Genetic variants and functional pathways associated with resilience to Alzheimer's disease

Logan Dumitrescu 1 2, Emily R Mahoney 1 2, Shubhabrata Mukherjee 3, Michael L Lee 3, William S Bush 4, Corinne D Engelman 5, Qiongshi Lu 6 7, David W Fardo 8 9, Emily H Trittschuh 10 11, Jesse Mez 12, Catherine Kaczorowski 13, Hector Hernandez Saucedo 14, Keith F Widaman 15, Rachel Buckley 16 17 18, Michael Properzi 16, Elizabeth Mormino 19, Hyun-Sik Yang 16 17, Tessa Harrison 20, Trey Hedden 21, Kwangsik Nho 22 23, Shea J Andrews 21, Doug Tommet 24, Niran Hadad 13, R Elizabeth Sanders 3, Douglas M Ruderfer 2, Katherine A Gifford 1, Annah M Moore 1 2, Francis Cambronero 1, Xiaoyuan Zhong 6 7, Neha S Raghavan 25 26 27, Badri Vardarajan 25 26 27, Alzheimer’s Disease Neuroimaging Initiative (ADNI); Alzheimer’s Disease Genetics Consortium (ADGC), A4 Study Team; Margaret A Pericak-Vance 28, Lindsay A Farrer 12 29 30, Li-San Wang 31, Carlos Cruchaga 32, Gerard Schellenberg 31, Nancy J Cox 2, Jonathan L Haines 4, C Dirk Keene 33, Andrew J Saykin 34, Eric B Larson 3 35, Reisa A Sperling 16, Richard Mayeux 25 26 27, David A Bennett 36, Julie A Schneider 36, Paul K Crane 3, Angela L Jefferson 1, Timothy J Hohman 1 2

Affiliations

PMID: 32844198
PMCID: PMC7447518
DOI: 10.1093/brain/awaa209

Free PMC article

Abstract

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer's disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired 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 modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer's disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired 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 Alzheimer's disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 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 of ATPB81 (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 Alzheimer's disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.

Keywords: Alzheimer’s disease; GWAS; amyloid; reserve; resilience.