Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes
Open accessPreprint — published as 10.1038/s41467-019-14279-8 · Paper page
Abstract
Each additional copy of the apolipoprotein E4 (APOE4) allele is associated with a higher risk of Alzheimer’s dementia, such that APOE4 homozygotes have a particularly high risk. While the APOE2 allele is associated with a lower risk of Alzheimer’s dementia, it is not yet known whether APOE2 homozygotes have a particularly low risk. We generated Alzheimer’s dementia odds ratios and other findings in more than 5,000 clinically characterized and neuropathologically characterized Alzheimer’s dementia cases and controls. APOE2/2 was associated with exceptionally low Alzheimer’s dementia odds ratios compared to APOE2/3, 3/3 and 4/4, and the impact of APOE2 and APOE4 gene dose was significantly greater in the neuropathologically confirmed group than in more than 24,000 neuropathologically unconfirmed cases and controls. Finding and targeting the factors by which APOE and its variants influence Alzheimer’s disease could have a major impact on the understanding, treatment and prevention of this terrible disease.
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APOE2/4 carriers exhibit an intermediate AD risk phenotype, with 2.7-fold higher risk than APOE3/3 but lower than APOE3/4 (6.1-fold) or APOE4/4 (31-fold).
“Limited neuropathological evidence suggests that APOE2/4 carriers exhibit an intermediate phenotype, showing a 2.7-fold higher AD risk than APOE3/3 individuals but much lower than APOE3/4 (6.1-fold) or APOE4/4 (31-fold) carriers 6 .”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [6]
APOE2 confers partial protection even in the presence of APOE4, although APOE4's deleterious effects tend to dominate.
“These data suggest that APOE2 confers partial protection even in the presence of APOE4 , although APOE4 ' s deleterious effects tend to dominate.”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [6]
In humans, the APOE2/4 genotype confers an intermediate risk, higher than that of APOE3/3 but lower than APOE3/4 and APOE4/4.
“In humans, the APOE2/4 genotype confers an intermediate risk, higher than that of APOE3/3 but lower than APOE3/4 and APOE4/4 5,6 .”
From APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease (2026) · cites this paper as [6]
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Cites
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Research works printed but not linked: 6
- Reiman, E. M. et al. Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc. Natl Acad. Sci. USA 106, 6820-6825 (2009).
- Beecham, G. W. et al. Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias. PLoS Genet. 10, e1004606 (2014).
- Zhao, N. et al. APOE epsilon2 is associated with increased tau pathology in primary tauopathy. Nat. Commun. 9, 4388 (2018).
- Rauch, J. N. et al. Tau internalization is regulated by 6-O sulfation on heparan sulfate proteoglycans (HSPGs). Sci. Rep. 8, 6382 (2018).
- Olah, M. et al. A transcriptomic atlas of aged human microglia. Nat. Commun. 9, 539 (2018).
- Yamazaki, Y., Painter, M. M., Bu, G. & Kanekiyo, T. Apolipoprotein E as a therapeutic target in Alzheimer's disease: a review of basic research and clinical evidence. CNS Drugs 30, 773-789 (2016).
Cited by
Sorted by citations
Vance, J. M., Farrer, L. A., Huang, Y., Cruchaga, C., Hyman, B. T., Pericak‐Vance, M. A., Goate, A. M., Greicius, M. D., Griswold, A. J., Haines, J. L., et al. (2024) · Annals of Neurology · doi:10.1002/ana.26864 · Cited by 52 · see citing works
Self-citationPanitch, R., Hu, J.-M., Chung, J., Zhu, C.-C., Meng, G., Xia, W., Bennett, D. A., Lunetta, K., Ikezu, T., Au, R., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-021-01266-z · Cited by 50 · see citing works
Self-citationNHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque loadPreprint
Pohlkamp, T., Xian, X., Wong, C. H. Y., Durakoglugil, M. S., Werthmann, G. C., Saido, T., Evers, B. M., White, C. L., Connor, J., Hammer, R., et al. (2021) · bioRxiv · doi:10.1101/2021.03.22.436385 · Cited by 40 · see citing works
“ApoE2 homozygous carriers have an exceptionally low likelihood of developing AD (Reiman et al., 2020).”
Salvadó, G., Ferreira, D., Operto, G., Cumplido-Mayoral, I., Arenaza-Urquijo, E., Cacciaglia, R., Falcón, C., Vilor-Tejedor, N., Minguillón, C., Groot, C., et al. (2021) · Alzheimer's & Dementia · doi:10.1002/alz.12487 · Cited by 21 · see citing works
“We hypothesized that (1) APOE ε2 carriership would be associated to larger GMvolumes in areas known to be affected in AD19 and areas related to successful aging,21 (2) a higher dose of ε2 allele would be related to largerGMvolumes, and (3) theseeffectswould contribute to the global APOE genotype-related AD risk effect…”
BackgroundGenetics of Alzheimer’s disease
König, T., & Stögmann, E. (2021) · Wiener Medizinische Wochenschrift · doi:10.1007/s10354-021-00819-9 · Cited by 20 · see citing works
“6 compared to individuals with an APOE 3/3 genotype [36].”
BackgroundAndrieieva, D., Falltrick, I., Chiang, C.-Y., Beaumont, B., Guen, Y. L., Liu, C., Pergolesi, S., Ma, C.-T., Jackson, M. R., Hyman, B. T., et al. (2026) · doi:10.64898/2026.05.09.26352797 · Cited by 2 · see citing works
Self-citationChen, K., Chen, Y., Ren, Y., Wang, Z., Huang, Y., Pan, M., Li, Z., Casey, M. C., Qiao, W., Shi, J., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-78407-x
Self-citationJackson, R. J., Dierksmeier, S., Nishtar, M., Meltzer, J., Balduin, F., Beaumont, B., Fan, Z., Sergienko, E., Olson, S., Jackson, M. R., et al. (2026) · doi:10.64898/2026.06.09.730809
Self-citationGupta, A. (2026) · Natural Resources for Human Health · doi:10.53365/nrfhh.787
- Authors
- Reiman, E. M., Arboleda-Velasquez, J. F., Quiroz, Y. T., Huentelman, M. J., Beach, T. G., Caselli, R. J., Chen, Y., Su, Y., Myers, A. J., Hardy, J., Vonsattel, J. P., Younkin, S. G., Bennett, D. A., De Jager, P. L., Larson, E. B., Crane, P. K., Keene, C. D., Kamboh, M. I., Kofler, J. K., Duque, L., Gilbert, J. R., Gwirtsman, H. E., Buxbaum, J. D., Dickson, D. W., Frosch, M. P., Ghetti, B., Lunetta, K. L., Wang, L.-S., Hyman, B. T., Kukull, W. A., Foroud, T., Haines, J. L., Mayeux, R. P., Pericak-Vance, M. A., Schneider, J. A., Trojanowski, J. Q., Farrer, L. A., Schellenberg, G. D., Beecham, G. W., Montine, T. J., Jun, G. R., & for the Alzheimer’s Disease Genetics Consortium
- Affiliations
- Translational Genomics Research Institute (US)
- Harvard University (US)
- Banner Alzheimer’s Institute (US)
- Mayo Clinic in Arizona (US)
- University of Miami (US)
- UCL Queen Square Institute of Neurology (GB)
- NewYork–Presbyterian Hospital (US)
- Mayo Clinic in Florida (US)
- Rush University Medical Center (US)
- Kaiser Permanente Washington Health Research Institute (US)
- University of Washington (US)
- University of Pittsburgh (US)
- Vanderbilt University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Mayo Clinic (US)
- Massachusetts General Hospital (US)
- Indiana University Indianapolis (US)
- Boston University (US)
- University of Pennsylvania (US)
- Case Western Reserve University (US)
- Columbia University Irving Medical Center (US)
- Stanford Medicine (US)
- Corresponding author
- Reiman, Eric M.
- ORCID
- Reiman, Eric M.
- Arboleda-Velasquez, Joseph F.
- Quiroz, Yakeel T.
- Huentelman, Matthew J.
- Beach, Thomas G.
- Caselli, Richard J.
- Chen, Yinghua
- Su, Yi
- Myers, Amanda J.
- Hardy, John
- Bennett, David A.
- De Jager, Philip L.
- Larson, Eric B.
- Crane, Paul K.
- Keene, C. Dirk
- Kamboh, M. Ilyas
- Kofler, Julia K.
- Gilbert, John R.
- Buxbaum, Joseph D.
- Dickson, Dennis W.
- Frosch, Matthew P.
- Ghetti, Bernardino
- Lunetta, Kathryn L.
- Wang, Li-San
- Hyman, Bradley T.
- Kukull, Walter A.
- Foroud, Tatiana
- Haines, Jonathan L.
- Mayeux, Richard P.
- Schneider, Julie A.
- Trojanowski, John Q.
- Farrer, Lindsay A.
- Schellenberg, Gerard D.
- Beecham, Gary W.
- Montine, Thomas J.
- Jun, Gyungah R.
- Venue
- Nature Communications
- Publisher
- openRxiv
- Published
- 2019-11-02
- Volume
- 11
- Issue
- 1
- Pages
- 667-667
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6997393
- OpenAlex
- W3003860558
- Cited by
- 473
- References
- 33
- Citations by year
- 2026: 57 · 2025: 73 · 2024: 92 · 2023: 69 · 2022: 74 · 2021: 64 · 2020: 44
- FWCI
- 37.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Nature Communications (publishedVersion, cc-by)
- medRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UA Campus Repository (The University of Arizona) (acceptedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
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- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- U.S. Department of Health and Human Services (R01 AG15819, R01AG17917, RF1-AG057519, P30-AG10161)
- U.S. Department of Veterans Affairs (P50AG005136)
- Michael J. Fox Foundation for Parkinson's Research (05-901, 211002)
- Pfizer
- McKnight Foundation
- Brigham and Women's Hospital
- University of Southern California
- Children's Hospital of Philadelphia
- University of Miami
- Brigham Young University
- University of Pennsylvania (U24‐AG041689)
- Emory University
- Northwestern University
- Texas Tech University
- Arizona Department of Health Services (RC2AG036528, AG041718, AG030653, P50 AG005136, 05-901, P30 AG010133, U01AG032984, 211002, Contract 211002)
- Cleveland Clinic
- Nancy and Buster Alvord Endowment (AG005136, P50 AG005136)
- University of Washington (P50-AG005136)
- Johns Hopkins University
- University of Pittsburgh (AG030653, AG041718)
- Rush University (P30AG10161, R01 AG15819)
- University of South Florida
- University of North Texas
- USF Health Byrd Alzheimer's Institute
- Hope Center for Neurological Disorders
- York University
- Parkinson's UK (G-0907)
- Rosetrees Trust
- University of Toronto
- Arizona Biomedical Research Commission (05–901, and 1001, 211002)
- National Institutes of Health (UL1TR002369)
- University of California, Los Angeles
- University of California, San Diego
- Perelman School of Medicine, University of Pennsylvania
- Feinberg School of Medicine
- University of Texas Health Science Center at San Antonio
- University of California, Irvine
- Leonard M. Miller School of Medicine
- Leonard M. Miller School of Medicine, University of Miami
- Department of Pathology, Johns Hopkins University
- Geriatric Research Education and Clinical Center
- Medical Research Council (MR/L501542/1, MR/N026004/1)
- Cambridge Institute for Medical Research, University of Cambridge
- National Institute on Aging (AG006781, 211002, R01AG017917, AG010133, R01AG064877, P30-AG 10161, P30-AG-19610, P30AG010133, RF1AG051504, R01‐AG17917, R01 AG15819, AG-005133, AG046139, R01-NS080820, AG051504, U01AG006781, AG-19610, AG041718, RF1AG015473, R01AG048927, P30AG010124, R01AG030653, R01AG015819, P30AG010161, U01AG032984, RF1AG054023, R01AG031581, P50AG008702, AG032984, R01AG032990, P30AG019610, 05-901, RF1AG057519, P30-AG10161, R01AG15819, R01AG17917, U01AG046139, P50AG005136, R01AG061796, RF1AG057519, U01AG058922, RC2AG036528, U24AG056270, P30AG062429, P01AG019724, U24AG041689, P30AG066462, P30AG066518, P30AG062715, U24AG021886, P30AG062421, RF1AG057902, AG 030653)
- National Institute of Neurological Disorders and Stroke (RF1NS110048, R01NS080820, P30 AG10161, NS072026, 211002, NS080820, U24NS072026, 05-901)
- NIH Clinical Center
- National Center for Advancing Translational Sciences
- University of Colorado School of Medicine, Anschutz Medical Campus
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plants and Neuroprotection
- Keywords
- Alzheimer's disease, APOE ε4, apolipoprotein E, gene dosage, dementia risk, neuropathology
- MeSH terms
- Neuropathology, Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Brain, Female, Genotype, Homozygote, Humans, Male, Middle Aged, Probability, Genetic Predisposition to Disease, Apolipoprotein E3, Apolipoprotein E4, Apolipoprotein E2, Genetic Association Studies
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