Anti‐N‐homocysteine‐protein autoantibodies are associated with impaired cognition

INTRODUCTION: Elevated homocysteine (Hcy) and related metabolites accelerate Alzheimer's disease. Hcy‐lowering B vitamins slow brain atrophy/cognitive decline in mild cognitive impairment (MCI). Modification with Hcy‐thiolactone generates auto‐immunogenic N‐Hcy‐protein. We tested a hypothesis that anti‐N‐Hcy‐protein autoantibodies predict cognition in individuals with MCI participating in a randomized, double‐blind, placebo‐controlled VITACOG trial of B vitamins. METHODS: Participants with MCI (n = 196, 76.8 years old, 60% women) were randomly assigned to receive a daily dose of folic acid (0.8 mg), vitamin B(12) (0.5 mg), and B(6) (20 mg) (n = 98) or placebo (n = 98) for 2 years. Cognition was analyzed by neuropsychological tests. Brain atrophy was quantified in a subset of patients (n = 167) by magnetic resonance imaging. Anti N‐Hcy‐protein auto‐antibodies were quantified by enzyme‐linked immunosorbent assay. Associations among anti‐N‐Hcy‐protein autoantibodies, cognition, and brain atrophy were examined by multiple regression analysis. RESULTS: At baseline, anti‐N‐Hcy‐protein autoantibodies were significantly associated with impaired global cognition (Mini‐Mental State Examination [MMSE]), episodic memory (Hopkins Verbal Learning Test‐revised), and attention/processing speed (Map Search). At the end of the study, anti‐N‐Hcy‐protein autoantibodies were associated with impaired global cognition (MMSE) and attention/processing speed (Trail Making A). In the placebo group, baseline anti‐N‐Hcy‐protein autoantibodies predicted, independently of Hcy, global cognition (Telephone Inventory for Cognitive Status modified [TICS‐m]; MMSE) and attention/processing speed (Trail Making A) but not brain atrophy, at the end of study. B‐vitamin treatment abrogated association of anti‐N‐Hcy‐protein autoantibodies with cognition. DISCUSSION: These findings suggest that anti‐N‐Hcy‐protein autoantibodies can impair functional (attention/processing speed and global cognition), but not structural (brain atrophy), aspects of cognition. Anti‐N‐Hcy‐protein autoantibodies are a new factor associated with impaired cognition, which could be ameliorated by B vitamins.