Assessment of the genetic variance of late-onset Alzheimer's disease
Open accessAbstract
Alzheimer's disease (AD) is a complex genetic disorder with no effective treatments. More than 20 common markers have been identified, which are associated with AD. Recently, several rare variants have been identified in Amyloid Precursor Protein (APP), Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Unc-5 Netrin Receptor C (UNC5C) that affect risk for AD. Despite the many successes, the genetic architecture of AD remains unsolved. We used Genome-wide Complex Trait Analysis to (1) estimate phenotypic variance explained by genetics; (2) calculate genetic variance explained by known AD single nucleotide polymorphisms (SNPs); and (3) identify the genomic locations of variation that explain the remaining unexplained genetic variance. In total, 53.24% of phenotypic variance is explained by genetics, but known AD SNPs only explain 30.62% of the genetic variance. Of the unexplained genetic variance, approximately 41% is explained by unknown SNPs in regions adjacent to known AD SNPs, and the remaining unexplained genetic variance outside these regions.
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Twin and sporadic AD studies estimated heritability of AD between 53% and 79%.
“Twin and sporadic AD studies have estimated the herita bility of AD at between 53% and 79%”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [18]
The Results report that SNPs explained 53.24% of phenotypic variance in the paper’s AD dataset, approximately matching the claim’s lower bound. The paper does not report a 79% estimate or attribute the stated range to twin and sporadic AD studies (searched: “79,” “twin studies,” and “heritability”). (LLM, conf=0.86)
Experimental — accuracy not yet measuredAPOE remains the most significant genetic risk factor for Alzheimer's disease across populations.
“Among the AD susceptibility genes/loci identified to date, APOE remains the most significant genetic risk factor across populations.”
From Association of rare <i>APOE</i> missense variants with Alzheimer's disease in the Japanese population (2025) · cites this paper as [11]
The Results (section 3; page unavailable) identify APOE as the dominant contributor among the known AD variants examined: it explained 13% of phenotypic variance, versus almost 3% for other genes combined. The paper does not establish that APOE is the most significant genetic risk factor across populations; that extension is unsupported by this analysis. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMore than 45 genes/loci have been associated with the risk of developing AD.
“Together, these genetic analyses have pointed out more than 45 genes/loci associated with the risk of developing AD even if it is estimated that a large part of the genetic component of AD is still unknown [103].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [103]
The Introduction reports more than 20 distinct AD-associated loci and additional rare variants in several genes, but does not establish the claimed count of more than 45 genes or loci. The Conclusions state that 69% of genetic variance remains unexplained, supporting the citing sentence’s separate point about the unknown genetic component. No page numbers are available in our copy. (LLM, conf=0.86)
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References 33 · Cited by 236
Research works printed but not linked: 16
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- Authors
- Ridge, P. G., Hoyt, K. B., Boehme, K., Mukherjee, S., Crane, P. K., Haines, J. L., Mayeux, R., Farrer, L. A., Pericak-Vance, M. A., Schellenberg, G. D., Kauwe, J. S. K., Adams, P. M., Albert, M. S., Albin, R. L., Apostolova, L. G., Arnold, S. E., Asthana, S., Atwood, C. S., Baldwin, C. T., Barber, R. C., Barmada, M. M., Barnes, L. L., Barral, S., Beach, T. G., Becker, J. T., Beecham, G. W., Beekly, D., Bennett, D. A., Bigio, E. H., Bird, T. D., Blacker, D., Boeve, B. F., Bowen, J. D., Boxer, A., Burke, J. R., Burns, J. M., Buxbaum, J. D., Cairns, N. J., Cantwell, L. B., Cao, C., Carlson, C. S., Carlsson, C. M., Carney, R. M., Carrasquillo, M. M., Carroll, S. L., Chui, H. C., Clark, D. G., Corneveaux, J., Crane, P. K., Cribbs, D. H., Crocco, E. A., Cruchaga, C., De Jager, P. L., DeCarli, C., Demirci, F. Y., Dick, M., Dickson, D. W., Doody, R. S., Duara, R., Ertekin-Taner, N., Evans, D. A., Faber, K. M., Fairchild, T. J., Fallon, K. B., Fardo, D. W., Farlow, M. R., Ferris, S., Foroud, T. M., Frosch, M. P., Galasko, D. R., Gearing, M., Geschwind, D. H., Ghetti, B., Gilbert, J. R., Goate, A. M., Graff-Radford, N. R., Green, R. C., Growdon, J. H., Hakonarson, H., Hamilton, R. L., Hamilton-Nelson, K. L., Hardy, J., Harrell, L. E., Honig, L. S., Huebinger, R. M., Huentelman, M. J., Hulette, C. M., Hyman, B. T., Jarvik, G. P., Jicha, G. A., Jin, L.-W., Jun, G., Kamboh, M. I., Karydas, A., Katz, M. J., Kauwe, J. S. K., Kaye, J. A., Kim, R., Kowall, N. W., Kramer, J. H., Kukull, W. A., Kunkle, B. W., LaFerla, F. M., Lah, J. J., Larson, E. B., Leverenz, J. B., Levey, A. I., Li, G., Lieberman, A. P., Lin, C.-F., Lipton, R. B., Lopez, O. L., Lunetta, K. L., Lyketsos, C. G., Mack, W. J., Marson, D. C., Martin, E. R., Martiniuk, F., Mash, D. C., Masliah, E., McCormick, W. C., McCurry, S. M., McDavid, A. N., McKee, A. C., Mesulam, M., Miller, B. L., Miller, C. A., Miller, J. W., Montine, T. J., Morris, J. C., Mukherjee, S., Murrell, J. R., Myers, A. J., Naj, A. C., O'Bryant, S., Olichney, J. M., Pankratz, V. S., Parisi, J. E., Partch, A., Paulson, H. L., Perry, W., Peskind, E., Petersen, R. C., Pierce, A., Poon, W. W., Potter, H., Quinn, J. F., Raj, A., Raskind, M., Reiman, E. M., Reisberg, B., Reisch, J. S., Reitz, C., Ringman, J. M., Roberson, E. D., Rogaeva, E., Rosen, H. J., Rosenberg, R. N., Royall, D. R., Sager, M. A., Sano, M., Saykin, A. J., Schneider, J. A., Schneider, L. S., Seeley, W. W., Smith, A. G., Sonnen, J. A., Spina, S., St George-Hyslop, P., Stern, R. A., Swerdlow, R. H., Tanzi, R. E., Thornton-Wells, T. A., Trojanowski, J. Q., Troncoso, J. C., Tsuang, D. W., Valladares, O., Van Deerlin, V. M., Van Eldik, L. J., Vardarajan, B. N., Vinters, H. V., Vonsattel, J. P., Wang, L.-S., Weintraub, S., Welsh-Bohmer, K. A., Wendland, J. R., Wilhelmsen, K. C., Williamson, J., Wingo, T. S., Winslow, A. R., Wishnek, S., Woltjer, R. L., Wright, C. B., Wu, C.-K., Younkin, S. G., Yu, C.-E., & Yu, L.
- Affiliations
- Brigham Young University (US)
- Case Western Reserve University (US)
- Columbia University (US)
- Boston University (US)
- University of Pennsylvania (US)
- The University of Texas Southwestern Medical Center (US)
- Johns Hopkins University (US)
- University of Kentucky (US)
- University of California, Los Angeles (US)
- University of Wisconsin–Madison (US)
- University of North Texas Health Science Center (US)
- University of Pittsburgh (US)
- Rush University Medical Center (US)
- University of Miami (US)
- University of Washington (US)
- Northwestern University (US)
- Harvard University (US)
- Mayo Clinic (US)
- Swedish Medical Center (US)
- Duke University (US)
- University of California, San Francisco (US)
- ORCID
- Ridge, Perry G.
- Boehme, Kevin
- Haines, Jonathan L.
- Mayeux, Richard
- Farrer, Lindsay A.
- Schellenberg, Gerard D.
- Adams, Perrie M.
- Albert, Marilyn S.
- Albin, Roger L.
- Apostolova, Liana G.
- Arnold, Steven E.
- Asthana, Sanjay
- Atwood, Craig S.
- Barber, Robert C.
- Barmada, Michael M.
- Barnes, Lisa L.
- Beach, Thomas G.
- Becker, James T.
- Beecham, Gary W.
- Bennett, David A.
- Bigio, Eileen H.
- Bird, Thomas D.
- Blacker, Deborah
- Boeve, Bradley F.
- Bowen, James D.
- Boxer, Adam
- Burke, James R.
- Burns, Jeffrey M.
- Buxbaum, Joseph D.
- Cairns, Nigel J.
- Cao, Chuanhai
- Carlsson, Cynthia M.
- Carrasquillo, Minerva M.
- Carroll, Steven L.
- Chui, Helena C.
- Clark, David G.
- Cribbs, David H.
- Crocco, Elizabeth A.
- Cruchaga, Carlos
- DeCarli, Charles
- Demirci, F. Yesim
- Dickson, Dennis W.
- Duara, Ranjan
- Evans, Denis A.
- Faber, Kelley M.
- Fardo, David W.
- Farlow, Martin R.
- Ferris, Steven
- Foroud, Tatiana M.
- Frosch, Matthew P.
- Galasko, Douglas R.
- Gearing, Marla
- Geschwind, Daniel H.
- Ghetti, Bernardino
- Gilbert, John R.
- Goate, Alison M.
- Green, Robert C.
- Hakonarson, Hakon
- Hamilton, Ronald L.
- Hardy, John
- Honig, Lawrence S.
- Huebinger, Ryan M.
- Huentelman, Matthew J.
- Hyman, Bradley T.
- Jarvik, Gail P.
- Jicha, Gregory A.
- Jun, Gyungah
- Kamboh, M. Ilyas
- Katz, Mindy J.
- Kaye, Jeffrey A.
- Kowall, Neil W.
- Kramer, Joel H.
- Kukull, Walter A.
- Kunkle, Brian W.
- LaFerla, Frank M.
- Lah, James J.
- Larson, Eric B.
- Leverenz, James B.
- Levey, Allan I.
- Li, Ge
- Lieberman, Andrew P.
- Lin, Chiao-Feng
- Lipton, Richard B.
- Lunetta, Kathryn L.
- Lyketsos, Constantine G.
- Mack, Wendy J.
- Marson, Daniel C.
- Martin, Eden R.
- Martiniuk, Frank
- Mash, Deborah C.
- Masliah, Eliezer
- McCurry, Susan M.
- McDavid, Andrew N.
- McKee, Ann C.
- Mesulam, Marsel
- Miller, Bruce L.
- Montine, Thomas J.
- Morris, John C.
- Murrell, Jill R.
- Myers, Amanda J.
- Naj, Adam C.
- Olichney, John M.
- Pankratz, Vernon S.
- Paulson, Henry L.
- Perry, William
- Peskind, Elaine
- Petersen, Ronald C.
- Poon, Wayne W.
- Potter, Huntington
- Quinn, Joseph F.
- Raskind, Murray
- Reiman, Eric M.
- Reisberg, Barry
- Ringman, John M.
- Roberson, Erik D.
- Rogaeva, Ekaterina
- Sano, Mary
- Saykin, Andrew J.
- Schneider, Julie A.
- Schneider, Lon S.
- Seeley, William W.
- Smith, Amanda G.
- Sonnen, Joshua A.
- Spina, Salvatore
- Stern, Robert A.
- Swerdlow, Russell H.
- Tanzi, Rudolph E.
- Trojanowski, John Q.
- Troncoso, Juan C.
- Tsuang, Debby W.
- Valladares, Otto
- Vardarajan, Badri N.
- Vinters, Harry V.
- Welsh-Bohmer, Kathleen A.
- Wendland, Jens R.
- Wilhelmsen, Kirk C.
- Williamson, Jennifer
- Wingo, Thomas S.
- Winslow, Ashley R.
- Woltjer, Randall L.
- Yu, Chang-En
- Yu, Lei
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 41
- Pages
- 200.e13-200.e20
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC4948179
- OpenAlex
- W2289147497
- Cited by
- 236
- References
- 33
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 20 · 2023: 28 · 2022: 25 · 2021: 42 · 2020: 30 · 2019: 30 · 2018: 23 · 2017: 9 · 2016: 3 · 2015: 1
- FWCI
- 17.45
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neurobiology of Aging (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institutes of Health (R01AG042611)
- 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
- late-onset Alzheimer's disease, genetic variance explained, genetic architecture, single nucleotide polymorphisms, APP, TREM2, UNC5C, rare variants, GCTA
- MeSH terms
- Netrin Receptors, Aged, Aged, 80 and over, Alzheimer Disease, Female, Humans, Male, Membrane Glycoproteins, Receptors, Cell Surface, Receptors, Immunologic, Risk, Genetic Variation, Amyloid beta-Protein Precursor, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Datasets as Topic
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