Genetic Variants and Functional Pathways Associated with Resilience to Alzheimer’s Disease
Authors: Dumitrescu Logan , Mahoney Emily R. , Mukherjee Shubhabrata , Lee Michael L. , Bush William S. , Engelman Corinne D. , Lu Qiongshi , Fardo David W. , Trittschuh Emily H. , Mez Jesse , Kaczorowski Catherine , Saucedo Hector Hernandez , Widaman Keith F. , Buckley Rachel , Properzi Michael , Mormino Elizabeth , Yang Hyun-Sik , Harrison Tessa , Hedden Trey , Nho Kwangsik , Andrews Shea J. , Tommet Doug , Hadad Niran , Sanders R. Elizabeth , Ruderfer Douglas M. , Gifford Katherine A. , Moore Annah M. , Cambronero Francis , Zhong Xiaoyuan , Raghavan Neha S. , Vardarajan Badri ,   The Alzheimer’s Disease Neuroimaging Initiative (ADNI),   Alzheimer’s Disease Genetics Consortium (ADGC), A4 Study Team, Pericak-Vance Margaret A. , Farrer Lindsay A. , Wang Li-San , Cruchaga Carlos , Schellenberg Gerard , Cox Nancy J. , Haines Jonathan L. , Keene C. Dirk , Saykin Andrew J. , Larson Eric B. , Sperling Reisa A. , Mayeux Richard , Bennett David A. , Schneider Julie A. , Crane Paul K. , Jefferson Angela L. , Hohman Timothy J. 
Published: February 2020

Approximately 30% of older adults exhibit the neuropathologic features of Alzheimer’s disease (AD) without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively normal in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modeling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5,108 participants from a clinical trial of AD and three longitudinal cohort studies of cognitive aging. All analyses were run across all participants and repeated restricting the sample to individuals with normal cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (p-values<2.5×10−20), and we observed novel correlations with neuropsychiatric conditions (p-values<7.9×10−4). Notably, neither resilience metric was genetically correlated with clinical AD (p-values>0.42) nor associated withAPOE(p-values>0.13). In single variant analyses, we observed a genome-wide significant locus among participants with normal cognition on chromosome 18 upstream ofATP8B1(index SNP rs2571244, MAF=0.08, p=2.3×10−8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream ofATPB81(cg19596477; p=2×10−13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway.

Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical AD, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.