Testing a Polygenic Risk Score for Morphological Microglial Activation in Alzheimer’s Disease and Aging

Article type: Research Article

Authors: Tio, Earvin S.^{a; b} | Hohman, Timothy J.^c | Milic, Milos^a | Bennett, David A.^d | Felsky, Daniel^{a; b; e; f; *} | for the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada | [b] Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada | [c] Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, USA | [d] Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA | [e] Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada | [f] Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada

Correspondence: [*] Correspondence to: Daniel Felsky, PhD, Independent Scientist, Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health; Assistant Professor, Department of Psychiatry and Dalla Lana School of Public Health, University of Toronto, 12th Floor, 250 College Street, Toronto ON, M5T 1R8, Canada. Tel.: +1 416 535 8501 /Ex: 33587; E-mail: [email protected] and [email protected].

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (https://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: https://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Background:Neuroinflammation and the activation of microglial cells are among the earliest events in Alzheimer’s disease (AD). However, direct observation of microglia in living people is not currently possible. Here, we indexed the heritable propensity for neuroinflammation with polygenic risk scores (PRS), using results from a recent genome-wide analysis of a validated post-mortem measure of morphological microglial activation. Objective:We sought to determine whether a PRS for microglial activation (PRSmic) could augment the predictive performance of existing AD PRSs for late-life cognitive impairment. Methods:First, PRSmic were calculated and optimized in a calibration cohort (Alzheimer’s Disease Neuroimaging Initiative (ADNI), n = 450), with resampling. Second, predictive performance of optimal PRSmic was assessed in two independent, population-based cohorts (total n = 212,237). Finally, we explored associations of PRSmic with a comprehensive set of imaging and fluid AD biomarkers in ADNI. Results:Our PRSmic showed no significant improvement in predictive power for either AD diagnosis or cognitive performance in either external cohort. Some nominal associations were found in ADNI, but with inconsistent effect directions. Conclusion:While genetic scores capable of indexing risk for neuroinflammatory processes in aging are highly desirable, more well-powered genome-wide studies of microglial activation are required. Further, biobank-scale studies would benefit from phenotyping of proximal neuroinflammatory processes to improve the PRS development phase.

Keywords: Alzheimer’s disease, Canadian Longitudinal Study on Aging, computational modelling, microglial cell, neuroinflammation, polygenic traits, statistical data analysis

DOI: 10.3233/JAD-230434

Journal: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1549-1561, 2023