Cognitively healthy centenarians are genetically protected against Alzheimer's disease
Open accessAbstract
BACKGROUND: Alzheimer's disease (AD) prevalence increases with age, yet a small fraction of the population reaches ages > 100 years without cognitive decline. We studied the genetic factors associated with such resilience against AD. METHODS: Genome‐wide association studies identified 86 single nucleotide polymorphisms (SNPs) associated with AD risk. We estimated SNP frequency in 2281 AD cases, 3165 age‐matched controls, and 346 cognitively healthy centenarians. We calculated a polygenic risk score (PRS) for each individual and investigated the functional properties of SNPs enriched/depleted in centenarians. RESULTS: Cognitively healthy centenarians were enriched with the protective alleles of the SNPs associated with AD risk. The protective effect concentrated on the alleles in/near ANKH, GRN, TMEM106B, SORT1, PLCG2, RIN3 , and APOE genes. This translated to >5‐fold lower PRS in centenarians compared to AD cases ( P = 7.69 × 10 −71 ), and 2‐fold lower compared to age‐matched controls ( P = 5.83 × 10 −17 ). DISCUSSION: Maintaining cognitive health until extreme ages requires complex genetic protection against AD, which concentrates on the genes associated with the endolysosomal and immune systems. Highlights: Cognitively healthy cent enarians are enriched with the protective alleles of genetic variants associated with Alzheimer's disease (AD). The protective effect is concentrated on variants involved in the immune and endolysosomal systems. Combining variants into a polygenic risk score (PRS) translated to > 5‐fold lower PRS in centenarians compared to AD cases, and ≈ 2‐fold lower compared to middle‐aged healthy controls.
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PLCG2P522R is overrepresented among centenarians.
“and is overrepresented among centenarians. 18”
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 [18]
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Nichols, E., Szoeke, C. E. I., Vollset, S. E., Abbasi, N., Abd-Allah, F., Abdela, J., Aichour, M. T. E., Akinyemi, R. O., Alahdab, F., Asgedom, S. W., et al. (2019) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30403-4 · Cited by 2,412 · see citing works
Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17
Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., et al. (2006) · Nature · doi:10.1038/nature05016 · Cited by 2,058 · see citing works
Naj, A. C., Jun, G., Beecham, G. W., Wang, L.-S., Vardarajan, B. N., Buros, J., Gallins, P. J., Buxbaum, J. D., Jarvik, G. P., Crane, P. K., et al. (2011) · Nature Genetics · doi:10.1038/ng.801 · Cited by 1,901 · see citing works
A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline
Jonsson, T., Atwal, J. K., Steinberg, S., Snaedal, J., Jonsson, P. V., Bjornsson, S., Stefansson, H., Sulem, P., Gudbjartsson, D., Maloney, J., et al. (2012) · Nature · doi:10.1038/nature11283 · Cited by 1,738 · see citing works
Dementia incidence continues to increase with age in the oldest old: The 90+ study
Corrada, M. M., Brookmeyer, R., Paganini‐Hill, A., Berlau, D., & Kawas, C. H. (2010) · Annals of Neurology · doi:10.1002/ana.21915 · Cited by 523 · see citing works
A meta-analysis of genome-wide association studies identifies multiple longevity genes
Deelen, J., Evans, D. S., Arking, D. E., Tesi, N., Nygaard, M., Liu, X., Wojczynski, M. K., Biggs, M. L., van der Spek, A., Atzmon, G., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11558-2 · Cited by 370 · see citing works
Self-citationThe <i>MS4A</i> gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk
Deming, Y., Filipello, F., Cignarella, F., Cantoni, C., Hsu, S., Mikesell, R., Li, Z., Del-Aguila, J. L., Dube, U., Farias, F. G., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aau2291 · Cited by 271 · see citing works
DESGESCO (Dementia Genetics Spanish Consortium), E. (. D. E. D. B., van der Lee, S. J., biobank), E. (. D. E. D., IFGC (International FTD-Genomics Consortium), I. (. I. P. D. G. C., IPDGC (The International Parkinson Disease Genomics Consortium), Dementia), R.-F. (. A. M. F. I. F.-T., (NBB), N. B. B., The GIFT (Genetic Investigation in Frontotemporal Dementia and Alzheimer’s Disease) Study Group, Conway, O. J., Jansen, I., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02026-8 · Cited by 120 · see citing works
Self-citationDysfunction of phospholipase Cγ in immune disorders and cancer
Koss, H., Bunney, T. D., Behjati, S., & Katan, M. (2014) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2014.09.004 · Cited by 115 · see citing works
Tesi, N., van der Lee, S. J., Hulsman, M., Jansen, I. E., Stringa, N., van Schoor, N., Meijers-Heijboer, H., Huisman, M., Scheltens, P., Reinders, M. J. T., et al. (2019) · European Journal of Human Genetics · doi:10.1038/s41431-018-0273-5 · Cited by 65 · see citing works
Self-citationThe Netherlands Brain Bank for Psychiatry
(2018) · Handbook of Clinical Neurology · doi:10.1016/b978-0-444-63639-3.00001-3 · Cited by 22 · see citing works
Kutukculer, N., Topyildiz, E., Berdeli, A., Guven Bilgin, B., Aykut, A., Durmaz, A., Cogulu, O., Aksu, G., & Edeer Karaca, N. (2021) · Clinical Case Reports · doi:10.1002/ccr3.3934 · Cited by 21 · see citing works
Flagged first, then by citations
Research works printed but not linked: 45
- [3]2012 Alzheimer's disease facts and figures. Alzheimer's & Dementia. 2012; 8: 131‐ 168. 22404854
- [4]Perls T. Dementia‐free centenarians. Exp Gerontol. 2004; 39: 1587‐ 1593. 15582273
- [5]Holstege H, Beker N, Dijkstra T, et al. The 100‐plus Study of cognitively healthy centenarians: rationale, design and cohort description. Eur J Epidemiol. 2018; 33: 1229‐ 1249. doi: 10.1007/s10654-018-0451-3 30362018 PMC6290855 · DOI
- [6]Winblad B, Amouyel P, Andrieu S, et al. Defeating Alzheimer's disease and other dementias: a priority for European science and society. The Lancet Neurology. 2016; 15: 455‐ 532. 26987701
- [8]Holstege H, Hulsman M, Charbonnier C, et al. Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease. Nat Genet. 2022; 54: 1786‐ 1794. 36411364 PMC9729101
- [9]Gatz M, Reynolds CA, Fratiglioni L, et al. Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry. 2006; 63: 168‐ 174. 16461860
- [10]Bellenguez C, Küçükali F, Jansen IE, et al. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022; 54: 412‐ 436. 35379992 PMC9005347
- [11]Malik M, Simpson JF, Parikh I, et al. CD33 Alzheimer's risk‐altering polymorphism, CD33 expression, and exon 2 splicing. J Neurosci. 2013; 33: 13320‐ 13325. 23946390 PMC3742922
- [12]Sebastiani P, Perls TT. The genetics of extreme longevity: lessons from the new England centenarian study. Front Genet. 2012; 3: 277. 23226160 PMC3510428
- [13]Seto M, Weiner RL, Dumitrescu L, Hohman TJ. Protective genes and pathways in Alzheimer's disease: moving towards precision interventions. Mol Neurodegeneration. 2021; 16: 29. PMC8086309 33926499
- [14]Joshi PK, Pirastu N, Kentistou KA, et al. Genome‐wide meta‐analysis associates HLA‐DQA1/DRB1 and LPA and lifestyle factors with human longevity. Nat Commun. 2017; 8(1): 910. 29030599 PMC5715013
- [17]van der Flier WM, Scheltens P. Amsterdam dementia cohort: performing research to optimize care. Journal of Alzheimer's Disease. 2018; 62: 1091‐ 1111. PMC5870023 29562540
- [18]Dreves MAE, van Harten AC, Visser LNC, et al. Rationale and design of the ABOARD project (A Personalized Medicine Approach for Alzheimer's Disease). A&D Transl Res & Clin Interv. 2023; 9: e12401. PMC10242186 37287472
- [19]van der Flier WM, de Vugt ME, Smets EMA, Blom M, Teunissen CE. Towards a future where Alzheimer's disease pathology is stopped before the onset of dementia. Nat Aging. 2023; 3: 494‐ 505. 37202515
- [21]Hoogendijk EO, Deeg DJH, Poppelaars J, et al. The Longitudinal Aging Study Amsterdam: cohort update 2016 and major findings. Eur J Epidemiol. 2016; 31: 927‐ 945. 27544533 PMC5010587
- [22]Willemsen G, de Geus EJC, Bartels M, et al. The Netherlands twin register biobank: a resource for genetic epidemiological studies. Twin Research and Human Genetics. 2010; 13: 231‐ 245. 20477721
- [23]de Rojas I, Moreno‐Grau S, Tesi N, et al. Common variants in Alzheimer's disease and risk stratification by polygenic risk scores. Nat Commun. 2021; 12: 3417. 34099642 PMC8184987
- [25]Anderson CA, Pettersson FH, Clarke GM, Cardon LR, Morris AP, Zondervan KT. Data quality control in genetic case‐control association studies. Nat Protoc. 2010; 5: 1564‐ 1573. 21085122 PMC3025522
- [26]1000 Genomes Project Consortium, Auton A, Brooks LD, et al, 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature. 2015; 526: 68‐ 74. 26432245 PMC4750478
- [27]Tesi N, van der Lee S, Hulsman M, Holstege H, Reinders MJT. snpXplorer: a web application to explore human SNP‐associations and annotate SNP‐sets. Nucleic Acids Res. 2021; 49: W603‐ W612. 34048563 PMC8262737
- [28]Moore CM, Jacobson SA, Fingerlin TE. Power and sample size calculations for genetic association studies in the presence of genetic model misspecification. Hum Hered. 2019; 84: 256‐ 271. 32721961 PMC7666027
- [29]Slot RER, Verfaillie SCJ, Overbeek JM, et al. Subjective Cognitive Impairment Cohort (SCIENCe): study design and first results. Alzheimer's Research & Therapy. 2018; 10(1): 76. PMC6080529 30081935
- [30]Katsumata Y, Shade LM, Hohman TJ, et al. Multiple gene variants linked to Alzheimer's‐type clinical dementia via GWAS are also associated with non‐Alzheimer's neuropathologic entities. Neurobiol Dis. 2022; 174: 105880. 36191742 PMC9641973
- [31]Nugent S, Potvin O, Cunnane SC, Chen T‐H, Duchesne S. Associating Type 2 diabetes risk factor genes and FDG‐PET brain metabolism in normal aging and Alzheimer's disease. Front Aging Neurosci. 2020; 12: 580633. 33192474 PMC7661639
- [32]Pendleton A, Johnson MD, Hughes A, et al. Mutations in ANKH cause chondrocalcinosis. Am Hum Genet. 2002; 71: 933‐ 940. PMC378546 12297987
- [33]Rhinn H, Abeliovich A. Differential aging analysis in human cerebral cortex identifies variants in TMEM106B and GRN that Regulate Aging Phenotypes. Cell Syst. 2017; 4: 404‐ 415..e5. 28330615
- [34]Finch N, Carrasquillo MM, Baker M, et al. TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology. 2011; 76: 467‐ 474. 21178100 PMC3034409
- [35]Simon MJ, Logan T, DeVos SL, Di Paolo G. Lysosomal functions of progranulin and implications for treatment of frontotemporal dementia. Trends Cell Biol. 2023; 33: 324‐ 339. 36244875
- [36]Van Deerlin VM, Sleiman PMA, Martinez‐Lage M, et al. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP‐43 inclusions. Nat Genet. 2010; 42: 234‐ 239. 20154673 PMC2828525
- [38]Shen R, Zhao X, He L, et al. Upregulation of RIN3 induces endosomal dysfunction in Alzheimer's disease. Transl Neurodegener. 2020; 9: 26. 32552912 PMC7301499
- [39]Shashoua VE. Ependymin, a brain extracellular glycoprotein, and CNS plasticity. Ann NY Acad Sci. 1991; 627: 94‐ 114. 1831964
- [40]Li M, Geng R, Li C, et al. Dysregulated gene‐associated biomarkers for Alzheimer's disease and aging. Translational Neuroscience. 2021; 12: 83‐ 95. 33623715 PMC7885957
- [41]Xing L, Martyniuk CJ, Esau C, Da Fonte DF, Trudeau VL. Proteomic profiling reveals dopaminergic regulation of progenitor cell functions of goldfish radial glial cells in vitro. J Proteomics. 2016; 144: 123‐ 132. 27185549
- [42]Tesi N, van der Lee SJ, Hulsman M, et al. Polygenic risk score of longevity predicts longer survival across an age continuum. The Journals of Gerontology: Series A. 2020; 76(5): 750‐ 759. PMC8087277 33216869
- [45]Zhong L, Chen X‐F, Wang T, et al. Soluble TREM2 induces inflammatory responses and enhances microglial survival. J Exp Med. 2017; 214: 597‐ 607. 28209725 PMC5339672
- [46]Diks AM, Teodosio C, De Mooij B, et al. Carriers of the p.P522R variant in PLCγ2 have a slightly more responsive immune system. Mol Neurodegeneration. 2023; 18: 25. PMC10116473 37081539
- [48]Mishra S, Knupp A, Szabo MP, et al. The Alzheimer's gene SORL1 is a regulator of endosomal traffic and recycling in human neurons. Cell Mol Life Sci. 2022; 79: 162. 35226190 PMC8885486
- [49]Zhang M, Ganz AB, Rohde S, et al. The correlation between neuropathology levels and cognitive performance in centenarians. Alzheimer's & Dementia. 2023; 19(11): 5036‐ 5047. 37092333
- [51]Arboleda‐Velasquez JF, Lopera F, O'Hare M, et al. Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019; 25: 1680‐ 1683. 31686034 PMC6898984
- [52]Beker N, Sikkes SAM, Hulsman M, et al. Longitudinal maintenance of cognitive health in centenarians in the 100‐plus Study. JAMA Netw Open. 2020; 3: e200094. 32101309 PMC7137688
- [53]Deelen J, Beekman M, Uh H‐W, et al. Genome‐wide association meta‐analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age. Hum Mol Genet. 2014; 23: 4420‐ 4432. 24688116 PMC4103672
- [55]Timmers PR, Mounier N, Lall K, et al. Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances. eLife. 2019; 8: e39856. 30642433 PMC6333444
- [56]Timmers PRHJ, Wilson JF, Joshi PK, Deelen J. Multivariate genomic scan implicates novel loci and haem metabolism in human ageing. Nat Commun. 2020; 11: 3570. 32678081 PMC7366647
- [57]Poon LW, Woodard JL, Stephen Miller L, et al. Understanding dementia prevalence among centenarians. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2012; 67A: 358‐ 365. PMC3309877 22389466
- [58]Sherva R, Zhang R, Sahelijo N, et al. African ancestry GWAS of dementia in a large military cohort identifies significant risk loci. Mol Psychiatry. 2023; 28: 1293‐ 1302. 36543923 PMC10066923
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“45,46 To assess if reduced LDLR binding of lipApoE2 could be protective, we adopted a simple paradigm of treating cultured cells with lipid-complexed HEK293-purified ApoE isoforms.”
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 · see citing works
“18 Conversely, the partial loss-of-function M28L variant (PLCG2 M28L ) confers increased risk for AD.”
- Authors
- Tesi, N., van der Lee, S., Hulsman, M., van Schoor, N. M., Huisman, M., Pijnenburg, Y., van der Flier, W. M., Reinders, M., & Holstege, H.
- Affiliations
- Delft Bioinformatics Lab Delft University of Technology Delft The Netherlands
- Department of Clinical Genetics Section Genomics of Neurodegenerative Diseases and Aging Vrije Universiteit Amsterdam, Amsterdam UMC Amsterdam The Netherlands
- Amsterdam Neuroscience (NL)
- Department of Epidemiology and Data Sciences Amsterdam UMC location Vrije Universiteit Amsterdam Amsterdam The Netherlands
- Amsterdam Public Health (NL)
- Department of Neurology Alzheimer Center Amsterdam Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC Amsterdam The Netherlands
- Delft University of Technology (NL)
- Corresponding author
- Holstege, Henne
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2024-04-18
- Volume
- 20
- Issue
- 6
- Pages
- 3864-3875
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC11180929
- OpenAlex
- W4394917769
- Cited by
- 52
- References
- 12
- Citations by year
- 2026: 18 · 2025: 26 · 2024: 8
- FWCI
- 14.80
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- Funders
- ZonMw (LSHM20106, #73305095007)
- Hersenstichting
- 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, centenarians
- MeSH terms
- Aged, 80 and over, Alleles, Alzheimer Disease, Female, Humans, Male, Case-Control Studies, Genetic Predisposition to Disease, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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