Pilot Study of Second-Generation DNA Methylation Epigenetic Markers in Relation to Cognitive and Neuropsychiatric Symptoms in Older Adults

Article type: Research Article

Authors: Vyas, Chirag M.^{a; *} | Sadreyev, Ruslan I.^b | Gatchel, Jennifer R.^{a; c} | Kang, Jae H. ^d | Reynolds III, Charles F.^e | Mischoulon, David^a | Chang, Grace^f | Hazra, Aditi^g | Manson, JoAnn E.^{d; g; h} | Blacker, Deborah^{a; h} | De Vivo, Immaculata^{d; h} | Okereke, Olivia I.^{a; d; h}

Affiliations: [a] Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA | [b] Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA | [c] Division of Geriatric Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA, USA | [d] Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA | [e] Department of Psychiatry, UPMC and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA | [f] Department of Psychiatry, VA Boston Healthcare System and Harvard Medical School, Boston, MA, USA | [g] Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA | [h] Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA

Correspondence: [*] Correspondence to: Dr. Chirag M. Vyas, MBBS, MPH, Massachusetts General Hospital, One Bowdoin Square, 7th Floor, Boston, MA 02114. E-mail: cvyas@partners.org.

Abstract: Background:Associations between epigenetic aging with cognitive aging and neuropsychiatric measures are not well-understood. Objective:1) To assess cross-sectional correlations between second-generation DNA methylation (DNAm)-based clocks of healthspan and lifespan (i.e., GrimAge, PhenoAge, and DNAm-based estimator of telomere length [DNAmTL]) and cognitive and neuropsychiatric measures; 2) To examine longitudinal associations between change in DNAm markers and change in cognition over 2 years. Methods:Participants were members of VITAL-DEP (VITamin D and OmegA-3 TriaL- Depression Endpoint Prevention) study. From previously ascertained cognitive groups (i.e., cognitively normal and mild cognitive impairment), we randomly selected 45 participants, aged≥60 years, who completed in-person neuropsychiatric assessments at baseline and 2 years. The primary outcome was global cognitive score (averaging z-scores of 9 tests). Neuropsychiatric Inventory severity scores were mapped from neuropsychiatric symptoms (NPS) from psychological scales and structured diagnostic interviews. DNAm was assayed using Illumina MethylationEPIC 850K BeadChip at baseline and 2 years. We calculated baseline partial Spearman correlations between DNAm markers and cognitive and NPS measures. We constructed multivariable linear regression models to examine longitudinal relations between DNAm markers and cognition. Results:At baseline, we observed a suggestive negative correlation between GrimAge clock markers and global cognition but no signal between DNAm markers and NPS measures. Over 2 years: each 1-year increase in DNAmGrimAge was significantly associated with faster declines in global cognition; each 100-base pair increase in DNAmTL was significantly associated with better global cognition. Conclusion:We found preliminary evidence of cross-sectional and longitudinal associations between DNAm markers and global cognition.

Keywords: Alzheimer’s disease, cognition, DNA methylation, epigenetics, neuropsychiatric symptoms

DOI: 10.3233/JAD-230093

Journal: Journal of Alzheimer's Disease, vol. 93, no. 4, pp. 1563-1575, 2023