Longitudinal change in memory performance as a strong endophenotype for Alzheimer's disease

Derek B Archer; Jaclyn M Eissman; Shubhabrata Mukherjee; Michael L Lee; Seo-Eun Choi; Phoebe Scollard; Emily H Trittschuh; Jesse B Mez; William S Bush; Brian W Kunkle; Adam C Naj; Katherine A Gifford; Alzheimer's Disease Neuroimaging Initiative (ADNI); Alzheimer's Disease Genetics Consortium (ADGC); Alzheimer's Disease Sequencing Project (ADSP); Michael L Cuccaro; Margaret A Pericak-Vance; Lindsay A Farrer; Li-San Wang; Gerard D Schellenberg; Richard P Mayeux; Jonathan L Haines; Angela L Jefferson; Walter A Kukull; C Dirk Keene; Andrew J Saykin; Paul M Thompson; Eden R Martin; David A Bennett; Lisa L Barnes; Julie A Schneider; Paul K Crane; Logan Dumitrescu; Timothy J Hohman

doi:10.1002/alz.13508

Longitudinal change in memory performance as a strong endophenotype for Alzheimer's disease

Alzheimers Dement. 2024 Feb;20(2):1268-1283. doi: 10.1002/alz.13508. Epub 2023 Nov 20.

Authors

Derek B Archer^{1

2}, Jaclyn M Eissman^{1

2}, Shubhabrata Mukherjee³, Michael L Lee³, Seo-Eun Choi³, Phoebe Scollard³, Emily H Trittschuh^{4

5}, Jesse B Mez⁶, William S Bush⁷, Brian W Kunkle⁸, Adam C Naj^{9

10}, Katherine A Gifford¹; Alzheimer's Disease Neuroimaging Initiative (ADNI); Alzheimer's Disease Genetics Consortium (ADGC); Alzheimer's Disease Sequencing Project (ADSP); Michael L Cuccaro⁸, Margaret A Pericak-Vance⁸, Lindsay A Farrer^{6

11

12}, Li-San Wang¹⁰, Gerard D Schellenberg¹⁰, Richard P Mayeux^{13

14

15}, Jonathan L Haines⁷, Angela L Jefferson¹, Walter A Kukull¹⁶, C Dirk Keene¹⁷, Andrew J Saykin^{18

19

20}, Paul M Thompson²¹, Eden R Martin⁸, David A Bennett²², Lisa L Barnes²², Julie A Schneider²², Paul K Crane³, Logan Dumitrescu^{1

2}, Timothy J Hohman^{1

2}

Affiliations

¹ Vanderbilt Memory & Alzheimer's Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
² Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³ Department of Medicine, University of Washington, Seattle, Washington, USA.
⁴ Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
⁵ VA Puget Sound Health Care System, GRECC, Seattle, Washington, USA.
⁶ Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
⁷ Cleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
⁸ John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA.
⁹ Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹⁰ Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹¹ Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.
¹² Department of Medicine (Biomedical Genetics), Boston University Chobanian & Avedisian School of Medicine, Boston, Massachusetts, USA.
¹³ Columbia University, New York, New York, USA.
¹⁴ The Taub Institute for Research on Alzheimer's Disease and The Aging Brain, Columbia University, New York, New York, USA.
¹⁵ The Institute for Genomic Medicine, Columbia University Medical Center and The New York Presbyterian Hospital, New York, New York, USA.
¹⁶ Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA.
¹⁷ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.
¹⁸ Department of Radiology and Imaging Services, Indiana University School of Medicine, Indianapolis, Indiana, USA.
¹⁹ Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, Indiana, USA.
²⁰ Indiana Alzheimer's Disease Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.
²¹ Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey, California, USA.
²² Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.

Abstract

Introduction: Although large-scale genome-wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline.

Methods: We conducted a cross-ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts.

Results: We found high heritability for two ancestry backgrounds. Further, we found a novel ancestry locus for memory decline on chromosome 4 (rs6848524) and three loci in the non-Hispanic Black ancestry group for memory performance on chromosomes 2 (rs111471504), 7 (rs4142249), and 15 (rs74381744). In our gene-level analysis, we found novel genes for memory decline on chromosomes 1 (SLC25A44), 11 (BSX), and 15 (DPP8). Memory performance and memory decline shared genetic architecture with AD-related traits, neuropsychiatric traits, and autoimmune traits.

Discussion: We discovered several novel loci, genes, and genetic correlations associated with late-life memory performance and decline.

Highlights: Late-life memory has high heritability that is similar across ancestries. We discovered four novel variants associated with late-life memory. We identified four novel genes associated with late-life memory. Late-life memory shares genetic architecture with psychiatric/autoimmune traits.

Keywords: Alzheimer's disease; GWAS; genetics; memory.

MeSH terms

Alzheimer Disease* / genetics
Cognition
Endophenotypes
Genetic Predisposition to Disease / genetics
Genome-Wide Association Study
Humans
Memory Disorders / genetics
Polymorphism, Single Nucleotide / genetics

Abstract

MeSH terms

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