Review

. 2023 Nov;19 Suppl 9(Suppl 9):S64-S73.

doi: 10.1002/alz.13482. Epub 2023 Oct 6.

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

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.

PMID: 37801072
PMCID: PMC10783439
DOI: 10.1002/alz.13482

Review

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

Kelly N H Nudelman et al. Alzheimers Dement. 2023 Nov.

. 2023 Nov;19 Suppl 9(Suppl 9):S64-S73.

doi: 10.1002/alz.13482. Epub 2023 Oct 6.

Authors

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.

PMID: 37801072
PMCID: PMC10783439
DOI: 10.1002/alz.13482

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.

PubMed Disclaimer

Conflict of interest statement

Dr. Dage is an inventor on patents or patent applications of Eli Lilly and Company relating to the assays, methods, reagents and / or compositions of matter related to measurement of P-tau217. Dr. Dage has served as a consultant for Abbvie, Genotix Biotechnologies Inc, Gates Ventures, Karuna Therapeutics, AlzPath Inc, Cognito Therapeutics, Inc., and received research support from ADx Neurosciences, Fujirebio, AlzPath Inc, Roche Diagnostics and Eli Lilly and Company in the past two years. Dr. Dage is serving on a scientific advisory board for Eisai. Dr. Dage has received speaker fees from Eli Lilly and Company.

Dr. Day is supported by NIH (K23AG064029, U01AG057195, U19AG032438), the Alzheimer’s Association, and Chan Zuckerberg Initiative. He serves as a consultant for Parabon Nanolabs Inc, as a Topic Editor (Dementia) for DynaMed (EBSCO), and as the Clinical Director of the Anti-NMDA Receptor Encephalitis Foundation (Inc, Canada; uncompensated). He is the co-Project PI for a clinical trial in anti-NMDAR encephalitis, which receives support from Horizon Pharmaceuticals. He has developed educational materials for PeerView Media, Inc, and Continuing Education Inc. He owns stock in ANI pharmaceuticals. Dr. Day’s institution has received support from Eli Lilly for Dr. Day’s development and participation in an educational event promoting early diagnosis of symptomatic Alzheimer disease.

Dr. Wingo is as a co-founder of revXon.

Dr. Apostolova has received personal compensation for serving as a consultant for Biogen, Two Labs, FL Dept Health, Genetech, NIH Biobank, Eli Lilly, GE Healthcare, Eisai, Roche Diagnostics, and for serving on a Data Safety and Monitoring Board for IQVIA. Dr. Apostolova receives research support from the National Institute on Aging, the Alzheimer’s Association, Roche Diagnostics, AVID radiopharmaceuticals, Life Molecular Imaging, and Eli Lilly.

All other authors had nothing to report.

Figures

**Figure 1.. Pie Chart of EOAD and EOnonAD Pathogenic Variant Carriers.**
Percentages of LEADS EOAD participants carrying a *PSEN1* previously reported pathogenic variant and non-carriers (left) and LEADS EOnonAD participants carrying a *GRN*, *C9ORF72,* or *MAPT* previously reported pathogenic variant and non-carriers (right). Screening did not identify any *APP* or *PSEN2* pathogenic variant carriers.

**Figure 2.. Pie Chart of *APOE e4* Allele Carriers and Non-Carriers.**
Participant counts and percentages of LEADS EOAD and EOnonAD pathogenic variant carriers and non-carriers, as well as PPMI controls, carrying one or two *APOE e4* alleles (blue) compared to individuals with no *APOE e4* alleles (orange).

See this image and copyright information in PMC

References

1. Wingo TS, Lah JJ, Levey AI, Cutler DJ. Autosomal recessive causes likely in early-onset Alzheimer disease. Arch Neurol. 2012;69:59–64. - PMC - PubMed
1. Greaves CV, Rohrer JD. An update on genetic frontotemporal dementia. J Neurol. 2019;266:2075–86. - PMC - PubMed
1. Apostolova LG, Aisen P, Eloyan A, Fagan A, Fargo KN, Foroud T, et al. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS): Framework and methodology. Alzheimers Dement. 2021;17:2043–55. - PMC - PubMed
1. Jack CR Jr., Knopman DS, Chetelat G, Dickson D, Fagan AM, Frisoni GB, et al. Suspected non-Alzheimer disease pathophysiology--concept and controversy. Nat Rev Neurol. 2016;12:117–24. - PMC - PubMed
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Pathogenic variants in the Longitudinal Early-onset Alzheimer's Disease Study cohort

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

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