Pathogenic variants in the Longitudinal Early-onset Alzheimer's Disease Study cohort

Kelly N H Nudelman; Trever Jackson; Malia Rumbaugh; Ani Eloyan; Marco Abreu; Jeffrey L Dage; Casey Snoddy; Kelley M Faber; Tatiana Foroud; Dustin B Hammers; DIAN/DIAN-TU Clinical/Genetics Committee; Alexander Taurone; Maryanne Thangarajah; Paul Aisen; Laurel Beckett; Joel Kramer; Robert Koeppe; Walter A Kukull; Melissa E Murray; Arthur W Toga; Prashanthi Vemuri; Alireza Atri; Gregory S Day; Ranjan Duara; Neill R Graff-Radford; Lawrence S Honig; David T Jones; Joseph C Masdeu; Mario Mendez; Erik Musiek; Chiadi U Onyike; Meghan Riddle; Emily Rogalski; Stephen Salloway; Sharon J Sha; R Scott Turner; Thomas S Wingo; David A Wolk; Maria C Carrillo; Bradford C Dickerson; Gil D Rabinovici; Liana G Apostolova; LEADS Consortium

doi:10.1002/alz.13482

Pathogenic variants in the Longitudinal Early-onset Alzheimer's Disease Study cohort

Alzheimers Dement. 2023 Nov;19 Suppl 9(Suppl 9):S64-S73. doi: 10.1002/alz.13482. Epub 2023 Oct 6.

Authors

Kelly N H Nudelman^{1

2}, Trever Jackson¹, Malia Rumbaugh¹, Ani Eloyan³, Marco Abreu¹, Jeffrey L Dage^{1

2

4}, Casey Snoddy¹, Kelley M Faber¹, Tatiana Foroud^{1

2}, Dustin B Hammers⁴; DIAN/DIAN-TU Clinical/Genetics Committee^{5

6

7}; Alexander Taurone³, Maryanne Thangarajah³, Paul Aisen⁸, Laurel Beckett⁹, Joel Kramer¹⁰, Robert Koeppe¹¹, Walter A Kukull¹², Melissa E Murray¹³, Arthur W Toga¹⁴, Prashanthi Vemuri¹⁵, Alireza Atri¹⁶, Gregory S Day¹⁷, Ranjan Duara¹⁸, Neill R Graff-Radford¹⁷, Lawrence S Honig¹⁹, David T Jones^{15

20}, Joseph C Masdeu²¹, Mario Mendez²², Erik Musiek²³, Chiadi U Onyike²⁴, Meghan Riddle²⁵, Emily Rogalski²⁶, Stephen Salloway²⁵, Sharon J Sha²⁷, R Scott Turner²⁸, Thomas S Wingo²⁹, David A Wolk³⁰, Maria C Carrillo³¹, Bradford C Dickerson³², Gil D Rabinovici¹⁰, Liana G Apostolova^{2

4

8

33}; LEADS Consortium

Affiliations

¹ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
² Indiana Alzheimer's Disease Research Center, Indianapolis, Indiana, USA.
³ Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, Rhode Island, USA.
⁴ Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁵ Washington University School of Medicine, St. Louis, Missouri, USA.
⁶ Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁷ Mayo Clinic College of Medicine, Jacksonville, Florida, USA.
⁸ Alzheimer's Therapeutic Research Institute, University of Southern California, San Diego, California, USA.
⁹ Department of Public Health Sciences, University of California - Davis, Davis, California, USA.
¹⁰ Department of Neurology, University of California - San Francisco, San Francisco, California, USA.
¹¹ Department of Radiology, University of Michigan, Ann Arbor, Michigan, USA.
¹² Department of Epidemiology, University of Washington, Seattle, Washington, USA.
¹³ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
¹⁴ Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, California, USA.
¹⁵ Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁶ Banner Sun Health Research Institute, Sun City, Arizona, USA.
¹⁷ Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
¹⁸ Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami, Florida, USA.
¹⁹ Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
²⁰ Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA.
²¹ Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, Texas, USA.
²² Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
²³ Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.
²⁴ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
²⁵ Department of Neurology, Alpert Medical School, Brown University, Providence, Rhode Island, USA.
²⁶ Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer's Disease, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
²⁷ Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, California, USA.
²⁸ Department of Neurology, Georgetown University, Washington D.C., USA.
²⁹ Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
³⁰ Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³¹ Medical & Scientific Relations Division, Alzheimer's Association, Chicago, Illinois, USA.
³² Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
³³ Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, Indiana, USA.

Abstract

Introduction: One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants.

Methods: LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study.

Results: Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases.

Discussion: Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases.

Highlights: Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.

Keywords: APP; Alzheimer's disease; C9ORF7; GRN; MAPT; PSEN1; PSEN2; dementia; early onset; genetics; sequencing.

Publication types

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

MeSH terms

Alzheimer Disease* / genetics
Amyloid beta-Protein Precursor / genetics
C9orf72 Protein / genetics
Genetic Testing
Humans
Longitudinal Studies
Mutation
Presenilin-1 / genetics
Presenilin-2 / genetics

Substances

Amyloid beta-Protein Precursor
C9orf72 Protein
Presenilin-1
Presenilin-2

Abstract

Publication types

MeSH terms

Substances

Grants and funding