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

Author:

Dumitrescu Logan12ORCID,Mahoney Emily R12,Mukherjee Shubhabrata3,Lee Michael L3ORCID,Bush William S4ORCID,Engelman Corinne D5,Lu Qiongshi67ORCID,Fardo David W89,Trittschuh Emily H1011,Mez Jesse12,Kaczorowski Catherine13,Hernandez Saucedo Hector14,Widaman Keith F15,Buckley Rachel161718,Properzi Michael16,Mormino Elizabeth19,Yang Hyun-Sik1617,Harrison Tessa20,Hedden Trey21,Nho Kwangsik2223,Andrews Shea J21,Tommet Doug24,Hadad Niran13,Sanders R Elizabeth3,Ruderfer Douglas M2,Gifford Katherine A1,Moore Annah M12,Cambronero Francis1,Zhong Xiaoyuan67,Raghavan Neha S252627,Vardarajan Badri252627,Pericak-Vance Margaret A28,Farrer Lindsay A122930,Wang Li-San31,Cruchaga Carlos32,Schellenberg Gerard31,Cox Nancy J2,Haines Jonathan L4,Keene C Dirk33,Saykin Andrew J34,Larson Eric B335,Sperling Reisa A16,Mayeux Richard252627,Bennett David A36,Schneider Julie A36,Crane Paul K3,Jefferson Angela L1,Hohman Timothy J12, ,

Affiliation:

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

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.

Funder

NIH

National Institute on Aging

Howard Hughes Medical Institute James H. Gilliam Fellowship for Advanced Study

FEC

Vanderbilt Memory & Alzheimer’s Center

NIA

NINDS

CurePSP Foundation

Mayo Foundation

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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