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Robert Clarke, MD; A. David Smith, DPhil; Kim A. Jobst, DM; Helga Refsum, MD; Lesley Sutton, BSc; Per M. Ueland, MD

Arch Neurol. 1998;55:1449-1455.

Background  Recent studies suggest that vascular disease may contribute to the cause of Alzheimer disease (AD). Since elevated plasma total homocysteine (tHcy) level is a risk factor for vascular disease, it may also be relevant to AD.

Objective  To examine the association of AD with blood levels of tHcy, and its biological determinants folate and vitamin B₁₂.

Design  Case-control study of 164 patients, aged 55 years or older, with a clinical diagnosis of dementia of Alzheimer type (DAT), including 76 patients with histologically confirmed AD and 108 control subjects.

Setting  Referral population to a hospital clinic between July 1988 and April 1996.

Main Outcome Measures  Serum tHcy, folate, and vitamin B₁₂ levels in patients and controls at entry; the odds ratio of DAT or confirmed AD with elevated tHcy or low vitamin levels; and the rate of disease progression in relation to tHcy levels at entry.

Results  Serum tHcy levels were significantly higher and serum folate and vitamin B₁₂ levels were lower in patients with DAT and patients with histologically confirmed AD than in controls. The odds ratio of confirmed AD associated with a tHcy level in the top third (14 µmol/L) compared with the bottom third (11 µmol/L) of the control distribution was 4.5 (95% confidence interval, 2.2-9.2), after adjustment for age, sex, social class, cigarette smoking, and apolipoprotein E 4. The corresponding odds ratio for the lower third compared with the upper third of serum folate distribution was 3.3 (95% confidence interval, 1.8-6.3) and of vitamin B₁₂ distribution was 4.3 (95% confidence interval, 2.1-8.8). The mean tHcy levels were unaltered by duration of symptoms before enrollment and were stable for several years afterward. In a 3-year follow-up of patients with DAT, radiological evidence of disease progression was greater among those with higher tHcy levels at entry.

Conclusions  Low blood levels of folate and vitamin B₁₂, and elevated tHcy levels were associated with AD. The stability of tHcy levels over time and lack of relationship with duration of symptoms argue against these findings being a consequence of disease and warrant further studies to assess the clinical relevance of these associations for AD.

From the Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Clinical Medicine (Dr Clarke), Oxford Project to Investigate Memory and Ageing (OPTIMA), University Department of Pharmacology, University of Oxford, and Radcliffe Infirmary Trust (Drs Smith and Jobst and Ms Sutton), Oxford, England; and Department of Pharmacology, University of Bergen, Bergen, Norway (Drs Refsum and Ueland).

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