Background: Elevated total homocysteine (tHcy) levels are associated with cognitive impairment and dementia, but it is uncertain if these associations are causal. Previous studies have shown that elevated tHcy in unimpaired older people predicts risk of dementia, but the relevance of low folate or vitamin B12 (B12) status for cognitive decline is uncertain. Objectives: To examine the associations of B12 and folate status with cognitive decline between year 0 and 2, and year 0 and 10, respectively, in the Oxford Healthy Aging Project (n=2741). Methods: Cognitive function was assessed sequentially over 10 years using the Mini-Mental State Examination (MMSE). Blood was collected from 1648 individuals at year 2 and from 472 individuals at year 10. Serum levels of B12, holotranscobalamin (holoTC), folate, tHcy and methylmalonic acid (MMA) were measured. Repeated measurements over time on individuals were analyzed using random effects mixed models to examine associations of cognitive decline with vitamin status after adjustment for age, sex, smoking, education, apoE and prior vascular disease. Individuals were also classified as having significant cognitive decline at year 10 if their MMSE score declined by ≥3 points/10 years. Results: The self-correlation (r) for MMSE scores at 6 months (n=352) was high (r=0.82). The self-correlation for biochemical markers of B12 status at 8 years between measurements was also high (r=0.68 for holoTC, 0.59 for B12, 0.53 for tHcy and 0.70 for MMA), but not for folate (r=0.23). After adjustment for relevant covariates, low holoTC was associated with more rapid cognitive decline at year 2 (p=0.03), but this association was no longer significant at year 10. Individuals with significant cognitive decline at year 10 (n=154) compared with those without it (n=520) had lower serum levels at year 2 of B12 (p<0.001), higher tHcy (p=0.04) and MMA levels (p=0.001), respectively, but there were no differences in folate levels. Conclusions: The rates of cognitive decline were more rapid in individuals with low holoTC levels at baseline. Low B12 status at baseline also predicted cognitive decline at 10 years. Large trials are required to assess the clinical relevance of B12 supplementation for maintenance of cognitive function in older people.
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