Original ArticlesNeuropathology-driven Whole-genome Sequencing Study Points to Novel Candidate Genes for Healthy Brain AgingAlexander, John PhD*; Ströbel, Thomas PhD†; Georgitsi, Marianthi PhD*,‡; Hönigschnabl, Selma MD§; Reiner, Angelika MD§; Fischer, Peter MD∥; Tsifintaris, Margaritis BSc*; Paschou, Peristera PhD¶; Kovacs, Gabor G. MD, PhD†Author Information *Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli ‡Department of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece †Institute of Neurology, Medical University of Vienna §Institute of Pathology, Danube Hospital of Vienna ∥Department of Psychiatry, Medical Research Society Vienna D.C., Danube Hospital, Vienna, Austria ¶Department of Biological Sciences, Purdue University, West Lafayette, IN P.P. and G.G.K. contributed equally. This study was performed in the frame of the EU FP7 Project DEVELAGE (#278486; G.G.K.). J.A.: performed the statistical analysis, interpreted findings, and wrote the manuscript. P.P. and G.G.K.: were responsible for study design, supervised analysis and interpreted findings, and wrote the manuscript. G.G.K.: supervised neuropathologic evaluations. T.S., M.T., M.G.: processed samples, performed Sanger sequencing analysis and participated in the interpretation of results and wrote the manuscript. S.H., A.R., G.G.K., and P.F.: were responsible for the VITA study including clinical, pathologic, and neuropathologic evaluations. The authors declare no conflicts of interest. Reprints: Gabor G. Kovacs, MD, PhD, Institute of Neurology, AKH 4J, Waehringer Gürtel 18-20, 1097 Vienna, Austria (e-mail: [email protected]). Alzheimer Disease & Associated Disorders: January–March 2019 - Volume 33 - Issue 1 - p 7-14 doi: 10.1097/WAD.0000000000000294 Buy SDC Metrics Abstract Purpose: Understanding the healthy brain aging process is key to uncover the mechanisms that lead to pathologic age-related neurodegeneration, including progression to Alzheimer disease (AD). We aimed to address the issue of pathologic heterogeneity that often underlies a clinical AD diagnosis. Methods: We performed a deep whole-genome sequencing study aiming to identify variants that are associated specifically with healthy brain aging. Patients: We examined samples from the community-based longitudinal Vienna Transdanubian Aging study comparing neuropathologically “healthy” aging in individuals above 80 years of age with pure AD patients of the same age. Results: Focusing on potentially functional variants, we discovered a single variant (rs10149146) that lies on the autophagy-associated TECPR2 gene and was carried by 53.6% of the “healthy” brain elderly individuals (15/28). An additional nonsynonymous variant on the CINP gene (encoding a cell cycle checkpoint protein) was also found in 46% of healthy controls. Both variants are absent from all AD cases. TECPR2 and CINP appear to be “partner” genes in terms of regulation and their associated transcription factors have been previously implicated in AD and neurodegeneration. Conclusions: Our study underlines the strength of neuropathology-driven definitions in genetic association studies and points to a potentially neuroprotective effect of key molecules of autophagy and cell cycle control. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.