Unraveling Homocysteine's Role in Dementia: No Specific Association with Alzheimer's Disease, but a Connection to White Matter Hyperintensities

Hyperhomocysteinemia (HHcy) is an established risk factor for cognitive impairment. The specific role of HHcy in the pathophysiology of Alzheimer's disease (AD) is debated, as most of the suspected mechanisms overlap with those of vascular dementia (VD). The aim of this study was to explore the association between plasma homocysteine (Hcy) levels and cerebrospinal fluid (CSF) biomarkers of AD, as well as brain magnetic resonance imaging (MRI) features. Cross-sectional observational analysis from a single-center tertiary memory clinic. We first assessed the association between Hcy in tertiles and the CSF AD biomarkers (according to the Amyloid (A) Tau (T) Neurodegeneration (N) classification) with further adjustments for age and sex. Then, we analyzed the relationship between HHcy and hippocampal atrophy (Scheltens scale) and white matter lesions (WML) (Fazekas scale) on brain MRI. We included 507 patients [mean age 68.9 (standard deviation=8.9)] with mean plasma Hcy at 13.3 (4.7) µmol/L in this study. There was no significant association between Hcy tertiles and CSF AD biomarkers. Plasma Hcy levels showed no correlation with any CSF AD biomarkers. The severity of WML increased with higher Hcy tertiles (p<0.0001). Patients with a CSF AD (A+T+) profile exhibited elevated mean Hcy levels when they presented moderate to severe WML (p<0.0001). Our findings challenge the link between Hcy and AD pathophysiology while highlighting a significant connection between Hcy and microvascular cognitive impairment. Further longitudinal studies are needed to validate these conclusions.