Genome-wide association study of rate of cognitive decline in Alzheimer's disease patients identifies novel genes and pathways

Richard Sherva; Alden Gross; Shubhabrata Mukherjee; Ryan Koesterer; Philippe Amouyel; Celine Bellenguez; Carole Dufouil; David A Bennett; Lori Chibnik; Carlos Cruchaga; Jorge Del-Aguila; Lindsay A Farrer; Richard Mayeux; Leanne Munsie; Ashley Winslow; Stephen Newhouse; Andrew J Saykin; John S K Kauwe; Alzheimer's Disease Genetics Consortium; Paul K Crane; Robert C Green

doi:10.1002/alz.12106

Genome-wide association study of rate of cognitive decline in Alzheimer's disease patients identifies novel genes and pathways

Alzheimers Dement. 2020 Aug;16(8):1134-1145. doi: 10.1002/alz.12106. Epub 2020 Jun 23.

Authors

Richard Sherva¹, Alden Gross², Shubhabrata Mukherjee³, Ryan Koesterer⁴, Philippe Amouyel^{5

6

7}, Celine Bellenguez^{5

6

7}, Carole Dufouil⁸, David A Bennett^{9

10}, Lori Chibnik^{11

12}, Carlos Cruchaga^{13

14

15

16}, Jorge Del-Aguila^{13

14

15

16}, Lindsay A Farrer^{1

17

18

19

20

21}, Richard Mayeux^{22

23

24}, Leanne Munsie²⁵, Ashley Winslow²⁶, Stephen Newhouse^{27

28

29

30

31}, Andrew J Saykin³², John S K Kauwe³³; Alzheimer's Disease Genetics Consortium¹; Paul K Crane³, Robert C Green^{34

35

36

37}

Affiliations

¹ Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts, USA.
² Johns Hopkins Bloomberg School of Public Health, Johns Hopkins Center on Aging and Health, Baltimore, Maryland, USA.
³ Department of Medicine, University of Washington, Seattle, Washington, USA.
⁴ Programs in Metabolism and Medical & Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
⁵ Inserm, CHU Lille, Institute Pasteur de Lille, U1167 - RID-AGE - Risk factors and molecular determinants of age-related diseases; Institute Pasteur de Lille, University of Lille, Lille Cedex, France.
⁶ Institut Pasteur de Lille, Lille, France.
⁷ DISTALZ Laboratory of Excellence (LabEx), University of Lille, Lille, France.
⁸ Inserm Unit 1219 Bordeaux Population Health, CIC 1401-EC (Clinical Epidemiology), University of Bordeaux, ISPED (Bordeaux School of Public Health), Bordeaux University Hospital, Bordeaux, France.
⁹ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
¹⁰ Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
¹¹ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
¹² Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
¹³ Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁴ Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁵ Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁶ NeuroGenomics and Informatics, Washington University School of Medicine, Saint Louis, USA.
¹⁷ Bioinformatics Graduate Program, Boston University, Boston, Massachusetts, USA.
¹⁸ Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.
¹⁹ Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
²⁰ Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, USA.
²¹ Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA.
²² Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA.
²³ The Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
²⁴ Department of Neurology, College of Physicians and Surgeons, New York-Presbyterian Hospital, Columbia University Medical Center, New York, New York, USA.
²⁵ Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA.
²⁶ Orphan Disease Center, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, Pennsylvania, USA.
²⁷ Department of Biostatistics and Health Informatics, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
²⁸ NIHR BioResource Centre Maudsley, Psychology and Neuroscience (IoPPN), King's College London, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, London, UK.
²⁹ Health Data Research UK London, University College London, London, UK.
³⁰ Institute of Health Informatics, University College London, London, UK.
³¹ The National Institute for Health Research University College London Hospitals Biomedical Research Centre, University College London, London, UK.
³² Indiana Alzheimer Disease Center and Department of Radiology and Imaging Sciences, IU Health Neuroscience Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.
³³ Department of Biology, Brigham Young University, Provo, Utah, USA.
³⁴ Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
³⁵ The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
³⁶ Harvard Medical School, Boston, Massachusetts, USA.
³⁷ Partners HealthCare Personalized Medicine, Boston, Massachusetts, USA.

Abstract

Introduction: Variability exists in the disease trajectories of Alzheimer's disease (AD) patients. We performed a genome-wide association study to examine rate of cognitive decline (ROD) in patients with AD.

Methods: We tested for interactions between genetic variants and time since diagnosis to predict the ROD of a composite cognitive score in 3946 AD cases and performed pathway analysis on the top genes.

Results: Suggestive associations (P < 1.0 × 10^-6 ) were observed on chromosome 15 in DNA polymerase-γ (rs3176205, P = 1.11 × 10^-7 ), chromosome 7 (rs60465337,P = 4.06 × 10^-7 ) in contactin-associated protein-2, in RP11-384F7.1 on chromosome 3 (rs28853947, P = 5.93 × 10^-7 ), family with sequence similarity 214 member-A on chromosome 15 (rs2899492, P = 5.94 × 10^-7 ), and intergenic regions on chromosomes 16 (rs4949142, P = 4.02 × 10^-7 ) and 4 (rs1304013, P = 7.73 × 10^-7 ). Significant pathways involving neuronal development and function, apoptosis, memory, and inflammation were identified.

Discussion: Pathways related to AD, intelligence, and neurological function determine AD progression, while previously identified AD risk variants, including the apolipoprotein (APOE) ε4 and ε2 variants, do not have a major impact.

Keywords: cognitive decline; disease progression; genetic association; pathway analysis.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease / complications*
Alzheimer Disease / genetics*
Cognitive Dysfunction / etiology*
Cognitive Dysfunction / genetics*
Disease Progression
Female
Genetic Variation
Genome-Wide Association Study
Humans
Male

Abstract

Publication types

MeSH terms

Grants and funding