Cited by 72Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

GWAS of multiple neuropathology endophenotypes identifies new risk loci and provides insights into the genetic risk of dementia

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Shade, Lincoln M. P., Katsumata, Yuriko, Abner, Erin L., Aung, Khine Zin, Claas, Steven A., Qiao, Qi, Heberle, Bernardo Aguzzoli, Brandon, J. Anthony +276 more·2024·Nature Genetics

Abstract

Genome-wide association studies (GWAS) have identified >80 Alzheimer's disease and related dementias (ADRD)-associated genetic loci. However, the clinical outcomes used in most previous studies belie the complex nature of underlying neuropathologies. Here we performed GWAS on 11 ADRD-related neuropathology endophenotypes with participants drawn from the following three sources: the National Alzheimer's Coordinating Center, the Religious Orders Study and Rush Memory and Aging Project, and the Adult Changes in Thought study (n = 7,804 total autopsied participants). We identified eight independent significantly associated loci, of which four were new (COL4A1, PIK3R5, LZTS1 and APOC2). Separately testing known ADRD loci, 19 loci were significantly associated with at least one neuropathology after false-discovery rate adjustment. Genetic colocalization analyses identified pleiotropic effects and quantitative trait loci. Methylation in the cerebral cortex at two sites near APOC2 was associated with cerebral amyloid angiopathy. Studies that include neuropathology endophenotypes are an important step in understanding the mechanisms underlying genetic ADRD risk.

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  • Variants involved in resilience and resistance to disease establishment and progression can also be distinct.

    “Moreover, variants involved in resilience and resistance to disease establishment and progression can also be distinct [8].”

    From Genetic drivers of progression in Alzheimer’s disease are distinct from disease risk (2026) · cites this paper as [8]

    The Discussion (page unavailable) reports that some loci associated with clinical Alzheimer’s disease were not associated with its defining neuropathologies, supporting the narrower point that genetic associations can differ by outcome. The paper does not identify variants for resilience despite pathology or compare them with variants affecting disease establishment and progression. (LLM, conf=0.77)

    Experimental — accuracy not yet measured
  • Several ADRD loci were significantly associated with non-AD NPEs but not with AD NPEs.

    “several ADRD loci were significantly associated with non-AD NPEs, but not with AD NPEs (Supplementary Table 14)17.”

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Authors
Shade, L. M. P., Katsumata, Y., Abner, E. L., Aung, K. Z., Claas, S. A., Qiao, Q., Heberle, B. A., Brandon, J. A., Page, M. L., Hohman, T. J., Mukherjee, S., Mayeux, R. P., Farrer, L. A., Schellenberg, G. D., Haines, J. L., Kukull, W. A., Nho, K., Saykin, A. J., Bennett, D. A., Schneider, J. A., The National Alzheimer’s Coordinating Center, Biber, S., Albert, M., Asthana, S., Bennett, D., Brewer, J., Chui, H., Craft, S., DeCarli, C., Golde, T., Grabowski, T., Henderson, V., Hyman, B., Kaye, J., Kowall, N., LaFerla, F., Levey, A., Lopez, O., Miller, B., Morris, J., Paulson, H., Petersen, R., Reiman, E., Rosenberg, R., Sano, M., Saykin, A., Small, S., Strittmatter, S., Swerdlow, R., Trojanowski, J., Van Eldik, L., Vassar, R., Wisniewski, T., Stephens, K. A., Chan, K. C. G., O’Connell, H., Gauthreaux, K., Mock, C., Chen, Y.-C., Oswald, S., Miller, Z., Shibata, D. K., Ormsby, K., Culhane, J., Yasuda, S., The Alzheimer’s Disease Genetics Consortium, Bowen, J. D., Crane, P. K., Jarvik, G. P., Keene, C. D., Larson, E. B., McCormick, W. C., McCurry, S. M., Mukherjee, S., Kowall, N. W., McKee, A. C., Stern, R. A., Honig, L. S., Vonsattel, J. P., Williamson, J., Small, S., Burke, J. R., Hulette, C. M., Welsh-Bohmer, K. A., Gearing, M., Lah, J. J., Levey, A. I., Wingo, T. S., Apostolova, L. G., Farlow, M. R., Ghetti, B., Saykin, A. J., Spina, S., Albert, M. S., Lyketsos, C. G., Troncoso, J. C., Frosch, M. P., Green, R. C., Growdon, J. H., Hyman, B. T., Tanzi, R. E., Potter, H., Dickson, D. W., Ertekin-Taner, N., Graff-Radford, N. R., Parisi, J. E., Petersen, R. C., Duara, R., Buxbaum, J. D., Goate, A. M., Sano, M., Masurkar, A. V., Wisniewski, T., Bigio, E. H., Mesulam, M., Weintraub, S., Vassar, R., Kaye, J. A., Quinn, J. F., Woltjer, R. L., Barnes, L. L., Bennett, D. A., Schneider, J. A., Yu, L., Henderson, V., Fallon, K. B., Harrell, L. E., Marson, D. C., Roberson, E. D., DeCarli, C., Jin, L.-W., Olichney, J. M., Kim, R., LaFerla, F. M., Monuki, E., Head, E., Sultzer, D., Geschwind, D. H., Vinters, H. V., Chesselet, M.-F., Galasko, D. R., Brewer, J. B., Boxer, A., Karydas, A., Kramer, J. H., Miller, B. L., Rosen, H. J., Seeley, W. W., Burns, J. M., Swerdlow, R. H., Abner, E., Fardo, D. W., Van Eldik, L. J., Albin, R. L., Lieberman, A. P., Paulson, H. L., Arnold, S. E., Trojanowski, J. Q., Van Deerlin, V. M., Hamilton, R. L., Kamboh, M. I., Lopez, O. L., Becker, J. T., Cao, C., Raj, A., Smith, A. G., Chui, H. C., Miller, C. A., Ringman, J. M., Schneider, L. S., Bird, T. D., Sonnen, J. A., Yu, C.-E., Peskind, E., Raskind, M., Li, G., Tsuang, D. W., Atwood, C. S., Carlsson, C. M., Sager, M. A., Chin, N. A., Craft, S., Cairns, N. J., Morris, J. C., Cruchaga, C., Strittmatter, S., Reiman, E. M., Beach, T. G., Huentelman, M. J., Hardy, J., Myers, A. J., Kauwe, J. S. K., Hakonarson, H., Blacker, D., Montine, T. J., Baldwin, C. T., Farrer, L. A., Jun, G., Lunetta, K. L., Bush, W. S., Haines, J. L., Lerner, A. J., Zhou, X., Barral, S., Reitz, C., Vardarajan, B. N., Mayeux, R., Beecham, G. W., Carney, R. M., Cuccaro, M. L., Gilbert, J. R., Hamilton-Nelson, K. L., Kunkle, B. W., Martin, E. R., Pericak-Vance, M. A., Vance, J. M., Cantwell, L. B., Kuzma, A. P., Malamon, J., Naj, A. C., Qu, L., Schellenberg, G. D., Valladares, O., Wang, L.-S., Zhao, Y., Leverenz, J. B., De Jager, P. L., Evans, D. A., Katz, M. J., Lipton, R. B., Boeve, B. F., Allen, M., Carrasquillo, M. M., Younkin, S. G., Faber, K. M., Foroud, T. M., Pavlik, V., Massman, P., Darby, E., Rodriguear, M., Khaleeq, A., Royall, D. R., Stevens, A., Ory, M., DeToledo, J. C., Wilms, H., Johnson, K., Perez, V., Hernandez, M., Wilhelmsen, K. C., Tilson, J., Chasse, S., Barber, R. C., Fairchild, T. J., O’Bryant, S. E., Knebl, J., Hall, J. R., Johnson, L., Mains, D., Alvarez, L., Gamboa, A., Paydarfar, D., Bertelson, J., Woon, M., Ayres, G., Aguirre, A., Palmer, R., Polk, M., Adams, P. M., Huebinger, R. M., Reisch, J. S., Rosenberg, R. N., Cullum, M., Williams, B., Quiceno, M., Hynan, L., Smith, J., Davis, B., Nguyen, T., Rogaeva, E., George-Hyslop, P. S., Ebbert, M. T. W., Nelson, P. T., & Fardo, D. W.
Affiliations
  • University of Kentucky (US)
  • Vanderbilt University Medical Center (US)
  • University of Washington (US)
  • Indiana University Indianapolis (US)
  • Case Western Reserve University (US)
  • Indiana University School of Medicine (US)
  • Rush University Medical Center (US)
  • University of Pennsylvania (US)
Venue
Nature Genetics
Published
2024-10-08
Volume
56
Issue
11
Pages
2407-2421
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
OpenAlex
W4403228432
Cited by
72
References
110
Citations by year
2026: 38 · 2025: 32 · 2024: 2
FWCI
20.49
Type
journal article
Language
en
Open access
Locations
  • Nature Genetics (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
  • UKnowledge (University of Kentucky) (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | NIH | National Institute on Aging (RF1AG082339)
  • Funding sources listed in the acknowledgments
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 and related dementias, genetic susceptibility loci, COL4A1, PIK3R5, APOC2, cerebral amyloid angiopathy, DNA methylation, cerebral cortex, genetic colocalization, pleiotropy, quantitative trait loci, neuropathology
MeSH terms
Neuropathology, Aged, Aged, 80 and over, Alzheimer Disease, Dementia, Female, Humans, Male, Risk Factors, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Genome-Wide Association Study, Endophenotypes

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