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

Abstract

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 autoimmunogenic 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-Hcyprotein 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.

Paraoxonase 1, B Vitamins Supplementation, and Mild Cognitive Impairment

“…Iron and other metals [ 52 ], triglycerides and fatty acids [ 53 ] have been postulated to affect cognition in AD. The association of anti- N -Hcy autoantibodies with cognition in MCI has been previously reported [ 42 ]. Value of these variables as predictors of cognitive decline in MCI patients need to be confirmed in larger studies.…”

“…Values for serum anti- N -Hcy-protein autoantibodies [ 42 ], plasma total homocysteine (tHcy), and other metabolites [ 5 ] were obtained from analyses reported previously.…”

Homocysteine Thiolactone: Biology and Chemistry

“…N-homocysteinylated proteins exhibit biological responses, including cytotoxicity, immune activation (anti-N-homocysteinylated proteins IgG antibodies), and atherothrombosis [31,48]. Anti-N-homocysteinylated protein autoantibodies can be beneficial by clearing damaged proteins from circulation.…”

“…The macrophages will bind to the complex and digest it, causing damage to the vascular wall and tissue damage. If this process were to occur in brain vasculature, it would result in cognitive domain-specific outcomes depending on which brain region was damaged [48]. Thus, anti-N-homocysteinylated protein autoantibodies can impair functional, but not structural, aspects of cognition [48].…”

“…If this process were to occur in brain vasculature, it would result in cognitive domain-specific outcomes depending on which brain region was damaged [48]. Thus, anti-N-homocysteinylated protein autoantibodies can impair functional, but not structural, aspects of cognition [48]. The authors [48] suggest anti-N-homocysteinylated protein autoantibodies as a risk factor for cognitive impairment.…”