Background: Identification of modifiable risk factors that affect cognitive decline is important for the development of preventive and treatment strategies. Status of paraoxonase 1 (PON1), a high-density lipoprotein-associated enzyme, may play a role in the development of neurological diseases, including Alzheimer’s disease. Objective: We tested a hypothesis that PON1 status predicts cognition in individuals with mild cognitive impairment (MCI). Methods: Individuals with MCI (n = 196, 76.8-years-old, 60% women) participating in a randomized, double-blind placebo-controlled trial (VITACOG) were assigned to receive a daily dose of folic acid (0.8 mg), vitamin B12 (0.5 mg) and B6 (20 mg) (n = 95) or placebo (n = 101) for 2 years. Cognition was analyzed by neuropsychological tests. Brain atrophy was quantified in a subset of participants (n = 168) by MRI. PON1 status, including PON1 Q192R genotype, was determined by quantifying enzymatic activity of PON1 using paraoxon and phenyl acetate as substrates. Results: In the placebo group, baseline phenylacetate hydrolase (PhAcase) activity of PON1 (but not paraoxonase activity or PON1 Q192R genotype) was significantly associated with global cognition (Mini-Mental State Examination, MMSE; Telephone Inventory for Cognitive Status-modified, TICS-m), verbal episodic memory (Hopkins Verbal Learning Test-revised: Total Recall, HVLT-TR; Delayed Recall, HVLT-DR), and attention/processing speed (Trail Making A and Symbol Digits Modalities Test, SDMT) at the end of study. In addition to PhAcase, baseline iron and triglycerides predicted MMSE, baseline fatty acids predicted SDMT, baseline anti-N-Hcy-protein autoantibodies predicted TICS-m, SDMT, Trail Making A, while BDNF V66M genotype predicted HVLT-TR and HVLT-DR scores at the end of study. B-vitamins abrogated associations of PON1 and other variables with cognition. Conclusion: PON1 is a new factor associated with impaired cognition that can be ameliorated by B-vitamins in individuals with MCI.

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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.