The DOI matches its Crossref record; 149 of the 149 references it cites were found in a registry or an index.
Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis
Open accessAbstract
We review the genetic risk factors for late-onset Alzheimer's disease (AD) and their role in AD pathogenesis. More recent advances in understanding of the human genome-technologic advances in methods to analyze millions of polymorphisms in thousands of subjects-have revealed new genes associated with AD risk, including ABCA7, BIN1, CASS4, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5-DBR1, INPP5D, MS4A, MEF2C, NME8, PICALM, PTK2B, SLC24H4-RIN3, SORL1, and ZCWPW1. Emerging technologies to analyze the entire genome in large data sets have also revealed coding variants that increase AD risk: PLD3 and TREM2. We review the relationship between these AD risk genes and the cellular and neuropathologic features of AD. Understanding the mechanisms underlying the association of these genes with risk for disease will provide the most meaningful targets for therapeutic development to date.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“PSEN1 is the catalytical component of 𝛄 -secretase (304).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [304]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“To date, 228 PSEN1 mutations have been identified causing ADAD (49, 303, 304, 440, 566, 580).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [304]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Some PSEN1 mutations lead to very early onset ADAD ( < 35 yr of age) (177, 304).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [304]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“TREM2 loss‐of‐function impairs microglial protective functions and worsens neuronal dystrophy. 9 , 37 , 38 , 41 , 42 , 61”
From PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology (2025) · cites this paper as [9]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“approximately 40% of the susceptibility genes identified in genetic studies of LOAD are immune- and microglia-related, suggesting that microglia are involved in modulating AD pathology [8].”
From PLCG2 is associated with the inflammatory response and is induced by amyloid plaques in Alzheimer’s disease (2022) · cites this paper as [8]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In addition, genome-wide association studies have identified associations between inflammation- and immune-related variants in genes (such as a missense mutation in the gene encoding for TREM2, a receptor expressed on microglia) and increased AD risk [36].”
From Cerebrospinal fluid levels of the neurotrophic factor neuroleukin are increased in early Alzheimer’s disease, but not in cerebral amyloid angiopathy (2021) · cites this paper as [36]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Most notably, these genetic studies implicate central roles for the innate immune system, with many AD risk genes being primarily expressed in microglia (Efthymiou and Goate, 2017; Karch and Goate, 2015; Lopes et al., 2022).”
From Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis (2026) · cites this paper as Karch and Goate, 2015
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“among the top risk genes for sporadic AD, APOE, TREM2, APOJ, PICALM, ABCA7, and SORL1 are all directly involved in lipid trafficking or metabolism (Karch and Goate, 2015).”
From ApoE4 Impairs Neuron-Astrocyte Coupling of Fatty Acid Metabolism (2021) · cites this paper as Karch and Goate, 2015
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“More than half of the reported genetic risk factors of AD are related to microglia-mediated immune response and cholesterol metabolism (Karch and Goate, 2015).”
From Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy (2024) · cites this paper as Karch and Goate, 2015
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Disruption of retromer-dependent endosomal trafficking is considered pathogenic in late-onset Alzheimer’s disease (AD).”
From The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease (2022) · cites this paper as Karch and Goate, 2015
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“the main genetic risk factor in SAD is the APOE gene [91,92,93,94].”
From Alzheimer's Disease: Treatment Strategies and Their Limitations. (2022) · cites this paper as [94]
The cited source says what the claim attributes to it.
In the citing paper
“Autosomal-dominant AD (ADAD) is an inherited form of AD caused by mutations in amyloid precursor protein ( APP ) and presenilin-1 and 2 ( PSEN1; PSEN2 ) genes (49, 177, 303, 304, 580).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [304]
The cited source says what the claim attributes to it.
In the citing paper
“Genetic studies have identified numerous AD risk variants in immune‐ and microglial‐associated genes, highlighting the importance of microglia function in disease progression. 3 , 4 , 5 , 6 , 7”
From Alzheimer's disease–associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell–derived microglia‐like cells (2025) · cites this paper as [5]
The cited source says what the claim attributes to it.
In the citing paper
“Moreover, HLA‐DRB polymorphisms are associated with increased risk of AD 2 , 19 , 20”
From The P522R protective variant of PLCG2 promotes the expression of antigen presentation genes by human microglia in an Alzheimer's disease mouse model (2022) · cites this paper as [2]
The cited source says what the claim attributes to it.
In the citing paper
“Identifying functional variants, such as the variants in APP, APOE, PLD3, and TREM2 provide key insights into disease mechanisms [14, 15].”
From Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience (2017) · cites this paper as [15]
The cited source says what the claim attributes to it.
In the citing paper
“In recent years, genetic and functional studies have highlighted the endo-lysosomal network as a key biological pathway central to AD pathogenesis [3–5].”
From Retromer Stabilization Improves Cognitive Function and Synaptic Plasticity in a Mouse Model of Down Syndrome (2023) · cites this paper as [3]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Inpp5d is expressed predominantly in microglia but its function in brain is poorly understood.”
From Loss of Inpp5d has disease‐relevant and sex‐specific effects on glial transcriptomes (2024) · cites this paper as [16]
Experimental — accuracy not yet measuredIn the citing paper
“Likewise, genome-wide association studies (GWAS) have identified several single-nucleotide polymorphisms (SNPs) in immune genes as independent risk factors for LOAD [52–55], directly implicating microglia-mediated mechanisms in sporadic AD progression.”
From Systems-based proteomics to resolve the biology of Alzheimer’s disease beyond amyloid and tau (2021) · cites this paper as [55]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429
Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336
Self-citationApolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology
Mahley, R. W. (1988) · Science · doi:10.1126/science.3283935 · Cited by 4,028
Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M. L., Pahwa, J. S., Moskvina, V., Dowzell, K., Williams, A., et al. (2009) · Nature Genetics · doi:10.1038/ng.440 · Cited by 3,326
Self-citationTREM2 Variants in Alzheimer's Disease
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S. K., Younkin, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211851 · Cited by 3,020
Self-citationVariant of TREM2 Associated with the Risk of Alzheimer's Disease
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1211103 · Cited by 2,558
Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease
the European Alzheimer's Disease Initiative Investigators, Lambert, J.-C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., Combarros, O., Zelenika, D., Bullido, M. J., et al. (2009) · Nature Genetics · doi:10.1038/ng.439 · Cited by 2,234
Initiative, T. A. D. N., Hollingworth, P., CHARGE consortium, EADI1 consortium, Harold, D., Sims, R., Gerrish, A., Lambert, J.-C., Carrasquillo, M. M., Abraham, R., et al. (2011) · Nature Genetics · doi:10.1038/ng.803 · Cited by 1,997
Self-citation
Research works printed but not linked: 4
- Bertram, 2013, TREM2 and neurodegenerative disease, N Engl J Med, 369, 1565
- Benitez, 2013, TREM2 and neurodegenerative disease, N Engl J Med, 369, 1567
- Guerreiro, 2013, TREM2 and neurodegenerative disease, N Engl J Med, 369, 1569
- Rajagopalan, 2013, TREM2 and neurodegenerative disease, N Engl J Med, 369, 1565
Cited by
Sorted by citations
Items 101–126 of 126
Zhang, Q., Zhao, W., Hou, Y., Song, X., Yu, H., Tan, J., Zhou, Y., & Zhang, H. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14132 · Cited by 40
COVID-19 as a Risk Factor for Alzheimer’s Disease
Golzari-Sorkheh, M., Weaver, D. F., & Reed, M. A. (2023) · Journal of Alzheimer's Disease · doi:10.3233/jad-220800 · Cited by 39
Wang, Y., Sun, Y., Wang, Y., Jia, S., Qiao, Y., Zhou, Z., Shao, W., Zhang, X., Guo, J., Zhang, B., et al. (2023) · Alzheimer's Research & Therapy · doi:10.1186/s13195-023-01324-4 · Cited by 34
“Besides, PLD3 was suggested to be the gene that increases AD risk [45–47] and was downregulated in AD brains which might participate in AD pathogenesis through amyloid precursor protein (APP) processing [48, 49].”
BackgroundHe, S., Li, X., Mittra, N., Bhattacharjee, A., Wang, H., Song, S., Zhao, S., Liu, F., & Han, X. (2025) · Advanced Science · doi:10.1002/advs.202410910 · Cited by 34
Embryonal Fyn-associated substrate (EFS) and CASS4: The lesser-known CAS protein family members
Deneka, A., Korben, V. A., & Golemis, E. A. (2015) · Gene · doi:10.1016/j.gene.2015.06.062 · Cited by 33
The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease
Qureshi, Y. H., Berman, D. E., Marsh, S. E., Klein, R. L., Patel, V. M., Simoes, S., Kannan, S., Petsko, G. A., Stevens, B., & Small, S. A. (2022) · Cell Reports · doi:10.1016/j.celrep.2021.110262 · Cited by 31
Current therapeutics for Alzheimer’s disease and clinical trials
Xiao, D., & Zhang, C. (2024) · Exploration of Neuroscience · doi:10.37349/en.2024.00048 · Cited by 30
Fitzgerald, G. S., Chuchta, T. G., & McNay, E. C. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14160 · Cited by 22
Protective ApoE variants support neuronal function by effluxing oxidized phospholipids
Ralhan, I., Do, A. D., Bae, J.-Y., Feringa, F. M., Cai, W., Chang, J., Chik, K., Lee, N. Y. J., Gerry, C. J., van der Kant, R., et al. (2026) · Neuron · doi:10.1016/j.neuron.2025.10.040 · Cited by 23
Zhao, M., Ma, G., Yan, X., Li, X., Wang, E., Xu, X.-X., Zhao, J.-B., Ma, X., & Zeng, J. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02428-5 · Cited by 21
A microglia clonal inflammatory disorder in Alzheimer’s disease
Vicario, R., Fragkogianni, S., Weber, L., Lazarov, T., Hu, Y., Hayashi, S. Y., Craddock, B., Socci, N. D., Alberdi, A., Baako, A., et al. (2025) · eLife · doi:10.7554/elife.96519.3 · Cited by 21
Cholesterol Metabolism in CNS Diseases: The Potential of SREBP2 and LXR as Therapeutic Targets
Wang, N.-Q., Sun, P.-X., Shen, Q.-Q., & Deng, M.-Y. (2025) · Molecular Neurobiology · doi:10.1007/s12035-024-04672-w · Cited by 19
Ramos de Matos, M., Ferreira, C., Herukka, S.-K., Soininen, H., Janeiro, A., Santana, I., Baldeiras, I., Almeida, M. R., Lleó, A., Dols-Icardo, O., et al. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-180512 · Cited by 18
PLCG2 modulates TREM2 expression and signaling in response to Alzheimer's disease pathology
Messenger, E. J., Baar, S. A., Bedford, L. M., Tsai, A. P., Lin, P. B., Ferguson, C. A., Xu, G., Wallace, A., Landreth, G. E., Lamb, B. T., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70231 · Cited by 16
Inpp5d haplodeficiency alleviates tau pathology in the PS19 mouse model of Tauopathy
Soni, D. M., Lin, P. B., Lee‐Gosselin, A., Lloyd, C. D., Mason, E., Ingraham, C. M., Perkins, A., Moutinho, M., Lamb, B. T., Chu, S., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.14078 · Cited by 14
Wang, T., Liu, X., Wang, X., Hua, F., & Yan, L. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1739875 · Cited by 14
De Kort, A. M., Kuiperij, H. B., Alcolea, D., Kersten, I., Versleijen, A. A. M., Greenberg, S. M., Stoops, E., Schreuder, F. H. B. M., Klijn, C. J. M., Lleó, A., et al. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-021-00899-0 · Cited by 13
Neighborhood matters: Altered lipid metabolism in APOE4 microglia causes problems for neurons
Young, J. E., & Jayadev, S. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.07.001 · Cited by 10
Loss of Inpp5d has disease‐relevant and sex‐specific effects on glial transcriptomes
Dabin, L. C., Kersey, H., Kim, B., Acri, D. J., Sharify, D., Lee‐Gosselin, A., Lasagna‐Reeves, C. A., Oblak, A. L., Lamb, B. T., & Kim, J. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13901 · Cited by 10
Bedford, L. M., Tutrow, K. D., Hooper, K., Messenger, E. J., Hernandez, M., Lamb, B. T., Meyer, J. S., Richardson, T. I., & Bissel, S. J. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70772 · Cited by 8
PLCG2 as a Risk Factor for Alzheimer's Disease.
Tsai, A. P., Dong, C., Preuss, C., Moutinho, M., Lin, P. B.-C., Hajicek, N., Sondek, J., Bissel, S. J., Oblak, A. L., Carter, G. W., et al. (2020) · doi:10.21203/rs.3.rs-38216/v1 · Cited by 7
Microglial states revisited: from homeostasis to disease
Eggen, B. J. L., & Kooistra, S. M. (2026) · Nature Reviews Neuroscience · doi:10.1038/s41583-026-01066-w · Cited by 6
Protective ApoE variants support neuronal function by extracting peroxidated lipids
Ralhan, I., Do, A. D., Bae, J.-Y., Feringa, F. M., Cai, W., Chang, J., Chik, K., Lee, N. Y., Gerry, C., van der Kant, R., et al. (2025) · bioRxiv · doi:10.1101/2025.03.05.641722 · Cited by 4
Network analysis identifies strain-dependent response to tau and tau seeding-associated genes
Acri, D. J., You, Y., Tate, M. D., Karahan, H., Martinez, P., McCord, B., Sharify, A. D., John, S., Kim, B., Dabin, L. C., et al. (2023) · Journal of Experimental Medicine · doi:10.1084/jem.20230180 · Cited by 3
“Human genetic studies have identified variants that implicate several risk genes that influence AD pathogenesis (Karch and Goate, 2015).”
Curtis, M. E., Smith, T., Nenov, M., Blass, B. E., & Praticò, D. (2023) · Journal of Alzheimer's Disease · doi:10.3233/jad-230205 · Cited by 3
Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis
Walsh, A. E., Davis, B. A., Samuels, J. D., Mills, W. A., Thanos, J. M., Johnson, A. M., Moore, K. A., Puchalski, M. A., Steacy, E. J., Wendell, B. W., et al. (2026) · Journal of Experimental Medicine · doi:10.1084/jem.20260104
Metadata
- Authors
- Karch, C. M., & Goate, A. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Goate, Alison M.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 77
- Issue
- 1
- Pages
- 43-51
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4234692
- OpenAlex
- W1999794509
- Cited by
- 1,357
- References
- 149
- Citations by year
- 2026: 80 · 2025: 136 · 2024: 130 · 2023: 132 · 2022: 151 · 2021: 153 · 2020: 146 · 2019: 117 · 2018: 94 · 2017: 94 · 2016: 74 · 2015: 44
- FWCI
- 8.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust (503147, G0801418)
- National Institute on Aging (K01AG046374, R01AG035083, P50AG005681, U01AG032438)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, late-onset Alzheimer's disease, genetic risk factors, susceptibility genes, Alzheimer's disease pathogenesis, single nucleotide polymorphisms, ABCA7, BIN1, SORL1, TREM2, PLD3, CD33, PICALM, clusterin, neuropathology, therapeutic target
- MeSH terms
- Alzheimer Disease, Cholesterol, Endocytosis, Humans, Phenotype, Risk Factors, Amyloid beta-Protein Precursor, Genetic Predisposition to Disease, Presenilin-1, Presenilin-2, Genome-Wide Association Study
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
