Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

A global view of the genetic basis of Alzheimer disease

Nature Reviews Neurology volume 19, pages 261–277 (2023)Cite this article

Subjects

Abstract

The risk of Alzheimer disease (AD) increases with age, family history and informative genetic variants. Sadly, there is still no cure or means of prevention. As in other complex diseases, uncovering genetic causes of AD could identify underlying pathological mechanisms and lead to potential treatments. Rare, autosomal dominant forms of AD occur in middle age as a result of highly penetrant genetic mutations, but the most common form of AD occurs later in life. Large-scale, genome-wide analyses indicate that 70 or more genes or loci contribute to AD. One of the major factors limiting progress is that most genetic data have been obtained from non-Hispanic white individuals in Europe and North America, preventing the development of personalized approaches to AD in individuals of other ethnicities. Fortunately, emerging genetic data from other regions — including Africa, Asia, India and South America — are now providing information on the disease from a broader range of ethnicities. Here, we summarize the current knowledge on AD genetics in populations across the world. We predominantly focus on replicated genetic discoveries but also include studies in ethnic groups where replication might not be feasible. We attempt to identify gaps that need to be addressed to achieve a complete picture of the genetic and molecular factors that drive AD in individuals across the globe.

Key points

  • The genetic variation underlying Alzheimer disease (AD) differs across ethnic groups.

  • Large-scale genomic studies have identified over 70 genes or genetic loci associated with AD risk, but these data have largely been obtained from populations in Europe and North America, which hinders our understanding of the molecular mechanism(s) underlying the disease in under-represented populations and the development of a personalized therapeutic approach.

  • Expansion of efforts to sequence and analyse the genomes of people from under-studied areas of the world, combined with acquisition of additional multiomics data and appropriate development of infrastructure, resources, training and ethical guidelines, will be essential to improve our understanding of global genetic variation profiles underlying dementia.

  • Pathological heterogeneity is the norm in AD and efforts to incorporate this information into genetic studies is underway.

  • Incorporation of improved biomarkers that can be obtained in low-resource countries will be critical to increase diagnostic accuracy in these efforts.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Genetic loci associated with Alzheimer disease in genome-wide association studies of non-Hispanic white individuals.
Fig. 2: Timeline and routes of human migration inferred from genomic data.
Fig. 3: Admixture mapping of Alzheimer disease in Caribbean Hispanic individuals.
Fig. 4: Prevalence of dementia in Africa.
Fig. 5: Pathology in clinically diagnosed Alzheimer disease.
Fig. 6: An integrated multiomics approach.

Similar content being viewed by others

References

  1. 2022 Alzheimer’s disease facts and figures. Alzheimers Dement. 18, 700–789 (2022).

  2. Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168–174 (2006).

    Article  PubMed  Google Scholar 

  3. Chartier-Harlin, M. C. et al. Early-onset Alzheimer’s disease caused by mutations at codon 717 of the β-amyloid precursor protein gene. Nature 353, 844–846 (1991).

    Article  CAS  PubMed  Google Scholar 

  4. Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706 (1991).

    Article  CAS  PubMed  Google Scholar 

  5. Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375, 754–760 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Sherrington, R. et al. Alzheimer’s disease associated with mutations in presenilin 2 is rare and variably penetrant. Hum. Mol. Genet. 5, 985–988 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Cacace, R., Sleegers, K. & Van Broeckhoven, C. Molecular genetics of early-onset Alzheimer’s disease revisited. Alzheimers Dement. 12, 733–748 (2016).

    Article  PubMed  Google Scholar 

  8. Jarmolowicz, A. I., Chen, H. Y. & Panegyres, P. K. The patterns of inheritance in early-onset dementia: Alzheimer’s disease and frontotemporal dementia. Am. J. Alzheimers Dis. Other Demen 30, 299–306 (2015).

    Article  PubMed  Google Scholar 

  9. Wallon, D. et al. The French series of autosomal dominant early onset Alzheimer’s disease cases: mutation spectrum and cerebrospinal fluid biomarkers. J. Alzheimers Dis. 30, 847–856 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Cruchaga, C. et al. Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer’s disease families. PLoS One 7, e31039 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Arboleda-Velasquez, J. F. et al. Resistance to autosomal dominant Alzheimer’s disease in an APOE3 Christchurch homozygote: a case report. Nat. Med. 25, 1680–1683 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pericak-Vance, M. A. et al. Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am. J. Hum. Genet. 48, 1034–1050 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Wingo, T. S., Lah, J. J., Levey, A. I. & Cutler, D. J. Autosomal recessive causes likely in early-onset Alzheimer disease. Arch. Neurol. 69, 59–64 (2012).

    Article  PubMed  Google Scholar 

  14. Wightman, D. P. et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat. Genet. 53, 1276–1282 (2021).

    Article  CAS  PubMed  Google Scholar 

  15. Kunkle, B. W. et al. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat. Genet. 51, 414–430 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bellenguez, C. et al. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nat. Genet. 54, 412–436 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jansen, I. E. et al. Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers. Acta Neuropathol. 144, 821–842 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rubinski, A. et al. Polygenic effect on tau pathology progression in Alzheimer’s disease. Ann. Neurol. https://doi.org/10.1002/ana.26588 (2022).

    Article  Google Scholar 

  19. Vigilant, L., Stoneking, M., Harpending, H., Hawkes, K. & Wilson, A. C. African populations and the evolution of human mitochondrial DNA. Science 253, 1503–1507 (1991).

    Article  CAS  PubMed  Google Scholar 

  20. Schlebusch, C. M. et al. Genomic variation in seven Khoe-San groups reveals adaptation and complex African history. Science 338, 374–379 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gronau, I., Hubisz, M. J., Gulko, B., Danko, C. G. & Siepel, A. Bayesian inference of ancient human demography from individual genome sequences. Nat. Genet. 43, 1031–1034 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rasmussen, M. et al. Ancient human genome sequence of an extinct Palaeo-Eskimo. Nature 463, 757–762 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Green, R. E. et al. A draft sequence of the Neandertal genome. Science 328, 710–722 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ramachandran, S. et al. Support from the relationship of genetic and geographic distance in human populations for a serial founder effect originating in Africa. Proc. Natl Acad. Sci. USA 102, 15942–15947 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jakobsson, M. et al. Genotype, haplotype and copy-number variation in worldwide human populations. Nature 451, 998–1003 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Li, J. Z. et al. Worldwide human relationships inferred from genome-wide patterns of variation. Science 319, 1100–1104 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Rosenberg, N. A. et al. Genetic structure of human populations. Science 298, 2381–2385 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Gurdasani, D. et al. The African Genome Variation Project shapes medical genetics in Africa. Nature 517, 327–332 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Beltrame, M. H., Rubel, M. A. & Tishkoff, S. A. Inferences of African evolutionary history from genomic data. Curr. Opin. Genet. Dev. 41, 159–166 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tishkoff, S. A. et al. The genetic structure and history of Africans and African Americans. Science 324, 1035–1044 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Duncan, L. et al. Analysis of polygenic risk score usage and performance in diverse human populations. Nat. Commun. 10, 3328 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. The 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature 526, 68–74 (2015).

    Article  Google Scholar 

  33. Rotimi, C. N. & Adeyemo, A. A. From one human genome to a complex tapestry of ancestry. Nature 590, 220–221 (2021).

    Article  CAS  PubMed  Google Scholar 

  34. Hong, S. et al. TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer’s disease biomarker levels. Alzheimers Dement. 17, 1628–1640 (2021).

    Article  CAS  PubMed  Google Scholar 

  35. Rotimi, C. N. et al. The genomic landscape of African populations in health and disease. Hum. Mol. Genet. 26, R225–R236 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kunkle, B. W. et al. Novel Alzheimer disease risk loci and pathways in African American individuals using the African genome resources panel: a meta-analysis. JAMA Neurol. 78, 102–113 (2021).

    Article  PubMed  Google Scholar 

  37. Hohman, T. J. et al. Global and local ancestry in African-Americans: implications for Alzheimer’s disease risk. Alzheimers Dement. 12, 233–243 (2016).

    Article  PubMed  Google Scholar 

  38. Reitz, C. et al. Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ε4, and the risk of late-onset Alzheimer disease in African Americans. JAMA 309, 1483–1492 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bussies, P. L. et al. Use of local genetic ancestry to assess TOMM40-523’ and risk for Alzheimer disease. Neurol. Genet. 6, e404 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Vardarajan, B. N. et al. Whole genome sequencing of Caribbean Hispanic families with late-onset Alzheimer’s disease. Ann. Clin. Transl. Neurol. 5, 406–417 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vardarajan, B. N. et al. Ultra-rare mutations in SRCAP segregate in Caribbean Hispanic families with Alzheimer disease. Neurol. Genet. 3, e178 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Feliciano-Astacio, B. E. et al. The Puerto Rico Alzheimer Disease Initiative (PRADI): a multisource ascertainment approach. Front. Genet. 10, 538 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Tosto, G. et al. F-box/LRR-repeat protein 7 is genetically associated with Alzheimer’s disease. Ann. Clin. Transl. Neurol. 2, 810–820 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tosto, G. et al. Association of variants in PINX1 and TREM2 with late-onset Alzheimer disease. JAMA Neurol. 76, 942–948 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Farrer, L. A. et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 278, 1349–1356 (1997).

    Article  CAS  PubMed  Google Scholar 

  46. Maestre, G. et al. Apolipoprotein E and Alzheimer’s disease: ethnic variation in genotypic risks. Ann. Neurol. 37, 254–259 (1995).

    Article  CAS  PubMed  Google Scholar 

  47. Tang, M. X. et al. The APOE-ε4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics. JAMA 279, 751–755 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. Raghavan, N. S. et al. Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer’s disease. Ann. Clin. Transl. Neurol. 5, 832–842 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Griswold, A. J. et al. Increased APOE ε4 expression is associated with the difference in Alzheimer’s disease risk from diverse ancestral backgrounds. Alzheimers Dement. 17, 1179–1188 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jun, G. R. et al. Transethnic genome-wide scan identifies novel Alzheimer’s disease loci. Alzheimers Dement. 13, 727–738 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Cukier, H. N. et al. ABCA7 frameshift deletion associated with Alzheimer disease in African Americans. Neurol. Genet. 2, e79 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Bryc, K. et al. Genome-wide patterns of population structure and admixture in West Africans and African Americans. Proc. Natl Acad. Sci. USA 107, 786–791 (2010).

    Article  CAS  PubMed  Google Scholar 

  54. Kunkle, B. W. et al. Targeted sequencing of ABCA7 identifies splicing, stop-gain and intronic risk variants for Alzheimer disease. Neurosci. Lett. 649, 124–129 (2017).

    Article  CAS  PubMed  Google Scholar 

  55. De Roeck, A. et al. Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer’s disease. Acta Neuropathol. 134, 475–487 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Cuyvers, E. et al. Mutations in ABCA7 in a Belgian cohort of Alzheimer’s disease patients: a targeted resequencing study. Lancet Neurol. 14, 814–822 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Luukkainen, L. et al. Mutation analysis of the genes linked to early onset Alzheimer’s disease and frontotemporal lobar degeneration. J. Alzheimers Dis. 69, 775–782 (2019).

    Article  CAS  PubMed  Google Scholar 

  58. Thordardottir, S. & Graff, C. Findings from the Swedish study on familial Alzheimer’s disease including the APP Swedish double mutation. J. Alzheimers Dis. 64, S491–S496 (2018).

    Article  CAS  PubMed  Google Scholar 

  59. Al-Thani, H. F., Ahmad, M. N., Younes, S. & Zayed, H. Genetic variants associated with Alzheimer disease in the 22 Arab countries: a systematic review. Alzheimer Dis. Assoc. Disord. 35, 178–186 (2021).

    Article  CAS  PubMed  Google Scholar 

  60. Eryilmaz, I. E. et al. Evaluation of the clinical features accompanied by the gene mutations: the 2 novel PSEN1 variants in a Turkish early-onset Alzheimer disease cohort. Alzheimer Dis. Assoc. Disord. 35, 214–222 (2021).

    Article  CAS  PubMed  Google Scholar 

  61. Lee, J. H. et al. Disease-related mutations among Caribbean Hispanics with familial dementia. Mol. Genet. Genom. Med. 2, 430–437 (2014).

    Article  CAS  Google Scholar 

  62. Athan, E. S. et al. A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families. JAMA 286, 2257–2263 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Bertoli Avella, A. M. et al. A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease. Neurogenetics 4, 97–104 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Arnold, S. E. et al. Frequency and clinicopathological characteristics of presenilin 1 Gly206Ala mutation in Puerto Rican Hispanics with dementia. J. Alzheimers Dis. 33, 1089–1095 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ramos, C., Aguillon, D., Cordano, C. & Lopera, F. Genetics of dementia: insights from Latin America. Dement. Neuropsychol. 14, 223–236 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Itzcovich, T. et al. A novel mutation in PSEN1 (p.T119I) in an Argentine family with early- and late-onset Alzheimer’s disease. Neurobiol. Aging 85, 155.e9–155.e12 (2020).

    Article  CAS  PubMed  Google Scholar 

  67. Abdala, B. B. et al. Influence of low frequency PSEN1 variants on familial Alzheimer’s disease risk in Brazil. Neurosci. Lett. 653, 341–345 (2017).

    Article  CAS  PubMed  Google Scholar 

  68. El Kadmiri, N. et al. Novel mutations in the amyloid precursor protein gene within Moroccan patients with Alzheimer’s disease. J. Mol. Neurosci. 53, 189–195 (2014).

    CAS  PubMed  Google Scholar 

  69. El Kadmiri, N. et al. Novel presenilin mutations within Moroccan patients with early-onset Alzheimer’s disease. Neuroscience 269, 215–222 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Heckmann, J. M. et al. Novel presenilin 1 mutation with profound neurofibrillary pathology in an indigenous Southern African family with early-onset Alzheimer’s disease. Brain 127, 133–142 (2004).

    Article  PubMed  Google Scholar 

  71. Guerreiro, R. J. et al. Genetic screening of Alzheimer’s disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol. Aging 31, 725–731 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Joshi, P., Gardner, M., Lintott, C. & Anderson, T. Novel presenilin-1 mutation (Ala275Ser) associated with clinical features of dementia with Lewy bodies. Alzheimer Dis. Assoc. Disord. 35, 350–352 (2021).

    Article  CAS  PubMed  Google Scholar 

  73. Bechara, J. A., Brooks, W. S., Kwok, J. B., Halliday, G. M. & Schofield, P. R. Familial Alzheimer’s disease in Australia. Alzheimer’s Dement. 16, e040062 (2020).

    Article  Google Scholar 

  74. Syama, A. et al. Mutation burden profile in familial Alzheimer’s disease cases from India. Neurobiol. Aging 64, 158.e7–158.e13 (2018).

    Article  CAS  PubMed  Google Scholar 

  75. Li, H. et al. The identification of PSEN1 p.Tyr159Ser mutation in a non-canonic early-onset Alzheimer’s disease family. Mol. Cell Neurosci. 120, 103715 (2022).

    Article  CAS  PubMed  Google Scholar 

  76. Qin, Q. et al. Gene mutations associated with early onset familial Alzheimer’s disease in China: an overview and current status. Mol. Genet. Genom. Med. 8, e1443 (2020).

    CAS  Google Scholar 

  77. Bagyinszky, E., Youn, Y. C., An, S. S. & Kim, S. Mutations, associated with early-onset Alzheimer’s disease, discovered in Asian countries. Clin. Interv. Aging 11, 1467–1488 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ikeuchi, T. et al. Mutational analysis in early-onset familial dementia in the Japanese population. The role of PSEN1 and MAPT R406W mutations. Dement. Geriatr. Cogn. Disord. 26, 43–49 (2008).

    Article  CAS  PubMed  Google Scholar 

  79. Hsu, J. L., Lin, C. H., Chen, P. L., Lin, K. J. & Chen, T. F. Genetic study of young-onset dementia using targeted gene panel sequencing in Taiwan. Am. J. Med. Genet. B Neuropsychiatr. Genet. 186, 67–76 (2021).

    Article  CAS  PubMed  Google Scholar 

  80. Bagyinszky, E., Ch’ng, G. S., Chan, M. Y., An, S. S. A. & Kim, S. A pathogenic presenilin-1 Val96Phe mutation from a Malaysian family. Brain Sci. 11, 1328 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Alzheimer’s Disease International. Dementia in Sub-Saharan Africa: Challenges and Opportunities (Alzheimer’s Disease International, 2017).

  82. Landoulsi, Z. et al. Genetic analysis of TREM2 variants in Tunisian patients with Alzheimer’s disease. Med. Princ. Pract. 27, 317–322 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Hendrie, H. C. et al. APOE ε4 and the risk for Alzheimer disease and cognitive decline in African Americans and Yoruba. Int. Psychogeriatr. 26, 977–985 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Hall, K. et al. Cholesterol, APOE genotype, and Alzheimer disease: an epidemiologic study of Nigerian Yoruba. Neurology 66, 223–227 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Chen, C. H. et al. A comparative study to screen dementia and APOE genotypes in an ageing East African population. Neurobiol. Aging 31, 732–740 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Gureje, O. et al. APOE ε4 is not associated with Alzheimer’s disease in elderly Nigerians. Ann. Neurol. 59, 182–185 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Haithem, H. et al. Association between dementia and vascular disease-associated polymorphisms in a Tunisian population. Int. J. Neurosci. 128, 32–41 (2018).

    Article  CAS  PubMed  Google Scholar 

  88. Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923 (1993).

    Article  CAS  PubMed  Google Scholar 

  89. Mayeux, R. et al. The apolipoprotein epsilon 4 allele in patients with Alzheimer’s disease. Ann. Neurol. 34, 752–754 (1993).

    Article  CAS  PubMed  Google Scholar 

  90. McKhann, G. et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services task force on Alzheimer’s disease. Neurology 34, 939–944 (1984).

    Article  CAS  PubMed  Google Scholar 

  91. World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines (WHO, 1992).

  92. Blue, E. E., Horimoto, A., Mukherjee, S., Wijsman, E. M. & Thornton, T. A. Local ancestry at APOE modifies Alzheimer’s disease risk in Caribbean Hispanics. Alzheimers Dement. 15, 1524–1532 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Rajabli, F. et al. Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations. PLoS Genet. 14, e1007791 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Rajabli, F. et al. A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer’s disease in African ancestry. PLoS Genet. 18, e1009977 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hendrie, H. C. et al. Incidence of dementia and Alzheimer disease in 2 communities: Yoruba residing in Ibadan, Nigeria, and African Americans residing in Indianapolis, Indiana. JAMA 285, 739–747 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Adhikari, K., Chacon-Duque, J. C., Mendoza-Revilla, J., Fuentes-Guajardo, M. & Ruiz-Linares, A. The genetic diversity of the Americas. Annu. Rev. Genomics Hum. Genet. 18, 277–296 (2017).

    Article  CAS  PubMed  Google Scholar 

  97. Adhikari, K., Mendoza-Revilla, J., Chacon-Duque, J. C., Fuentes-Guajardo, M. & Ruiz-Linares, A. Admixture in Latin America. Curr. Opin. Genet. Dev. 41, 106–114 (2016).

    Article  CAS  PubMed  Google Scholar 

  98. Salzano, F. M. & Bortolini, M. C. The Evolution and Genetics of Latin American Populations (Cambridge Univ. Press, 2001).

  99. Prince, M. et al. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 9, 63–75.e2 (2013).

    Article  PubMed  Google Scholar 

  100. Ferri, C. P. et al. Global prevalence of dementia: a Delphi consensus study. Lancet 366, 2112–2117 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Ramirez Aguilar, L. et al. Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr). Alzheimers Dement. 15, 709–719 (2019).

    Article  PubMed  Google Scholar 

  102. Lopera, F. et al. Clinical features of early-onset Alzheimer disease in a large kindred with an E280A presenilin-1 mutation. JAMA 277, 793–799 (1997).

    Article  CAS  PubMed  Google Scholar 

  103. Tariot, P. N. et al. The Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Trial: a study of crenezumab versus placebo in preclinical PSEN1 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer’s disease, including a placebo-treated noncarrier cohort. Alzheimers Dement. 4, 150–160 (2018).

    Article  Google Scholar 

  104. Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013).

    Article  CAS  PubMed  Google Scholar 

  105. Vardarajan, B. N. et al. Rare coding mutations identified by sequencing of Alzheimer disease genome-wide association studies loci. Ann. Neurol. 78, 487–498 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Vardarajan, B. N. et al. Inbreeding among Caribbean Hispanics from the Dominican Republic and its effects on risk of Alzheimer disease. Genet. Med. 17, 639–643 (2015).

    Article  PubMed  Google Scholar 

  107. An, F. et al. MiR-124 acts as a target for Alzheimer’s disease by regulating BACE1. Oncotarget 8, 114065–114071 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Sims, R. et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat. Genet. 49, 1373–1384 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kizil, C. et al. Admixture mapping of Alzheimer’s disease in Caribbean Hispanics identifies a new locus on 22q13.1. Mol. Psychiatry 27, 2813–2820 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Toral-Rios, D. et al. SORL1 polymorphisms in Mexican patients with Alzheimer’s disease. Genes 13, 587 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Jia, L. et al. Dementia in China: epidemiology, clinical management, and research advances. Lancet Neurol. 19, 81–92 (2020).

    Article  PubMed  Google Scholar 

  112. Gan, C. L., Zhang, T. & Lee, T. H. The genetics of Alzheimer’s disease in the Chinese population. Int. J. Mol. Sci. 21, 2381 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Miyashita, A., Kikuchi, M., Hara, N. & Ikeuchi, T. Genetics of Alzheimer’s disease: an East Asian perspective. J. Hum. Genet. 68, 115–124 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Jiang, T. et al. A rare coding variant in TREM2 increases risk for Alzheimer’s disease in Han Chinese. Neurobiol. Aging 42, 217 (2016).

    Article  Google Scholar 

  115. Jiang, T. et al. TREM2 p.H157Y variant and the risk of Alzheimer’s disease: a meta-analysis involving 14,510 subjects. Curr. Neurovasc Res. 13, 318–320 (2016).

    Article  CAS  PubMed  Google Scholar 

  116. Hirano, A. et al. A genome-wide association study of late-onset Alzheimer’s disease in a Japanese population. Psychiatr. Genet. 25, 139–146 (2015).

    Article  CAS  PubMed  Google Scholar 

  117. Jia, L. et al. Prediction of Alzheimer’s disease using multi-variants from a Chinese genome-wide association study. Brain 144, 924–937 (2021).

    Article  PubMed  Google Scholar 

  118. Kang, S. et al. Potential novel genes for late-onset Alzheimer’s disease in East-Asian descent identified by APOE-stratified genome-wide association study. J. Alzheimers Dis. 82, 1451–1460 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Park, J. H. et al. Novel Alzheimer’s disease risk variants identified based on whole-genome sequencing of APOE ε4 carriers. Transl. Psychiatry 11, 296 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Shigemizu, D. et al. Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer’s disease risk. Transl. Psychiatry 11, 151 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhou, X. et al. Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer’s disease pathogenesis. Proc. Natl Acad. Sci. USA 115, 1697–1706 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Wang, Y., Lu, D., Chung, Y. J. & Xu, S. Genetic structure, divergence and admixture of Han Chinese, Japanese and Korean populations. Hereditas 155, 19 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Dogan, M. et al. Clinical and molecular findings in a Turkish family who had a (c.869-1G>A) splicing variant in PSEN1 gene with a rare condition: the variant Alzheimer’s disease with spastic paraparesis. Curr. Alzheimer Res. 19, 223–235 (2022).

    Article  CAS  PubMed  Google Scholar 

  124. El Bitar, F. et al. Genetic study of Alzheimer’s disease in Saudi population. J. Alzheimers Dis. 67, 231–242 (2019).

    Article  CAS  PubMed  Google Scholar 

  125. Guven, G. et al. A novel PSEN2 p.Ser175Phe variant in a family with Alzheimer’s disease. Neurol. Sci. 42, 2497–2504 (2021).

    Article  PubMed  Google Scholar 

  126. Kalfon, L. et al. Familial early-onset Alzheimer’s caused by novel genetic variant and APP duplication: a cross-sectional study. Curr. Alzheimer Res. 19, 694–707 (2022).

    Article  CAS  PubMed  Google Scholar 

  127. Lohmann, E. et al. Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients. Neurobiol. Aging 33, 1850.e17–1850.e27 (2012).

    Article  CAS  PubMed  Google Scholar 

  128. Bazrgar, M. et al. Apolipoprotein E polymorphism in Southern Iran: E4 allele in the lowest reported amounts. Mol. Biol. Rep. 35, 495–499 (2008).

    Article  CAS  PubMed  Google Scholar 

  129. Abdi, S. et al. Association of Alzheimer’s disease with genetic variants of apolipoprotein E, clusterin, TNF-α, and IL-6 among elderly Saudis. Curr. Pharm. Biotechnol. 23, 1893–1902 (2022).

    Article  CAS  PubMed  Google Scholar 

  130. Abyadeh, M., Djafarian, K., Heydarinejad, F., Alizadeh, S. & Shab-Bidar, S. Association between apolipoprotein E gene polymorphism and Alzheimer’s disease in an Iranian population: a meta-analysis. J. Mol. Neurosci. 69, 557–562 (2019).

    Article  CAS  PubMed  Google Scholar 

  131. Amer, M. S. et al. Interaction between apolipoprotein E genotyping, serum inflammatory biomarkers and cognitive functions in Egyptian elderly. Egypt. J. Immunol. 28, 1–11 (2021).

    Article  PubMed  Google Scholar 

  132. Durmaz, A. et al. Genetic factors associated with the predisposition to late onset Alzheimer’s disease. Gene 707, 212–215 (2019).

    Article  CAS  PubMed  Google Scholar 

  133. El Shamieh, S., Costanian, C., Kassir, R., Visvkis-Siest, S. & Bissar-Tadmouri, N. APOE genotypes in Lebanon: distribution and association with hypercholesterolemia and Alzheimer’s disease. Per Med. 16, 15–23 (2019).

    Article  CAS  PubMed  Google Scholar 

  134. Isbir, T. et al. Interaction between apolipoprotein-E and angiotensin-converting enzyme genotype in Alzheimer’s disease. Am. J. Alzheimers Dis. Other Demen. 16, 205–210 (2001).

    Article  CAS  PubMed  Google Scholar 

  135. Gharesouran, J., Rezazadeh, M., Khorrami, A., Ghojazadeh, M. & Talebi, M. Genetic evidence for the involvement of variants at APOE, BIN1, CR1, and PICALM loci in risk of late-onset Alzheimer’s disease and evaluation for interactions with APOE genotypes. J. Mol. Neurosci. 54, 780–786 (2014).

    Article  CAS  PubMed  Google Scholar 

  136. Kleinberger, G. et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci. Transl. Med. 6, 243ra286 (2014).

    Article  Google Scholar 

  137. Manzali, S. B. et al. Association of the CD2AP locus with cognitive functioning among middle-aged individuals with a family history of Alzheimer’s disease. Neurobiol. Aging 101, 50–56 (2021).

    Article  CAS  PubMed  Google Scholar 

  138. Mehdizadeh, E. et al. Association of MS4A6A, CD33, and TREM2 gene polymorphisms with the late-onset Alzheimer’s disease. Bioimpacts 9, 219–225 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Mehrjoo, Z. et al. Association study of the TREM2 gene and identification of a novel variant in exon 2 in Iranian patients with late-onset Alzheimer’s disease. Med. Princ. Pract. 24, 351–354 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Rezazadeh, M. et al. Genetic factors affecting late-onset Alzheimer’s disease susceptibility. Neuromolecular Med. 18, 37–49 (2016).

    Article  CAS  PubMed  Google Scholar 

  141. Talebi, M. et al. ABCA7 and EphA1 genes polymorphisms in late-onset Alzheimer’s disease. J. Mol. Neurosci. 70, 167–173 (2020).

    Article  CAS  PubMed  Google Scholar 

  142. Masri, I., Salami, A., El Shamieh, S. & Bissar-Tadmouri, N. rs3851179G>A in PICALM is protective against Alzheimer’s disease in five different countries surrounding the Mediterranean. Curr. Aging Sci. 13, 162–168 (2020).

    Article  CAS  PubMed  Google Scholar 

  143. Akinyemi, R. O. et al. Dementia in Africa: current evidence, knowledge gaps, and future directions. Alzheimers Dement. 18, 790–809 (2022).

    Article  PubMed  Google Scholar 

  144. Bis, J. C. et al. Whole exome sequencing study identifies novel rare and common Alzheimer’s-associated variants involved in immune response and transcriptional regulation. Mol. Psychiatry 25, 1859–1875 (2020).

    Article  CAS  PubMed  Google Scholar 

  145. Mena, P. R. et al. The Alzheimer’s disease sequencing project–follow up study (ADSP-FUS): increasing ethnic diversity in Alzheimer’s genetics research with the addition of potential new cohorts. Alzheimer’s Dement. 16, e046400 (2020).

    Article  Google Scholar 

  146. John P. Hussman Institute to lead international genetic study of Alzheimer’s disease in people of Hispanic and African ancestry. Inventum https://physician-news.umiamihealth.org/john-p-hussman-institute-to-lead-international-genetic-study-of-alzheimers-disease-in-people-of-hispanic-and-african-ancestry/ (2022).

  147. Weiner, M. W. et al. Increasing participant diversity in AD research: plans for digital screening, blood testing, and a community-engaged approach in the Alzheimer’s Disease Neuroimaging Initiative 4. Alzheimers Dement. 19, 307–317 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  148. McKhann, G. M. et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 7, 263–269 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Ayodele, T., Rogaeva, E., Kurup, J. T., Beecham, G. & Reitz, C. Early-onset Alzheimer’s disease: what is missing in research? Curr. Neurol. Neurosci. Rep. 21, 4 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Reitz, C., Rogaeva, E. & Beecham, G. W. Late-onset vs nonmendelian early-onset Alzheimer disease: a distinction without a difference? Neurol. Genet. 6, e512 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Bateman, R. J. et al. Autosomal-dominant Alzheimer’s disease: a review and proposal for the prevention of Alzheimer’s disease. Alzheimers Res. Ther. 3, 1 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  152. van der Flier, W. M., Pijnenburg, Y. A., Fox, N. C. & Scheltens, P. Early-onset versus late-onset Alzheimer’s disease: the case of the missing APOE ε4 allele. Lancet Neurol. 10, 280–288 (2011).

    Article  PubMed  Google Scholar 

  153. Lee, S. et al. White matter hyperintensities are a core feature of Alzheimer’s disease: evidence from the dominantly inherited Alzheimer network. Ann. Neurol. 79, 929–939 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Moller, C. et al. Different patterns of gray matter atrophy in early- and late-onset Alzheimer’s disease. Neurobiol. Aging 34, 2014–2022 (2013).

    Article  PubMed  Google Scholar 

  155. Marshall, G. A., Fairbanks, L. A., Tekin, S., Vinters, H. V. & Cummings, J. L. Early-onset Alzheimer’s disease is associated with greater pathologic burden. J. Geriatr. Psychiatry Neurol. 20, 29–33 (2007).

    Article  PubMed  Google Scholar 

  156. Lowe, V. J. et al. Widespread brain tau and its association with ageing, Braak stage and Alzheimer’s dementia. Brain 141, 271–287 (2018).

    Article  PubMed  Google Scholar 

  157. Scholl, M. et al. Distinct 18F-AV-1451 tau PET retention patterns in early- and late-onset Alzheimer’s disease. Brain 140, 2286–2294 (2017).

    Article  PubMed  Google Scholar 

  158. Josephs, K. A. et al. Rates of hippocampal atrophy and presence of post-mortem TDP-43 in patients with Alzheimer’s disease: a longitudinal retrospective study. Lancet Neurol. 16, 917–924 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Attems, J. & Jellinger, K. A. The overlap between vascular disease and Alzheimer’s disease – lessons from pathology. BMC Med. 12, 206 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Kapasi, A., DeCarli, C. & Schneider, J. A. Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol. 134, 171–186 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Schneider, J. A., Arvanitakis, Z., Bang, W. & Bennett, D. A. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 69, 2197–2204 (2007).

    Article  PubMed  Google Scholar 

  162. DeTure, M. A. & Dickson, D. W. The neuropathological diagnosis of Alzheimer’s disease. Mol. Neurodegener. 14, 32 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Schneider, J. A., Wilson, R. S., Bienias, J. L., Evans, D. A. & Bennett, D. A. Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology 62, 1148–1155 (2004).

    Article  CAS  PubMed  Google Scholar 

  164. Barnes, D. E. & Yaffe, K. The projected effect of risk factor reduction on Alzheimer’s disease prevalence. Lancet Neurol. 10, 819–828 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Barker, W. W. et al. Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the State of Florida Brain Bank. Alzheimer Dis. Assoc. Disord. 16, 203–212 (2002).

    Article  PubMed  Google Scholar 

  166. Galvin, J. E., Pollack, J. & Morris, J. C. Clinical phenotype of Parkinson disease dementia. Neurology 67, 1605–1611 (2006).

    Article  PubMed  Google Scholar 

  167. Lippa, C. F. et al. Lewy bodies contain altered α-synuclein in brains of many familial Alzheimer’s disease patients with mutations in presenilin and amyloid precursor protein genes. Am. J. Pathol. 153, 1365–1370 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Chung, E. J. et al. Clinical features of Alzheimer disease with and without Lewy bodies. JAMA Neurol. 72, 789–796 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Azar, M. et al. Cognitive tests aid in clinical differentiation of Alzheimer’s disease versus Alzheimer’s disease with Lewy body disease: evidence from a pathological study. Alzheimers Dement. 16, 1173–1181 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Kraybill, M. L. et al. Cognitive differences in dementia patients with autopsy-verified AD, Lewy body pathology, or both. Neurology 64, 2069–2073 (2005).

    Article  CAS  PubMed  Google Scholar 

  171. Forstl, H., Burns, A., Luthert, P., Cairns, N. & Levy, R. The Lewy-body variant of Alzheimer’s disease. Clinical and pathological findings. Br. J. Psychiatry 162, 385–392 (1993).

    Article  CAS  PubMed  Google Scholar 

  172. Merdes, A. R. et al. Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies. Neurology 60, 1586–1590 (2003).

    Article  CAS  PubMed  Google Scholar 

  173. Ferreira, D. et al. Distinct subtypes of Alzheimer’s disease based on patterns of brain atrophy: longitudinal trajectories and clinical applications. Sci. Rep. 7, 46263 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Moreno-Grau, S. et al. Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer’s disease and three causality networks: the GR@ACE project. Alzheimers Dement. 15, 1333–1347 (2019).

    Article  PubMed  Google Scholar 

  175. Lee, A. J. et al. FMNL2 regulates gliovascular interactions and is associated with vascular risk factors and cerebrovascular pathology in Alzheimer’s disease. Acta Neuropathol. 144, 59–79 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Jack, C. R. Jr. et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 14, 535–562 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Jack, C. R. Jr. et al. A/T/N: an unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology 87, 539–547 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Balogun, W. G., Zetterberg, H., Blennow, K. & Karikari, T. K. Plasma biomarkers for neurodegenerative disorders: ready for prime time? Curr. Opin. Psychiatry 36, 112–118 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Apostolova, L. G. et al. Associations of the top 20 Alzheimer disease risk variants with brain amyloidosis. JAMA Neurol. 75, 328–341 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Shi, Z. et al. Amyloid PET in dementia syndromes: a Chinese multicenter study. J. Nucl. Med. 61, 1814–1819 (2020).

    Article  CAS  PubMed  Google Scholar 

  181. Raghavan, N. S. et al. Association between common variants in RBFOX1, an RNA-binding protein, and brain amyloidosis in early and preclinical Alzheimer disease. JAMA Neurol. 77, 1288–1298 (2020).

    Article  PubMed  Google Scholar 

  182. Kim, S. et al. Genome-wide association study of CSF biomarkers Aβ1-42, t-tau, and p-tau181p in the ADNI cohort. Neurology 76, 69–79 (2011).

    Article  CAS  PubMed  Google Scholar 

  183. Babapour Mofrad, R. et al. Sex differences in CSF biomarkers vary by Alzheimer disease stage and APOE ε4 genotype. Neurology 95, e2378–e2388 (2020).

    Article  CAS  PubMed  Google Scholar 

  184. Deming, Y. et al. Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta Neuropathol. 133, 839–856 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Deming, Y. et al. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk. Sci. Transl. Med. 11, eaau2291 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  186. Hong, S. et al. Genome-wide association study of Alzheimer’s disease CSF biomarkers in the EMIF-AD multimodal biomarker discovery dataset. Transl. Psychiatry 10, 403 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Li, W. W. et al. Association of polygenic risk score with age at onset and cerebrospinal fluid biomarkers of Alzheimer’s disease in a Chinese cohort. Neurosci. Bull. 36, 696–704 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Zhao, B. et al. Common genetic variation influencing human white matter microstructure. Science 372, eabf3736 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Zhao, B. et al. Large-scale GWAS reveals genetic architecture of brain white matter microstructure and genetic overlap with cognitive and mental health traits (n = 17,706). Mol. Psychiatry 26, 3943–3955 (2021).

    Article  PubMed  Google Scholar 

  190. Homann, J. et al. Genome-wide association study of Alzheimer’s disease brain imaging biomarkers and neuropsychological phenotypes in the European medical information framework for Alzheimer’s disease multimodal biomarker discovery dataset. Front. Aging Neurosci. 14, 840651 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Li, J. Q. et al. GWAS-linked loci and neuroimaging measures in Alzheimer’s disease. Mol. Neurobiol. 54, 146–153 (2017).

    Article  CAS  PubMed  Google Scholar 

  192. Squillario, M. et al. A telescope GWAS analysis strategy, based on SNPs-genes-pathways ensamble and on multivariate algorithms, to characterize late onset Alzheimer’s disease. Sci. Rep. 10, 12063 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Park, J. Y. et al. A missense variant in SHARPIN mediates Alzheimer’s disease-specific brain damages. Transl. Psychiatry 11, 590 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Janelidze, S. et al. Plasma P-tau181 in Alzheimer’s disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer’s dementia. Nat. Med. 26, 379–386 (2020).

    Article  CAS  PubMed  Google Scholar 

  195. Thijssen, E. H. et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat. Med. 26, 387–397 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Stevenson-Hoare, J. et al. Plasma biomarkers and genetics in the diagnosis and prediction of Alzheimer’s disease. Brain https://doi.org/10.1093/brain/awac128 (2022).

    Article  PubMed Central  Google Scholar 

  197. Wang, Z. T. et al. Genome-wide association study identifies CD1A associated with rate of increase in plasma neurofilament light in non-demented elders. Aging 11, 4521–4535 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Jiao, B. et al. Associations of risk genes with onset age and plasma biomarkers of Alzheimer’s disease: a large case-control study in mainland China. Neuropsychopharmacology 47, 1121–1127 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Kim, J. et al. miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1). Mol. Neurodegener. 11, 55 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Garcia-Aranda, M., Serrano, A. & Redondo, M. Regulation of clusterin gene expression. Curr. Protein Pept. Sci. 19, 612–622 (2018).

    Article  CAS  PubMed  Google Scholar 

  201. Kumar, P. et al. Circulating miRNA biomarkers for Alzheimer’s disease. PLoS One 8, e69807 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Hampel, H. et al. Omics sciences for systems biology in Alzheimer’s disease: state-of-the-art of the evidence. Ageing Res. Rev. 69, 101346 (2021).

    Article  CAS  PubMed  Google Scholar 

  203. Joyce, A. R. & Palsson, B. O. The model organism as a system: integrating ‘omics’ data sets. Nat. Rev. Mol. Cell Biol. 7, 198–210 (2006).

    Article  CAS  PubMed  Google Scholar 

  204. Ritchie, M. D., Holzinger, E. R., Li, R., Pendergrass, S. A. & Kim, D. Methods of integrating data to uncover genotype-phenotype interactions. Nat. Rev. Genet. 16, 85–97 (2015).

    Article  CAS  PubMed  Google Scholar 

  205. Choudhury, A. et al. High-depth African genomes inform human migration and health. Nature 586, 741–748 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Mez, J. et al. Two novel loci, COBL and SLC10A2, for Alzheimer’s disease in African Americans. Alzheimers Dement. 13, 119–129 (2017).

    Article  PubMed  Google Scholar 

  207. Miyashita, A. et al. SORL1 is genetically associated with late-onset Alzheimer’s disease in Japanese, Koreans and Caucasians. PLoS One 8, e58618 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Nielsen, R. et al. Tracing the peopling of the world through genomics. Nature 541, 302–310 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Tosto, G. et al. Polygenic risk scores in familial Alzheimer disease. Neurology 88, 1180–1186 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  210. DeMichele-Sweet, M. A. A. et al. Genome-wide association identifies the first risk loci for psychosis in Alzheimer disease. Mol. Psychiatry 26, 5797–5811 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Kunkle, B. W. et al. Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer’s disease. Alzheimers Dement. 12, 2–10 (2016).

    Article  PubMed  Google Scholar 

  212. Barral, S. et al. Linkage analyses in Caribbean Hispanic families identify novel loci associated with familial late-onset Alzheimer’s disease. Alzheimers Dement. 11, 1397–1406 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  213. Lanoiselee, H. M. et al. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: a genetic screening study of familial and sporadic cases. PLoS Med. 14, e1002270 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  214. Golan, M. P. et al. Early-onset Alzheimer’s disease with a de novo mutation in the presenilin 1 gene. Exp. Neurol. 208, 264–268 (2007).

    Article  CAS  PubMed  Google Scholar 

  215. Kukull, W. A. et al. Dementia and Alzheimer disease incidence: a prospective cohort study. Arch. Neurol. 59, 1737–1746 (2002).

    Article  PubMed  Google Scholar 

  216. Frenzel, S. et al. A biomarker for Alzheimer’s disease based on patterns of regional brain atrophy. Front. Psychiatry 10, 953 (2019).

    Article  PubMed  Google Scholar 

  217. Dickerson, B. C. et al. The cortical signature of Alzheimer’s disease: regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloid-positive individuals. Cereb. Cortex 19, 497–510 (2009).

    Article  PubMed  Google Scholar 

  218. Killiany, R. J. et al. MRI measures of entorhinal cortex vs hippocampus in preclinical AD. Neurology 58, 1188–1196 (2002).

    Article  CAS  PubMed  Google Scholar 

  219. Delaby, C. et al. Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer’s disease: an international overview. Alzheimers Dement. 18, 1868–1879 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  220. Morris, J. C. et al. Assessment of racial disparities in biomarkers for Alzheimer disease. JAMA Neurol. 76, 264–273 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  221. Chaudhry, A. & Rizig, M. Comparing fluid biomarkers of Alzheimer’s disease between African American or Black African and white groups: a systematic review and meta-analysis. J. Neurol. Sci. 421, 117270 (2021).

    Article  CAS  PubMed  Google Scholar 

  222. Leuzy, A. et al. Blood-based biomarkers for Alzheimer’s disease. EMBO Mol. Med. 14, e14408 (2022).

    Article  CAS  PubMed  Google Scholar 

  223. Zetterberg, H. et al. Hypoxia due to cardiac arrest induces a time-dependent increase in serum amyloid β levels in humans. PLoS One 6, e28263 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Gaiottino, J. et al. Increased neurofilament light chain blood levels in neurodegenerative neurological diseases. PLoS One 8, e75091 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Khalil, M. et al. Neurofilaments as biomarkers in neurological disorders. Nat. Rev. Neurol. 14, 577–589 (2018).

    Article  CAS  PubMed  Google Scholar 

  226. Ashton, N. J. et al. Increased plasma neurofilament light chain concentration correlates with severity of post-mortem neurofibrillary tangle pathology and neurodegeneration. Acta Neuropathol. Commun. 7, 5 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  227. Feinberg, A. P. Phenotypic plasticity and the epigenetics of human disease. Nature 447, 433–440 (2007).

    Article  CAS  PubMed  Google Scholar 

  228. Fransquet, P. D. & Ryan, J. Micro RNA as a potential blood-based epigenetic biomarker for Alzheimer’s disease. Clin. Biochem. 58, 5–14 (2018).

    Article  CAS  PubMed  Google Scholar 

  229. Lister, R. et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315–322 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Gertz, J. et al. Analysis of DNA methylation in a three-generation family reveals widespread genetic influence on epigenetic regulation. PLoS Genet. 7, e1002228 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Shoemaker, R., Deng, J., Wang, W. & Zhang, K. Allele-specific methylation is prevalent and is contributed by CpG-SNPs in the human genome. Genome Res. 20, 883–889 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Zhi, D. et al. SNPs located at CpG sites modulate genome-epigenome interaction. Epigenetics 8, 802–806 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Dehghani, R., Rahmani, F. & Rezaei, N. MicroRNA in Alzheimer’s disease revisited: implications for major neuropathological mechanisms. Rev. Neurosci. 29, 161–182 (2018).

    Article  CAS  PubMed  Google Scholar 

  234. Newgard, C. B. Metabolomics and metabolic diseases: where do we stand? Cell Metab. 25, 43–56 (2017).

    Article  CAS  PubMed  Google Scholar 

  235. Mittelstrass, K. et al. Discovery of sexual dimorphisms in metabolic and genetic biomarkers. PLoS Genet. 7, e1002215 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Shah, S. H. et al. Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss. Diabetologia 55, 321–330 (2012).

    Article  CAS  PubMed  Google Scholar 

  237. Shah, S. H., Kraus, W. E. & Newgard, C. B. Metabolomic profiling for the identification of novel biomarkers and mechanisms related to common cardiovascular diseases: form and function. Circulation 126, 1110–1120 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  238. Vardarajan, B. et al. Differences in plasma metabolites related to Alzheimer’s disease, APOE epsilon4 status, and ethnicity. Alzheimers Dement. 6, e12025 (2020).

    Google Scholar 

  239. Wang, T. J. et al. Metabolite profiles and the risk of developing diabetes. Nat. Med. 17, 448–453 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  240. Heath, L. et al. Manifestations of Alzheimer’s disease genetic risk in the blood are evident in a multiomic analysis in healthy adults aged 18 to 90. Sci. Rep. 12, 6117 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Walker, D. I. et al. High-resolution metabolomics of occupational exposure to trichloroethylene. Int. J. Epidemiol. 45, 1517–1527 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors acknowledge support from the National Institute on Aging of the National Institutes of Health in the USA. C.R. (U24AG056270, P30AG066462, U19AG074865, RO1AG064614); M.A.P.-V. (R56AG072547, RO1AG070864, UO1AG057659, UO1AG062943, UO1AG076482, U19AG074865); T.F. (U24AG021886, P30AG072976, U24AG056270), R.M. (U24AG056270, R01AG072474, RF1AG066107, R01AG067501). The authors also thank R. Akinyemi for his help with the review of genetics in Africa and M. Miller for continued encouragement and support of the investigation of AD worldwide.

Author information

Authors and Affiliations

  1. The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA

    Christiane Reitz & Richard Mayeux

  2. The Gertrude H. Sergievsky Center, Columbia University, New York, NY, USA

    Christiane Reitz & Richard Mayeux

  3. Department of Neurology, Columbia University, New York, NY, USA

    Christiane Reitz & Richard Mayeux

  4. Department of Epidemiology, Columbia University, New York, NY, USA

    Christiane Reitz & Richard Mayeux

  5. The John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA

    Margaret A. Pericak-Vance

  6. The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA

    Margaret A. Pericak-Vance

  7. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA

    Tatiana Foroud

  8. National Centralized Repository for Alzheimer’s Disease and Related Dementias, Indiana University School of Medicine, Indianapolis, IN, USA

    Tatiana Foroud

Authors
  1. Christiane Reitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Margaret A. Pericak-Vance
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tatiana Foroud
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard Mayeux
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article. All authors contributed substantially to discussion of the content. All authors wrote the article, and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Richard Mayeux.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Neurology thanks Ricardo Nitrini, who co-reviewed with Leonel Takada; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Alzheimer’s Disease Neuroimaging Initiative: https://adni.loni.usc.edu/

Alzheimer’s Disease Sequencing Project-Follow-Up Study (ADSP-FUS): https://adsp.niagads.org/

Alzheimer’s Disease Sequencing Project-Follow-Up Study: https://www.nia.nih.gov/research/ad-genetics

Asian Cohort for Alzheimer’s Disease: https://acadstudy.org/

Estudio Familiar de Influencia Genetica en Alzheimer (Puerto Rican Alzheimer Disease Initiative; EFIGA): https://dss.niagads.org/cohorts/estudio-familiar-de-influencia-genetica-en-alzheimer-efiga/

Gwangju Alzheimer’s and Related Dementias (GARD) Study: https://dss.niagads.org/cohorts/gwangju-alzheimers-and-related-dementia-gard/

Longitudinal Aging Study in India: https://lasi-india.org/

Mexican Health and Aging Study: https://www.mhasweb.org/Home/index.aspx

Research in African American Alzheimer’s Disease Initiative (REAAADI): https://med.miami.edu/centers-and-institutes/hihg/research-programs/alzheimers-disease-and-related-dementias/research-in-african-american-alzheimer-disease-initiative

WHO dementia fact sheet: https://www.who.int/news-room/fact-sheets/detail/dementia

Glossary

Kindred

An aggregate of genetically related individuals.

Principal components

Principal components analysis is a statistical method commonly used in population genetics to identify substructure in the distribution of genetic variation within populations.

Quantitative trait loci

Regions of DNA each associated with a particular quantitative phenotypic trait.

Recombination

Genetic recombination is the exchange of genetic material between different individuals which leads to offspring with combinations of traits that differ from those in either parent.

Variants of uncertain significance

Genetic variants for which association with a specific trait is unclear.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reitz, C., Pericak-Vance, M.A., Foroud, T. et al. A global view of the genetic basis of Alzheimer disease. Nat Rev Neurol 19, 261–277 (2023). https://doi.org/10.1038/s41582-023-00789-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-023-00789-z

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing