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

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

doi:10.1093/brain/awaa209

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

Brain. 2020 Aug 1;143(8):2561-2575. doi: 10.1093/brain/awaa209.

Authors

Logan Dumitrescu^{1

2}, Emily R Mahoney^{1

2}, Shubhabrata Mukherjee³, Michael L Lee³, William S Bush⁴, Corinne D Engelman⁵, Qiongshi Lu^{6

7}, David W Fardo^{8

9}, Emily H Trittschuh^{10

11}, Jesse Mez¹², Catherine Kaczorowski¹³, Hector Hernandez Saucedo¹⁴, Keith F Widaman¹⁵, Rachel Buckley^{16

17

18}, Michael Properzi¹⁶, Elizabeth Mormino¹⁹, Hyun-Sik Yang^{16

17}, Tessa Harrison²⁰, Trey Hedden²¹, Kwangsik Nho^{22

23}, Shea J Andrews²¹, Doug Tommet²⁴, Niran Hadad¹³, R Elizabeth Sanders³, Douglas M Ruderfer², Katherine A Gifford¹, Annah M Moore^{1

2}, Francis Cambronero¹, 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-Vance²⁸, Lindsay A Farrer^{12

29

30}, Li-San Wang³¹, Carlos Cruchaga³², Gerard Schellenberg³¹, Nancy J Cox², Jonathan L Haines⁴, C Dirk Keene³³, Andrew J Saykin³⁴, Eric B Larson^{3

35}, Reisa A Sperling¹⁶, Richard Mayeux^{25

26

27}, David A Bennett³⁶, Julie A Schneider³⁶, Paul K Crane³, Angela L Jefferson¹, Timothy J Hohman^{1

2}

Affiliations

¹ Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
² Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
³ Department of Medicine, University of Washington, Seattle, WA, USA.
⁴ Cleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
⁵ Department of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
⁶ Department of Statistics, University of Wisconsin-Madison, Madison, WI, USA.
⁷ Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA.
⁸ Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA.
⁹ Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
¹⁰ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA.
¹¹ VA Puget Sound Health Care System, GRECC, Seattle, WA, USA.
¹² Deparment of Neurology, Boston University School of Medicine, Boston, MA, USA.
¹³ The Jackson Laboratory, Bar Harbor, ME, USA.
¹⁴ UC Davis Alzheimer's Disease Research Center, Department of Neurology, University of California Davis Medical Center, Sacramento, CA, USA.
¹⁵ University of California at Riverside, Riverside, CA, USA.
¹⁶ Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
¹⁷ Center for Alzheimer's Research and Treatment, Department of Neurology, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA.
¹⁸ Melbourne School of Psychological Sciences, University of Melbourne, Melbourne, Australia.
¹⁹ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
²⁰ Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA.
²¹ Icahn School of Medicine at Mount Sinai, New York City, NY, USA.
²² Department of Radiology and Imaging Sciences, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
²³ Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.
²⁴ Department of Psychiatry and Human Behavior, Brown University School of Medicine, Providence, RI, USA.
²⁵ Department of Neurology, Columbia University, New York, NY, USA.
²⁶ The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University, New York, NY, USA.
²⁷ The Institute for Genomic Medicine, Columbia University Medical Center and The New York Presbyterian Hospital, New York, NY, USA.
²⁸ John P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, USA.
²⁹ Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
³⁰ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
³¹ Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
³² Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
³³ Department of Pathology, University of Washington, Seattle, WA, USA.
³⁴ Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
³⁵ Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
³⁶ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Aged, 80 and over
Aging / genetics*
Aging / pathology
Alzheimer Disease / pathology*
Brain / pathology*
Chromosomes, Human, Pair 18 / genetics
Cognitive Dysfunction / genetics*
Cognitive Reserve / physiology*
Female
Genome-Wide Association Study
Genotype
Humans
Male
Polymorphism, Single Nucleotide

Abstract

Publication types

MeSH terms

Grants and funding