Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease
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Abstract
Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70% 1 . The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants 2 . Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in TREM2 , SORL1 and ABCA7 , we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10 . Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.
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Genome-wide association studies and high-throughput sequencing have led to the characterization of 76 loci associated with AD risk.
“leading to the characterization of 76 loci associated with the AD risk6–8”
From PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures (2026) · cites this paper as [7]
The Main section says GWAS identified 75 AD-risk loci in populations with European ancestry and that DNA sequencing identified additional rare risk variants. It does not support the claimed count of 76 loci. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRare variants in ABCA1 increase the risk of developing Alzheimer's disease.
“Rare variants in ABCA1 increase the risk of developing Alzheimer's disease (AD).”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [5]
The ABCA1 gene is a novel genetic risk factor for AD.
“Recently, however, the ABCA1 gene was identified as a novel genetic risk factor for AD. 5 , 6”
From Deletion of miR-33, a regulator of the ABCA1–APOE pathway, ameliorates neuropathological phenotypes in APP/PS1 mice (2024) · cites this paper as [5]
The discovery of disease-relevant alleles that map to two well-studied ATP-dependent lipid pumps, ABCA1 and ABCA7, highlights a potential role for extracellular LNP modification.
“The discovery of disease-relevant alleles that map to two well-studied ATP-dependent lipid pumps, ABCA1 and ABCA7,55, 56 highlights a potential role for extracellular LNP modification.”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [55]
In the SRC gene, loss-of-function variants and missense variants with a REVEL score >50 were jointly associated with AD risk (OR = 4.23, 95% CI = 2.04-8.79, P = 1.06 × 10−4) in the ADES-ADSP summary statistics.
“In the SRC gene, loss-of-function variants and missense variants with a REVEL score of >50 were jointly associated with AD risk (odds ratio (OR) = 4.23, 95% confidence interval (CI) = 2.04–8.79, P = 1.06 × 10−4; Supplementary Table 8) in the Alzheimer Disease European Sequencing (ADES) - Alzheimer’s Disease Sequencing Project (ADSP) summary statistics10.”
From Consensus meta-analysis of genome-wide association studies for Alzheimer’s disease and related dementias (2026) · cites this paper as [10]
The Main section describes testing combined loss-of-function and REVEL-scored missense variants, but the passages found do not report a result for SRC. Searches for SRC, ADES–ADSP, OR 4.23, the stated confidence interval, and P = 1.06 × 10−4 found no passage supporting the specific association. (LLM, conf=0.76)
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- Authors
- Holstege, H., Hulsman, M., Charbonnier, C., Grenier-Boley, B., Quenez, O., Grozeva, D., van Rooij, J. G. J., Sims, R., Ahmad, S., Amin, N., Norsworthy, P. J., Dols-Icardo, O., Hummerich, H., Kawalia, A., Amouyel, P., Beecham, G. W., Berr, C., Bis, J. C., Boland, A., Bossù, P., Bouwman, F., Bras, J., Campion, D., Cochran, J. N., Daniele, A., Dartigues, J.-F., Debette, S., Deleuze, J.-F., Denning, N., DeStefano, A. L., Farrer, L. A., Fernández, M. V., Fox, N. C., Galimberti, D., Genin, E., Gille, J. J. P., Le Guen, Y., Guerreiro, R., Haines, J. L., Holmes, C., Ikram, M. A., Ikram, M. K., Jansen, I. E., Kraaij, R., Lathrop, M., Lemstra, A. W., Lleó, A., Luckcuck, L., Mannens, M. M. A. M., Marshall, R., Martin, E. R., Masullo, C., Mayeux, R., Mecocci, P., Meggy, A., Mol, M. O., Morgan, K., Myers, R. M., Nacmias, B., Naj, A. C., Napolioni, V., Pasquier, F., Pastor, P., Pericak-Vance, M. A., Raybould, R., Redon, R., Reinders, M. J. T., Richard, A.-C., Riedel-Heller, S. G., Rivadeneira, F., Rousseau, S., Ryan, N. S., Saad, S., Sanchez-Juan, P., Schellenberg, G. D., Scheltens, P., Schott, J. M., Seripa, D., Seshadri, S., Sie, D., Sistermans, E. A., Sorbi, S., van Spaendonk, R., Spalletta, G., Tesi, N., Tijms, B., Uitterlinden, A. G., van der Lee, S. J., Visser, P. J., Wagner, M., Wallon, D., Wang, L.-S., Zarea, A., Clarimon, J., van Swieten, J. C., Greicius, M. D., Yokoyama, J. S., Cruchaga, C., Hardy, J., Ramirez, A., Mead, S., van der Flier, W. M., van Duijn, C. M., Williams, J., Nicolas, G., Bellenguez, C., & Lambert, J.-C.
- Affiliations
- Amsterdam Neuroscience (NL)
- Inserm (FR)
- Cardiff University (GB)
- Erasmus MC (NL)
- MRC Prion Unit (GB)
- University of Cologne (DE)
- University of Miami (US)
- University of Washington (US)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Van Andel Institute (US)
- Agostino Gemelli University Polyclinic (IT)
- Boston University (US)
- University of Milan (IT)
- University of Southampton (GB)
- Universitat Autònoma de Barcelona (ES)
- Amsterdam University Medical Centers (NL)
- Università Cattolica del Sacro Cuore (IT)
- University of Perugia (IT)
- University of Nottingham (GB)
- Don Carlo Gnocchi Foundation (IT)
- Università di Camerino (IT)
- Centre National de la Recherche Scientifique (FR)
- UCL Queen Square Institute of Neurology (GB)
- Universidad de Cantabria (ES)
- Vrije Universiteit Amsterdam (NL)
- University of Bonn (DE)
- University of California, San Francisco (US)
- Washington University in St. Louis (US)
- Corresponding author
- Holstege, Henne
- Hulsman, Marc
- Nicolas, Gaël
- Lambert, Jean-Charles
- ORCID
- Holstege, Henne
- Hulsman, Marc
- Charbonnier, Camille
- Quenez, Olivier
- Grozeva, Detelina
- Sims, Rebecca
- Ahmad, Shahzad
- Amin, Najaf
- Norsworthy, Penny J.
- Dols-Icardo, Oriol
- Hummerich, Holger
- Kawalia, Amit
- Amouyel, Philippe
- Beecham, Gary W.
- Berr, Claudine
- Bis, Joshua C.
- Boland, Anne
- Bossù, Paola
- Bouwman, Femke
- Campion, Dominique
- Cochran, J. Nicholas
- Dartigues, Jean-François
- Debette, Stéphanie
- Deleuze, Jean-François
- Denning, Nicola
- DeStefano, Anita L.
- Farrer, Lindsay A.
- Fernández, Maria Victoria
- Fox, Nick C.
- Galimberti, Daniela
- Genin, Emmanuelle
- Le Guen, Yann
- Guerreiro, Rita
- Haines, Jonathan L.
- Holmes, Clive
- Ikram, M. Arfan
- Jansen, Iris E.
- Kraaij, Robert
- Lemstra, Afina W.
- Lleó, Alberto
- Mannens, Marcel M. A. M.
- Martin, Eden R.
- Masullo, Carlo
- Mayeux, Richard
- Mecocci, Patrizia
- Mol, Merel O.
- Morgan, Kevin
- Myers, Richard M.
- Nacmias, Benedetta
- Naj, Adam C.
- Napolioni, Valerio
- Pasquier, Florence
- Pastor, Pau
- Pericak-Vance, Margaret A.
- Raybould, Rachel
- Redon, Richard
- Reinders, Marcel J. T.
- Riedel-Heller, Steffi G.
- Rivadeneira, Fernando
- Ryan, Natalie S.
- Saad, Salha
- Sanchez-Juan, Pascual
- Schellenberg, Gerard D.
- Scheltens, Philip
- Schott, Jonathan M.
- Seripa, Davide
- Seshadri, Sudha
- Sie, Daoud
- Sistermans, Erik A.
- Sorbi, Sandro
- van Spaendonk, Resie
- Spalletta, Gianfranco
- Tesi, Niccolo’
- Tijms, Betty
- Uitterlinden, André G.
- van der Lee, Sven J.
- Visser, Pieter Jelle
- Wagner, Michael
- Wallon, David
- Wang, Li-San
- Greicius, Michael D.
- Yokoyama, Jennifer S.
- Cruchaga, Carlos
- Hardy, John
- Ramirez, Alfredo
- Mead, Simon
- van der Flier, Wiesje M.
- van Duijn, Cornelia M.
- Williams, Julie
- Nicolas, Gaël
- Bellenguez, Céline
- Lambert, Jean-Charles
- Venue
- Nature Genetics
- Published
- 2022-11-21
- Volume
- 54
- Issue
- 12
- Pages
- 1786-1794
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC9729101
- OpenAlex
- W4309664456
- Cited by
- 226
- References
- 7
- Citations by year
- 2026: 37 · 2025: 66 · 2024: 76 · 2023: 33 · 2022: 9 · 2021: 4 · 2020: 1
- FWCI
- 28.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Genetics (publishedVersion, cc-by)
- medRxiv (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
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- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
- VU Research Portal (publishedVersion, other-oa)
- ePrints Soton (University of Southampton) (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Pure Amsterdam UMC (acceptedVersion, cc-by)
- HAL (submittedVersion)
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- DZNE Pub (submittedVersion, other-oa)
- Unicam Scientific Publications (University of Camerino) (submittedVersion, other-oa)
- Research Repository (Delft University of Technology) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Funders
- Alzheimer's Association
- Alzheimer's Disease Neuroimaging Initiative
- New York Genome Center
- Agence Nationale de la Recherche (ANR-11-LABX-0009)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (17232, 15318)
- University of California, San Francisco
- Medical Research Council (MR/L023784/2, MR/N029402/1, MR/N026004/1, MC_PC_17112, MR/K013041/1, MR/M009076/1, MR/L023784/1)
- National Institute on Aging (R01AG067501, R00AG068271, R01AG062588, R01AG057234, U24AG056270, U24AG021886)
- National Heart, Lung, and Blood Institute (R01HL105756)
- National Institute of Neurological Disorders and Stroke
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, rare damaging variants, ABCA1, ADAM10, loss-of-function mutations, early-onset Alzheimer's disease, amyloid-beta aggregation, lipid metabolism, microglial function, genetic risk factors, TREM2, SORL1, ABCA7
- MeSH terms
- Adenosine Triphosphatases, Alzheimer Disease, Humans, Risk Factors, LDL-Receptor Related Proteins, Membrane Transport Proteins, Genome-Wide Association Study, Exosomes, ATP Binding Cassette Transporter 1
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