Plasma homocysteine levels, cerebrovascular risk factors, and cerebral white matter changes (leukoaraiosis) in patients with Alzheimer disease

Context: The pathogenesis of leukoaraiosis on computed tomographic (CT) scanning is unknown, but cerebrovascular risk factors for leukoaraiosis show overlap with those for Alzheimer disease (AD). Objective: To investigate the contribution of cerebrovascular risk factors, in particular plasma total homocysteine (tHcy), to leukoaraiosis in patients with AD and controls. Design: Cross-sectional case-control study. Setting: Referral population to a hospital clinic and community volunteers from the Oxfordshire region in England seen between July 1, 1988, and July 1, 2000. Participants: One hundred thirty-seven AD cases (104 confirmed post mortem) and 277 controls matched for age (mean+/-SD, 73+/-8 years) and sex. Main Outcome Measures: Cerebrovascular risk factors and leukoaraiosis on CT scans of cases and controls; the odds ratio (OR) of having moderate to severe leukoaraiosis with higher levels of plasma tHcy and cerebrovascular risk factors such as age, sex, systolic blood pressure, smoking, diabetes mellitus, and apolipoprotein E epsilon4 genotype. Results: Leukoaraiosis was more prevalent in AD cases. For a 5-mumol/L increase in tHcy levels, the OR for leukoaraiosis was 1.40 (95% confidence interval, 1.02-1.91) independent of other risk factors. The distribution pattern of leukoaraiosis was more marked in the deep white matter than in the periventricular area in individuals with elevated tHcy levels, particularly in patients with AD. Conclusions: Higher tHcy levels are an independent risk factor for moderate to severe leukoaraiosis in individuals with AD and of leukoaraiosis of the deep white matter in particular. The nature of the relationship between tHcy levels and leukoaraiosis in AD requires further longitudinal and intervention studies.