

In a recent study of older participants (age >/=60 years) in the 1999-2002 National Health and Nutrition Examination Survey (NHANES), we showed that a combination of high serum folate and low vitamin B(12) status was associated with higher prevalence of cognitive impairment and anemia than other combinations of vitamin B(12) and folate status. In the present study, we sought to determine the joint influence of serum folate and vitamin B(12) concentrations on two functional indicators of vitamin B(12) status, total homocysteine (tHcy) and methylmalonic acid (MMA), among adult participants in phase 2 of the NHANES III (1991-1994) and the NHANES 1999-2002. Exclusion of subjects who were <20 years old, were pregnant, had evidence of kidney or liver dysfunction, or reported a history of alcohol abuse or recent anemia therapy left 4,940 NHANES III participants and 5,473 NHANES 1999-2002 participants for the study. Multivariate analyses controlled for demographic factors, smoking, alcohol use, body mass index, self-reported diabetes diagnosis, and serum concentrations of creatinine and alanine aminotransferase revealed significant interactions between serum folate and serum vitamin B(12) in relation to circulating concentrations of both metabolites. In subjects with serum vitamin B(12) >148 pmol/liter (L), concentrations of both metabolites decreased significantly as serum folate increased. In subjects with lower serum vitamin B(12), however, metabolite concentrations increased as serum folate increased starting at approximately 20 nmol/L. These results suggest a worsening of vitamin B(12)'s enzymatic functions as folate status increases in people who are vitamin B(12)-deficient.

Intake of zinc and antioxidant micronutrients and early age-related maculopathy lesions.

BACKGROUND: Macular degeneration, the end stage of age-related maculopathy (ARM), is the leading cause of legal blindness worldwide, and few modifiable risk factors are known. The high concentration of carotenoids in the macula, plus evidence linking oxidative stress to ARM and carotenoids to antioxidation, generated the hypothesis that higher antioxidant intakes can prevent ARM. Results of observational and intervention studies have been inconsistent. OBJECTIVE: To evaluate associations between intakes of zinc and antioxidant micronutrients and early ARM. METHODS: Between 1993 and 1995, ARM was assessed in 398 Boston-area women aged 53-74 y using the Wisconsin Age-related Maculopathy System of grading retinal fundus photographs. The women were a subset of the Nurses' Health Study cohort. Micronutrient intake was assessed by semi-quantitative food frequency questionnaires administered four times between 1980 and the baseline eye examinations. RESULTS: After multivariate adjustment for potential confounders, 1980 energy-adjusted intakes of alpha-carotene, beta-carotene, lycopene, total retinol, total vitamin A, and total vitamin E were significantly inversely related to the prevalence of pigmentary abnormalities (PA). Furthermore, increasing frequency of consuming foods high in alpha-or beta-carotene was associated with lower odds of PA; compared to women consuming these foods < 5 times/wk, odds ratios (95% CI) were 0.7 (0.3-1.6) for 5-6 times/wk, 0.6 (0.2-1.3) for 7-9.5 times/wk, and 0.3 (0.1-0.7)for > or =10 times/wk. Lutein/zeaxanthin intakes and more recent intakes of most carotenoids were unrelated to PA, and intakes of zinc and antioxidant micronutrients were unrelated to having large or intermediate drusen alone.

Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification.

BACKGROUND: Historic reports on the treatment of pernicious anemia with folic acid suggest that high-level folic acid fortification delays the diagnosis of or exacerbates the effects of vitamin B-12 deficiency, which affects many seniors. This idea is controversial, however, because observational data are few and inconclusive. Furthermore, experimental investigation is unethical. OBJECTIVE: We examined the relations between serum folate and vitamin B-12 status relative to anemia, macrocytosis, and cognitive impairment (ie, Digit Symbol-Coding score < 34) in senior participants in the 1999-2002 US National Health and Nutrition Examination Survey. DESIGN: The subjects had normal serum creatinine concentrations and reported no history of stroke, alcoholism, recent anemia therapy, or diseases of the liver, thyroid, or coronary arteries (n = 1459). We defined low vitamin B-12 status as a serum vitamin B-12 concentration < 148 pmol/L or a serum methylmalonic acid concentration > 210 nmol/L-the maximum of the reference range for serum vitamin B-12-replete participants with normal creatinine. RESULTS: After control for demographic characteristics, cancer, smoking, alcohol intake, serum ferritin, and serum creatinine, low versus normal vitamin B-12 status was associated with anemia [odds ratio (OR): 2.7; 95% CI: 1.7, 4.2], macrocytosis (OR: 1.8; 95% CI: 1.01, 3.3), and cognitive impairment (OR: 2.5; 95% CI: 1.6, 3.8). In the group with a low vitamin B-12 status, serum folate > 59 nmol/L (80th percentile), as opposed to < or = 59 nmol/L, was associated with anemia (OR: 3.1; 95% CI: 1.5, 6.6) and cognitive impairment (OR: 2.6; 95% CI: 1.1, 6.1). In the normal vitamin B-12 group, ORs relating high versus normal serum folate to these outcomes were < 1.0 (P(interaction) < 0.05), but significantly < 1.0 only for cognitive impairment (0.4; 95% CI: 0.2, 0.9). CONCLUSION: In seniors with low vitamin B-12 status, high serum folate was associated with anemia and cognitive impairment. When vitamin B-12 status was normal, however, high serum folate was associated with protection against cognitive impairment.

The association between serum thyroid-stimulating hormone in its reference range and bone status in postmenopausal American women.

Evidence suggests that hyperthyroidism adversely affects bone, but the condition is rare and probably contributes little to postmenopausal osteoporosis. Subclinical hyperthyroidism, which can result from treatment with L-thyroxine, is more common, but its relationship to osteoporosis and fracture is uncertain. A recent study of healthy, postmenopausal Koreans with no history of thyroid disease reported associations between both below-normal and low-normal circulating thyroid-stimulating hormone (TSH) levels and osteoporosis. These findings raise the hypothesis that variation in thyroid function, or TSH itself, affects bone in normal women. In the present research, we used data collected in the third U.S. National Health and Nutrition Examination Survey to examine associations between TSH, as it varies over its reference range, and bone status in healthy, postmenopausal American women. In some analyses, we used osteoporosis and osteopenia defined according to World Health Organization guidelines as the outcome variable. In others, we used bone mineral density (BMD) as a continuum. After adjustment for age, race/ethnicity, body mass index, serum T(4), estrogen replacement therapy, smoking, and physical activity level, the odds ratios (95% CI) relating TSH between 0.39 and 1.8 mIU/L (the median of the reference range) versus TSH between 1.8 and 4.5 to osteoporosis and osteopenia were 3.4 (95% CI, 1.3-9.2) and 2.2 (1.2-3.8), respectively. Furthermore, BMD increased significantly as TSH increased over its reference range in both black and white women. After multivariate adjustment, least-square mean BMD for non-Hispanic white women in the bottom serum TSH quintile category was 0.79 g/cm(2) (95% CI, 0.76-0.82), as compared to 0.83 g/cm(2) (95% CI, 0.8-0.85) for those in the top quintile category. Least-square mean BMD (95% CI) for non-Hispanic black women in the bottom serum TSH quintile category was 0.85 g/cm(2) (95% CI, 0.81-0.89). For non-Hispanic black women in the top quintile category, least-square mean BMD was 0.94 g/cm(2) (95% CI, 0.88-0.99). These results may reflect the existence of clinically significant thyroid hyperfunction in women with serum TSH in the reference range. Alternatively, TSH itself may play a role in the preservation of bone after menopause.

Relation between homocysteine and B-vitamin status indicators and bone mineral density in older Americans.

Recent studies have found a connection between hyperhomocysteinemia and hip fracture. If this association is causal, it could be mediated through detrimental effects of low B-vitamin status on bone mineral density (BMD). Studies have linked homocysteine (Hcy) and the established Hcy determinants folate and vitamin B12, to BMD, but results have been inconsistent. Furthermore, only one study considered the specific marker of tissue vitamin B12 status, methylmalonic acid (MMA), and none have considered red blood cell (RBC) folate. To further explore associations between Hcy and B-vitamin status indicators and bone health, we used data collected on older (i.e., aged >55 years) men and women who underwent DEXA scans of the hip as participants in phase 2 of the third U.S. National Health and Nutrition Examination Survey (n = 1550). We used BMD at the total hip as a continuous outcome variable in some analyses. In others, we used osteoporosis defined on a sex- and race/ethnicity-specific basis according to World Health Organization (WHO) guidelines. After adjusting for demographic factors, body mass index, and other osteoporosis risk factors, BMD decreased and osteoporosis increased significantly with increasing serum MMA quartile category (P < 0.01). Serum vitamin B12 was related to BMD in dose-response fashion up to about 200 pmol/L, and subjects with serum Hcy > or = 20 micromol/L had significantly lower BMD than subjects with serum Hcy < 10 micromol/L. Furthermore, the OR (95% CI) relating a serum vitamin B12 concentration below the 25th percentile to osteoporosis/osteopenia was 2.0 (1.0-3.9), and dose-response trends relating both serum B12 and Hcy to this outcome were marginally statistically significant. Neither serum nor RBC folate was related to BMD or osteoporosis. We conclude that Hcy and vitamin B12 status indicators are associated with BMD in older Americans. Whether this association reflects a causal relation remains unclear and merits further study in light of age-related declines in B12 status and BMD, and the need for low-risk, easily implemented strategies for osteoporosis prevention.

Moderate alcoholic beverage intake and early nuclear and cortical lens opacities.

PURPOSE: To study the relationship between alcoholic beverage intake and early lens opacities. METHODS: 556 Boston-area women aged 53-74 years were sampled from the Nurses' Health Study cohort. Degree of opacity was assessed by eye examinations including lens photography. RESULTS: After multivariate adjustment, the odds of a nuclear opacity grade > or =2.3 increased by 30% (OR=1.3, 95% CI: 1.10-1.54) per 10-g increase in total alcohol intake. Furthermore, after control for intake of other alcoholic beverages, the odds of a higher nuclear opacity grade increased by 13% (OR=1.13, 95% CI: 1.02-1.26) for every two additional hard-alcoholic drinks consumed per week, and by 17% (OR=1.17, 95% CI: 1.03-1.33) for every two additional glasses of wine consumed per week. The odds of a cortical opacity grade > or =0.4 decreased by 12% (OR=0.88, 95% CI: 0.79-0.98) for every two additional glasses of wine consumed per week, but intake of other alcoholic beverages was unrelated to cortical opacity. CONCLUSIONS: Consumption of alcoholic beverages, particularly hard liquor and wine, was positively related to nuclear opacity. Wine drinking was inversely related to cortical opacity.

Homocysteine and Alzheimer's disease.

BACKGROUND: A high circulating concentration of the amino acid homocysteine is an independent risk factor for stroke. Alzheimer's disease (AD) commonly co-occurs with stroke. Epidemiological studies found associations between hyperhomocysteinaemia and both histologically confirmed AD and disease progression and revealed that dementia in AD was associated with evidence of brain infarcts on autopsy. Thus, hyperhomocysteinaemia and AD could be linked by stroke or microvascular disease. However, given known relations between B-group-vitamin deficiency and both hyperhomocysteinaemia and neurological dysfunction, direct causal mechanisms are also plausible. RECENT DEVELOPMENTS: A recent prospective study (S Seshadri and colleagues N Engl J Med; 2002 346: 476-83) showed hyperhomocysteinaemia to be a strong, independent risk factor for dementia and AD. The researchers found a graded increase in risk of both outcomes with rising plasma concentration of homocysteine after multivariate control for putative risk factors for AD. In conjunction with demonstration of a fall in homocysteine concentrations in response to increasing B-group-vitamin status, these findings give hope that mental decline, or AD itself, could be prevented by dietary modification or food fortification. WHERE NEXT? 25% of dementia cases are attributed to stroke. The possibility that some of the other 75% might be prevented by the lowering of homocysteine concentrations greatly increases the hope of maintaining self-sufficiency into old age. If homocysteine lowering can reduce the incidence of dementia or AD, decreased incidence of these disorders may be seen in Canada and the USA, where government-mandated folate-fortification programmes are in effect. Future research should focus on early detection of AD and on the possibility that the disease itself, or its primary symptom, could be prevented by folate supplementation.

Elevated serum methylmalonic acid concentrations are common among elderly Americans.

To describe serum methylmalonic acid (MMA) concentrations of elderly Americans and examine relationships between serum MMA and other factors, we used surplus serum samples collected from elderly (n = 1145) and young-adult (n = 1026) participants in Phase 2 of the third National Health and Nutrition Examination Survey (1991-1994). In approximately 20% of participants >/=65 y old, serum MMA was >370 nmol/L, the 90th percentile of the distribution of participants aged 30-39 y. Consistent with previous reports, we observed strong, independent positive associations between serum MMA concentration and serum concentrations of creatinine and homocysteine. After controlling for demographic factors and creatinine, geometric mean MMA concentration was lower in non-Hispanic blacks [223.6 nmol/L; 95% confidence interval (CI), 198.8-251.5] than non-Hispanic whites (265.1 nmol/L; 95% CI, 240.3-292.4). However, the prevalence of elevated levels did not vary with race/ethnicity. Serum MMA concentration bore a strong inverse relation to serum vitamin B-12 concentration. Nevertheless, elevated serum MMA concentrations affected approximately 15% of those with both normal serum creatinine concentrations and serum B-12 concentrations >148 pmol/L. We conclude that many elderly Americans demonstrate metabolic evidence of low B-12 status, that elevations occur frequently in the absence of traditional deficiency indicators and that levels vary with race/ethnicity and renal function.

Folate, homocysteine, and neurological function.

The study of different neurological problems, including stroke, Alzheimer's disease (AD), and depression, has propelled a greater interest in interrelationships among folate, homocysteine, and neurological function. Specifically, low folate status is a suspected risk factor for depression that also results in an increase in circulating levels of the sulfur amino acid homocysteine. Homocysteine has emerged as an independent risk factor for stroke, and recent studies suggest that vascular disease affecting the brain and Alzheimer's disease may result together in senile dementia. The relationship between stroke and AD was at first interpreted as coincidence, given the pathologic distinctions between the two diseases. However, the connection is now hypothesized to reflect some common pathogenic factors involving folate, homocysteine, or both. It remains unclear whether there is a causal relationship between neurological dysfunction in either condition with folate or homocysteine. Nevertheless, since improvement of folate status lowers homocysteine levels, the hypothesis that folate supplementation may lower the risk of several important health consequences of aging, including various forms of neuropsychiatric dysfunction, is worthy of current intensive exploration.