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The probabilistic model of Alzheimer disease: the amyloid hypothesis revised

Abstract

The current conceptualization of Alzheimer disease (AD) is driven by the amyloid hypothesis, in which a deterministic chain of events leads from amyloid deposition and then tau deposition to neurodegeneration and progressive cognitive impairment. This model fits autosomal dominant AD but is less applicable to sporadic AD. Owing to emerging information regarding the complex biology of AD and the challenges of developing amyloid-targeting drugs, the amyloid hypothesis needs to be reconsidered. Here we propose a probabilistic model of AD in which three variants of AD (autosomal dominant AD, APOE ε4-related sporadic AD and APOE ε4-unrelated sporadic AD) feature decreasing penetrance and decreasing weight of the amyloid pathophysiological cascade, and increasing weight of stochastic factors (environmental exposures and lower-risk genes). Together, these variants account for a large share of the neuropathological and clinical variability observed in people with AD. The implementation of this model in research might lead to a better understanding of disease pathophysiology, a revision of the current clinical taxonomy and accelerated development of strategies to prevent and treat AD.

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Fig. 1: The probabilistic model of Alzheimer disease.
Fig. 2: The lifetime dynamics of Aβ and tau in the three Alzheimer disease variants.

References

  1. Prince, M. et al. World Alzheimer Report 2015. The Global Impact of Dementia - An Analysis of Prevalence, Incidence, Cost and Trends. https://www.alzint.org/u/WorldAlzheimerReport2015.pdf (2015).

  2. Ballard, C. et al. Alzheimer’s disease. Lancet 377, 1019–1031 (2011).

    PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  4. Hardy, J. A. & Higgins, G. A. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).

    CAS  PubMed  Google Scholar 

  5. Selkoe, D. J. & Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 8, 595–608 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Sorel, N., Cayssials, É., Brizard, F. & Chomel, J. C. Treatment and molecular monitoring update in chronic myeloid leukemia management. Ann. Biol. Clin. 75, 129–145 (2017).

    Google Scholar 

  7. Trojanowski, J. Q. Tauists, baptists, syners, apostates, and new data. Ann. Neurol. 52, 263–265 (2002).

    PubMed  Google Scholar 

  8. Makin, S. The amyloid hypothesis on trial. Nature 559, S4–S7 (2018).

    CAS  PubMed  Google Scholar 

  9. De Strooper, B. & Karran, E. The cellular phase of Alzheimer’s disease. Cell 164, 603–615 (2016).

    PubMed  Google Scholar 

  10. Herrup, K. The case for rejecting the amyloid cascade hypothesis. Nat. Neurosci. 18, 794–799 (2015).

    CAS  PubMed  Google Scholar 

  11. Glenner, G. G. & Wong, C. W. Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem. Biophys. Res. Commun. 122, 1131–1135 (1984).

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  13. Jonsson, T. et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488, 96 (2012).

    CAS  PubMed  Google Scholar 

  14. Liu, C. C., Kanekiyo, T., Xu, H. & Bu, G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat. Rev. Neurol. 9, 106–118 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Van Cauwenberghe, C., Van Broeckhoven, C. & Sleegers, K. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet. Med. 18, 421–430 (2016).

    PubMed  Google Scholar 

  16. Sleegers, K. & Van Duijn, C. M. Alzheimer’s disease: genes, pathogenesis and risk prediction. Community Genet. 4, 197–203 (2001).

    PubMed  Google Scholar 

  17. Ringman, J. et al. Neuropathology of autosomal dominant Alzheimer disease in the National Alzheimer Coordinating Center database. J. Neuropathol. Exp. Neurol. 75, 284–290 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Jack, C. R. et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 9, 119–128 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. van der Kant, R., Goldstein, L. S. B. & Ossenkoppele, R. Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat. Rev. Neurosci. 21, 21–35 (2020).

    PubMed  Google Scholar 

  20. Götz, J., Chen, F., Van Dorpe, J. & Nitsch, R. M. Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Aβ42 fibrils. Science 293, 1491–1495 (2001).

    PubMed  Google Scholar 

  21. Lewis, J. et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293, 1487–1491 (2001).

    CAS  PubMed  Google Scholar 

  22. Gomes, L. A. et al. Aβ-induced acceleration of Alzheimer-related τ-pathology spreading and its association with prion protein. Acta Neuropathol. 138, 913–941 (2019).

    CAS  PubMed  Google Scholar 

  23. Choi, S. H. et al. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515, 274–278 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Oddo, S., Billings, L., Kesslak, J. P., Cribbs, D. H. & LaFerla, F. M. Aβ immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43, 321–332 (2004).

    CAS  PubMed  Google Scholar 

  25. Jack, C. R. et al. The bivariate distribution of amyloid-β and tau: relationship with established neurocognitive clinical syndromes. Brain 142, 3230–3242 (2019).

    PubMed  PubMed Central  Google Scholar 

  26. La Joie, R. et al. Prospective longitudinal atrophy in Alzheimer’s disease correlates with the intensity and topography of baseline tau-PET. Sci. Transl. Med. 12, eaau5732 (2020).

    PubMed  PubMed Central  Google Scholar 

  27. Bancher, C. et al. Accumulation of abnormally phosphorylated τ precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res. 477, 90–99 (1989).

    CAS  PubMed  Google Scholar 

  28. Koper, M. J. et al. Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer’s disease. Acta Neuropathol. 139, 463–484 (2020).

    CAS  PubMed  Google Scholar 

  29. Wiersma, V. I. et al. Granulovacuolar degeneration bodies are neuron-selective lysosomal structures induced by intracellular tau pathology. Acta Neuropathol. 138, 943–970 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018).

    PubMed  PubMed Central  Google Scholar 

  31. Tang, D. et al. The molecular machinery of regulated cell death. Cell Res. 29, 347–364 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Hanseeuw, B. J. et al. Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline. Ann. Neurol. 81, 583–596 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Bejanin, A. et al. Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease. Brain 140, 3286–3300 (2017).

    PubMed  PubMed Central  Google Scholar 

  34. Sevigny, J. et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537, 50–56 (2016).

    CAS  PubMed  Google Scholar 

  35. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02477800 (2021).

  36. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02484547 (2021).

  37. Haeberlein, S. B. et al. EMERGE and ENGAGE topline results: two phase 3 studies to evaluate aducanumab in patients with early Alzheimer’s disease. https://investors.biogen.com/static-files/ddd45672-9c7e-4c99-8a06-3b557697c06f (2019).

  38. ALZFORUM. Gantenerumab https://www.alzforum.org/therapeutics/gantenerumab (2021).

  39. ALZFORUM. AADvac1 https://www.alzforum.org/therapeutics/aadvac1 (2021).

  40. Villemagne, V. L. et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 12, 357–367 (2013).

    CAS  PubMed  Google Scholar 

  41. Jack, C. R. et al. Brain β-amyloid load approaches a plateau. Neurology 80, 890–896 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Swanson, C. J. et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res. Ther. 13, 80 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Mintun, M. A. et al. Donanemab in early Alzheimer’s disease. N. Engl. J. Med. 384, 1691–1704 (2021).

    CAS  PubMed  Google Scholar 

  44. Cummings, J., Lee, G., Ritter, A., Sabbagh, M. & Zhong, K. Alzheimer’s disease drug development pipeline: 2019. Alzheimers Dement. Transl. Res. Clin. Interv. 5, 272–293 (2019).

    Google Scholar 

  45. National Institute on Aging. NIA-funded active Alzheimer’s and related dementias clinical trials and studies. https://www.nia.nih.gov/research/ongoing-AD-trials#section2 (2021).

  46. Altomare, D. et al. Applying the ATN scheme in a memory clinic population: the ABIDE project. Neurology 93, E1635–E1646 (2019).

    PubMed  Google Scholar 

  47. Soldan, A. et al. ATN profiles among cognitively normal individuals and longitudinal cognitive outcomes. Neurology 92, E1567–E1579 (2019).

    PubMed  PubMed Central  Google Scholar 

  48. Ebenau, J. L. et al. ATN classification and clinical progression in subjective cognitive decline. Neurology https://doi.org/10.1212/wnl.0000000000009724 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Vos, S. J. B. et al. Preclinical Alzheimer’s disease and its outcome: a longitudinal cohort study. Lancet Neurol. 12, 957–965 (2013).

    PubMed  PubMed Central  Google Scholar 

  50. Weigand, A. et al. Is tau in the absence of amyloid on the Alzheimer’s continuum?: a study of discordant PET positivity. Brain Commun. 2, fcz046 (2020).

    PubMed  Google Scholar 

  51. Rabinovici, G. D. et al. Distinct MRI atrophy patterns in autopsy-proven Alzheimer’s disease and frontotemporal lobar degeneration. Am. J. Alzheimers. Dis. Other Demen. 22, 474–488 (2008).

    Google Scholar 

  52. Ekman, U., Ferreira, D. & Westman, E. The A/T/N biomarker scheme and patterns of brain atrophy assessed in mild cognitive impairment. Sci. Rep. 8, 8431 (2018).

    PubMed  PubMed Central  Google Scholar 

  53. Adams, D., Koike, H., Slama, M. & Coelho, T. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat. Rev. Neurol. 15, 387–404 (2019).

    CAS  PubMed  Google Scholar 

  54. Pascoal, T. A. et al. 18F-MK-6240 PET for early and late detection of neurofibrillary tangles. Brain https://doi.org/10.1093/brain/awaa180 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Leuzy, A. et al. Diagnostic performance of RO948 F 18 tau positron emission tomography in the differentiation of Alzheimer disease from other neurodegenerative disorders. JAMA Neurol. 77, 955–965 (2020).

    PubMed  Google Scholar 

  56. Crary, J. F. et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 128, 755–766 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Duyckaerts, C. et al. PART is part of Alzheimer disease. Acta Neuropathol. 129, 749–756 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Braak, H., Thal, D. R., Ghebremedhin, E. & Del Tredici, K. Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years. J. Neuropathol. Exp. Neurol. 70, 960–969 (2011).

    CAS  PubMed  Google Scholar 

  59. Spires-Jones, T. L., Attems, J. & Thal, D. R. Interactions of pathological proteins in neurodegenerative diseases. Acta Neuropathol. 134, 187–205 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Sturchler-Pierrat, C. et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc. Natl Acad. Sci. USA 94, 13287–13292 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Games, D. et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373, 523–527 (1995).

    CAS  PubMed  Google Scholar 

  62. Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).

    CAS  PubMed  Google Scholar 

  63. Corbett, G. T. et al. PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins. Acta Neuropathol. 139, 503–526 (2020).

    CAS  PubMed  Google Scholar 

  64. Salazar, S. V. et al. Conditional deletion of Prnp rescues behavioral and synaptic deficits after disease onset in transgenic Alzheimer’s disease. J. Neurosci. 37, 9207–9221 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathologica 82, 239–259 (1991).

    CAS  PubMed  Google Scholar 

  66. Thal, D. R., Rüb, U., Orantes, M. & Braak, H. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791–1800 (2002).

    PubMed  Google Scholar 

  67. Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017).

    PubMed  PubMed Central  Google Scholar 

  68. Karanth, S. et al. Prevalence and clinical phenotype of quadruple misfolded proteins in older adults. JAMA Neurol. https://doi.org/10.1001/jamaneurol.2020.1741 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  69. 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).

    PubMed  Google Scholar 

  70. Imbimbo, B. P. & Watling, M. Investigational BACE inhibitors for the treatment of Alzheimer’s disease. Expert Opin. Investig. Drugs 28, 967–975 (2019).

    CAS  PubMed  Google Scholar 

  71. Hochhaus, A. et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia 34, 966–984 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01760005 (2021).

  73. ALZFORUM. Solanezumab https://www.alzforum.org/therapeutics/solanezumab (2021).

  74. Alzheimer’s Association. DIAN-TU phase 3 clinical trials, topline results–news https://www.alz.org/news/2020/dian-tu-phase-3-clinical-trials-topline-results (2020).

  75. Eisai Co. Ltd. Eisai and Biogen announce presentation of additional data from the phase II clinical trial of BAN2401 in early Alzheimer’s disease and the 2018 Clinical Trials on Alzheimer’s Disease (CTAD) Conference https://www.eisai.com/news/2018/news201892.html (2018).

  76. Murray, M. E. et al. Neuropathologically defined subtypes of Alzheimer’s disease with distinct clinical characteristics: a retrospective study. Lancet Neurol. 10, 785–796 (2011).

    PubMed  PubMed Central  Google Scholar 

  77. Schott, J. M. et al. Genetic risk factors for the posterior cortical atrophy variant of Alzheimer’s disease. Alzheimers Dement. 12, 862–871 (2016).

    PubMed  PubMed Central  Google Scholar 

  78. Carrasquillo, M. M. et al. Late-onset Alzheimer disease genetic variants in posterior cortical atrophy and posterior AD. Neurology 82, 1455–1462 (2014).

    PubMed  PubMed Central  Google Scholar 

  79. Miller, Z. A. et al. Prevalence of mathematical and visuospatial learning disabilities in patients with posterior cortical atrophy. JAMA Neurol. 75, 728–737 (2018).

    PubMed  PubMed Central  Google Scholar 

  80. Miller, Z. A. et al. Handedness and language learning disability differentially distribute in progressive aphasia variants. Brain 136, 3461–3473 (2013).

    PubMed  PubMed Central  Google Scholar 

  81. Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 367, 795–804 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Hanseeuw, B. J. et al. PET staging of amyloidosis using striatum. Alzheimers Dement. 14, 1281–1292 (2018).

    PubMed  PubMed Central  Google Scholar 

  83. Stokin, G. B. et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s diseases. Science 307, 1282–1288 (2005).

    CAS  PubMed  Google Scholar 

  84. Johnson, V. E., Stewart, W. & Smith, D. H. Traumatic brain injury and amyloid-β pathology: a link to alzheimer’s disease? Nat. Rev. Neurosci. 11, 361–370 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Ikonomovic, M. D. et al. Alzheimer’s pathology in human temporal cortex surgically excised after severe brain injury. Exp. Neurol. 190, 192–203 (2004).

    CAS  PubMed  Google Scholar 

  86. Roberts, G. W., Gentleman, S. M., Lynch, A. & Graham, D. I. βA4 amyloid protein deposition in brain after head trauma. Lancet 338, 1422–1423 (1991).

    CAS  PubMed  Google Scholar 

  87. Rossor, M. N., Fox, N. C., Mummery, C. J., Schott, J. M. & Warren, J. D. The diagnosis of young-onset dementia. Lancet Neurol. 9, 793–806 (2010).

    PubMed  PubMed Central  Google Scholar 

  88. Ryman, D. C. et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 83, 253–260 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Sanchez, J. S. et al. Longitudinal amyloid and tau accumulation in autosomal dominant Alzheimer’s disease: findings from the Colombia-Boston (COLBOS) biomarker study. Alzheimers Res. Ther. 13, 27 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Gordon, B. A. et al. Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol. 17, 241–250 (2018).

    PubMed  PubMed Central  Google Scholar 

  91. Gordon, B. A. et al. Tau PET in autosomal dominant Alzheimer’s disease: relationship with cognition, dementia and other biomarkers. Brain 142, 1063–1076 (2019).

    PubMed  PubMed Central  Google Scholar 

  92. Cash, D. M. et al. The pattern of atrophy in familial Alzheimer disease: volumetric MRI results from the DIAN study. Neurology 81, 1425–1433 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Lloyd, G. M. et al. Prominent amyloid plaque pathology and cerebral amyloid angiopathy in APP V717I (London) carrier - phenotypic variability in autosomal dominant Alzheimer’s disease. Acta Neuropathol. Commun. 8, 31 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Sutovsky, S. et al. Neuropathology and biochemistry of early onset familial Alzheimer’s disease caused by presenilin-1 missense mutation Thr116Asn. J. Neural Transm. 125, 965–976 (2018).

    CAS  PubMed  Google Scholar 

  95. Gondim, D. D. et al. Diffuse Lewy body disease and Alzheimer disease: neuropathologic phenotype associated with the PSEN1 p.A396T mutation. J. Neuropathol. Exp. Neurol. 78, 585–594 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Mann, D. et al. Predominant deposition of amyloid-beta 42(43) in plaques in cases of Alzheimer’s disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene. Am. J. Pathol. 148, 1257–1266 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Mann, D. M. A. et al. Amyloid β protein (Aβ) deposition in chromosome 14-linked Alzheimer’s disease: predominance of Aβ(42(43)). Ann. Neurol. 40, 149–156 (1996).

    CAS  PubMed  Google Scholar 

  99. Taipa, R. et al. Inflammatory pathology markers (activated microglia and reactive astrocytes) in early and late onset Alzheimer disease: a post mortem study. Neuropathol. Appl. Neurobiol. 44, 298–313 (2018).

    CAS  PubMed  Google Scholar 

  100. Ryan, N. S. et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. Lancet Neurol. 15, 1326–1335 (2016).

    PubMed  Google Scholar 

  101. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Yu, C. E., Chen, S., Jayadev, S. & Bird, T. Lack of APOE Christchurch variant in five age of onset outliers with PSEN1, PSEN2 Alzheimer’s disease and MAPT frontotemporal dementia. J. Neurol. Sci. 418, 117143 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Müller, S. et al. Relationship between physical activity, cognition, and Alzheimer pathology in autosomal dominant Alzheimer’s disease. Alzheimers Dement. 14, 1427–1437 (2018).

    PubMed  PubMed Central  Google Scholar 

  104. Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C. C. & Bu, G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat. Rev. Neurol. 15, 501–518 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Mattsson, N. et al. Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer’s disease. Alzheimers Dement. 14, 913–924 (2018).

    PubMed  Google Scholar 

  106. Myers, R. H. et al. Apolipoprotein E ε4 association with dementia in a population-based study: The Framingham Study. Neurology 46, 673–677 (1996).

    CAS  PubMed  Google Scholar 

  107. Slooter, A. J. C. et al. Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: The Rotterdam Study. Arch. Neurol. 55, 964–968 (1998).

    CAS  PubMed  Google Scholar 

  108. Belloy, M. E., Napolioni, V. & Greicius, M. D. A quarter century of APOE and Alzheimer’s disease: progress to date and the path forward. Neuron 101, 820–838 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 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).

    CAS  PubMed  Google Scholar 

  110. Roses, A. D. Apolipoprotein E alleles as risk factors in Alzheimer’s disease. Annu. Rev. Med. 47, 387–400 (1996).

    CAS  PubMed  Google Scholar 

  111. Jansen, I. E. et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat. Genet. 51, 404–413 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Van Duijn, C. M. et al. Apolipoprotein E4 allele in a population–based study of early–onset Alzheimer’s disease. Nat. Genet. 7, 74–78 (1994).

    PubMed  Google Scholar 

  113. Collij, L. E. et al. Multitracer model for staging cortical amyloid deposition using PET imaging. Neurology 95, e1538–e1553 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Ossenkoppele, R. et al. Differential effect of APOE genotype on amyloid load and glucose metabolism in AD dementia. Neurology 80, 359–365 (2013).

    CAS  PubMed  Google Scholar 

  115. Lehmann, M. et al. Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients. J. Neurol. Neurosurg. Psychiatry 85, 266–273 (2014).

    PubMed  Google Scholar 

  116. Burnham, S. C. et al. Impact of APOE-ε4 carriage on the onset and rates of neocortical Aβ-amyloid deposition. Neurobiol. Aging 95, 46–55 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Toledo, J. B. et al. APOE effect on amyloid-β PET spatial distribution, deposition rate, and cut-points. J. Alzheimers Dis. 69, 783–793 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Schmechel, D. E. et al. Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 9649–9653 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Olichney, J. M. et al. Relationship between severe amyloid angiopathy, apolipoprotein E genotype, and vascular lesions in Alzheimer’s disease. Ann. N. Y. Acad. Sci. 903, 138–143 (2000).

    CAS  PubMed  Google Scholar 

  120. Thal, D. R. et al. Two types of sporadic cerebral amyloid angiopathy. J. Neuropathol. Exp. Neurol. 61, 282–293 (2002).

    PubMed  Google Scholar 

  121. Thal, D. R., Griffin, W. S. T., de Vos, R. A. I. & Ghebremedhin, E. Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathologica 115, 599–609 (2008).

    CAS  PubMed  Google Scholar 

  122. Thal, D. R. et al. Capillary cerebral amyloid angiopathy identifies a distinct APOE ε4-associated subtype of sporadic Alzheimer’s disease. Acta Neuropathol. 120, 169–183 (2010).

    CAS  PubMed  Google Scholar 

  123. Greenberg, S. M. et al. Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways. Nat. Rev. Neurol. 16, 30–42 (2020).

    CAS  PubMed  Google Scholar 

  124. Ossenkoppele, R. et al. Discriminative accuracy of [18F]flortaucipir positron emission tomography for Alzheimer disease vs other neurodegenerative disorders. JAMA 320, 1151–1162 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Frisoni, G. B. et al. The topography of grey matter involvement in early and late onset Alzheimer’s disease. Brain 130, 720–730 (2007).

    PubMed  Google Scholar 

  126. Mattsson, N. et al. Greater tau load and reduced cortical thickness in APOE ε4-negative Alzheimer’s disease: a cohort study. Alzheimers Res. Ther. 10, 77 (2018).

    PubMed  PubMed Central  Google Scholar 

  127. Emrani, S., Arain, H. A., DeMarshall, C. & Nuriel, T. APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: a systematic review. Alzheimers Res. Ther. 12, 141 (2020).

    PubMed  PubMed Central  Google Scholar 

  128. Therriault, J. et al. Association of apolipoprotein E ε4 with medial temporal tau independent of amyloid-β. JAMA Neurol. 77, 470–479 (2020).

    PubMed  Google Scholar 

  129. Geroldi, C. et al. APOE-ε4 is associated with less frontal and more medial temporal lobe atrophy in AD. Neurology 53, 1825–1832 (1999).

    CAS  PubMed  Google Scholar 

  130. Nelson, P. T. et al. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain 142, 1503–1527 (2019).

    PubMed  PubMed Central  Google Scholar 

  131. Twohig, D. et al. The relevance of cerebrospinal fluid α-synuclein levels to sporadic and familial Alzheimer’s disease. Acta Neuropathol. Commun. 6, 130 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Weintraub, S. et al. APOE is a correlate of phenotypic heterogeneity in Alzheimer disease in a national cohort. Neurology 94, e607–e612 (2020).

    PubMed  PubMed Central  Google Scholar 

  133. Reiman, E. M. et al. Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat. Commun. 11, 667 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Genin, E. et al. APOE and Alzheimer disease: a major gene with semi-dominant inheritance. Mol. Psychiatry 16, 903–907 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Bellenguez, C. et al. New insights on the genetic etiology of Alzheimer’s and related dementia. medRxiv 17, 10 (2020).

    Google Scholar 

  136. van der Lee, S. J. et al. The effect of APOE and other common genetic variants on the onset of Alzheimer’s disease and dementia: a community-based cohort study. Lancet Neurol. 17, 434–444 (2018).

    PubMed  Google Scholar 

  137. Desikan, R. S. et al. Genetic assessment of age-associated Alzheimer disease risk: development and validation of a polygenic hazard score. PLoS Med. 14, e1002258 (2017).

    PubMed  PubMed Central  Google Scholar 

  138. Chouraki, V. et al. Evaluation of a genetic risk score to improve risk prediction for Alzheimer’s disease. J. Alzheimers Dis. 53, 921–932 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Holstege, H. et al. The 100-plus Study of cognitively healthy centenarians: rationale, design and cohort description. Eur. J. Epidemiol. 33, 1229–1249 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Laurent, S., Boutouyrie, P., Cunha, P. G., Lacolley, P. & Nilsson, P. M. Concept of extremes in vascular aging: from early vascular aging to supernormal vascular aging. Hypertension 74, 218–228 (2019).

    CAS  PubMed  Google Scholar 

  141. Bruno, R. M. et al. Early and supernormal vascular aging. Hypertension 76, 1616–1624 (2020).

    CAS  PubMed  Google Scholar 

  142. Ding, Y.-N., Tang, X., Chen, H.-Z. & Liu, D.-P. Epigenetic regulation of vascular aging and age-related vascular diseases. Adv. Exp. Med. Biol. 1086, 55–75 (2018).

    CAS  PubMed  Google Scholar 

  143. Dang, C. et al. Relationship between amyloid-β positivity and progression to mild cognitive impairment or dementia over 8 years in cognitively normal older adults. J. Alzheimers Dis. 65, 1313–1325 (2018).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  145. Saddiki, H. et al. Age and the association between apolipoprotein E genotype and Alzheimer disease: a cerebrospinal fluid biomarker–based case–control study. PLoS Med. 17, e1003289 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Nelis, S. M. et al. The impact of co-morbidity on the quality of life of people with dementia: findings from the IDEAL study. Age Ageing 48, 361–367 (2019).

    PubMed  Google Scholar 

  147. Strittmatter, W. J. et al. Apolipoprotein E: High-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A. 90, 1977–1981 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Thal, D. R. et al. Occurrence and co-localization of amyloid β-protein and apolipoprotein E in perivascular drainage channels of wild-type and APP-transgenic mice. Neurobiol. Aging 28, 1221–1230 (2007).

    CAS  PubMed  Google Scholar 

  149. Deane, R. et al. apoE isoform-specific disruption of amyloid β peptide clearance from mouse brain. J. Clin. Invest. 118, 4002–4013 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Damotte, V. et al. Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: a genome-wide association study in over 12,000 non-demented participants. Alzheimers Dement. https://doi.org/10.1002/alz.12333 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Wang, C. et al. Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector article. Nat. Med. 24, 647–657 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Davis, A. A. et al. APOE genotype regulates pathology and disease progression in synucleinopathy. Sci. Transl. Med. 12, eaay3069 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Zhao, N. et al. APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid. Sci. Transl. Med. 12, eaay1809 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Yang, H. S. et al. Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status: a community-based cohort study. Lancet Neurol. 17, 773–781 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Montagne, A. et al. APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline. Nature 581, 1–6 (2020).

    Google Scholar 

  156. Blanchard, J. W. et al. Reconstruction of the human blood–brain barrier in vitro reveals a pathogenic mechanism of APOE4 in pericytes. Nat. Med. 26, 1–12 (2020).

    Google Scholar 

  157. Hecht, M., Krämer, L. M., von Arnim, C. A. F., Otto, M. & Thal, D. R. Capillary cerebral amyloid angiopathy in Alzheimer’s disease: association with allocortical/hippocampal microinfarcts and cognitive decline. Acta Neuropathol. 135, 681–694 (2018).

    CAS  PubMed  Google Scholar 

  158. Dean, D. C. et al. Brain differences in infants at differential genetic risk for late-onset Alzheimer disease: a cross-sectional imaging study. JAMA Neurol. 71, 11–22 (2014).

    PubMed  PubMed Central  Google Scholar 

  159. Reiman, E. M. et al. Preclinical evidence of Alzheimer’s disease in persons homozygous for the ε4 allele for apolipoprotein E. N. Engl. J. Med. 334, 752–758 (1996).

    CAS  PubMed  Google Scholar 

  160. Evans, S. L. et al. Mid age APOE ε4 carriers show memory-related functional differences and disrupted structure-function relationships in hippocampal regions. Sci. Rep. 10, 3110 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Reiman, E. M. et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc. Natl Acad. Sci. USA 101, 284–289 (2004).

    CAS  PubMed  Google Scholar 

  162. Reale,, M. et al. Relationship between inflammatory mediators, Aβ levels and ApoE genotype in Alzheimer disease. Curr. Alzheimer Res. 9, 447–457 (2012).

    CAS  Google Scholar 

  163. Gorelick, P. B. Role of inflammation in cognitive impairment: results of observational epidemiological studies and clinical trials. Ann. N. Y. Acad. Sci. 1207, 155–162 (2010).

    PubMed  Google Scholar 

  164. Morgan, A. R. et al. Inflammatory biomarkers in Alzheimer’s disease plasma. Alzheimers Dement. 15, 776–787 (2019).

    PubMed  PubMed Central  Google Scholar 

  165. Cattaneo, A. et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol. Aging 49, 60–68 (2017).

    CAS  PubMed  Google Scholar 

  166. Heneka, M. T. et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14, 388–405 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Friedberg, J. S. et al. Associations between brain inflammatory profiles and human neuropathology are altered based on apolipoprotein E ε4 genotype. Sci. Rep. 10, 29624 (2020).

    Google Scholar 

  168. Sheng, J., Mrak, R. & Griffin, W. Glial-neuronal interactions in Alzheimer disease: progressive association of IL-1alpha+ microglia and S100beta+ astrocytes with neurofibrillary tangle stages. J. Neuropathol. Exp. Neurol. 56, 285–290 (1997).

    CAS  PubMed  Google Scholar 

  169. Griffin, W. S. T., Sheng, J. G., Roberts, G. W. & Mrak, R. E. Interleukin-1 expression in different plaque types in Alzheimer’s disease significance in plaque evolution. J. Neuropathol. Exp. Neurol. 54, 276–281 (1995).

    CAS  PubMed  Google Scholar 

  170. Akiyama, H. et al. Inflammation and Alzheimer’s disease. Neurobiol. Aging 21, 383–421 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Scheltens, P. et al. Alzheimer’s disease. Lancet https://doi.org/10.1016/S0140-6736(20)32205-4 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

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

    PubMed  Google Scholar 

  173. Livingston, G. et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396, 413–446 (2020).

    PubMed  PubMed Central  Google Scholar 

  174. Sims, R., Hill, M. & Williams, J. The multiplex model of the genetics of Alzheimer’s disease. Nat. Neurosci. 23, 311–322 (2020).

    CAS  PubMed  Google Scholar 

  175. Zhang, Q. et al. Risk prediction of late-onset Alzheimer’s disease implies an oligogenic architecture. Nat. Commun. 11, 4799 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Andreone, B. J. et al. Alzheimer’s-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nat. Neurosci. 23, 927–938 (2020).

    CAS  PubMed  Google Scholar 

  177. Nugent, A. A. et al. TREM2 regulates microglial cholesterol metabolism upon chronic phagocytic challenge. Neuron 105, 837–854.e9 (2020).

    CAS  PubMed  Google Scholar 

  178. De Roeck, A., Van Broeckhoven, C. & Sleegers, K. The role of ABCA7 in Alzheimer’s disease: evidence from genomics, transcriptomics and methylomics. Acta Neuropathol. 138, 201–220 (2019).

    PubMed  PubMed Central  Google Scholar 

  179. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Wollmer, M. A. Cholesterol-related genes in Alzheimer’s disease. Biochim. Biophys. Acta 1801, 762–773 (2010).

    CAS  PubMed  Google Scholar 

  181. Cuyvers, E. & Sleegers, K. Genetic variations underlying Alzheimer’s disease: Evidence from genome-wide association studies and beyond. Lancet Neurol. 15, 857–868 (2016).

    CAS  PubMed  Google Scholar 

  182. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. van der Lee, S. J. et al. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity. Acta Neuropathol. 138, 237–250 (2019).

    PubMed  PubMed Central  Google Scholar 

  184. Magno, L. et al. Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph. Alzheimers Res. Ther. 11, 16 (2019).

    PubMed  PubMed Central  Google Scholar 

  185. Jiao, S. S. et al. Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer’s disease. Transl. Psychiatry 6, e907 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Belloy, M. E., Napolioni, V., Han, S. S., Le Guen, Y. & Greicius, M. D. Association of Klotho-VS heterozygosity with risk of Alzheimer disease in individuals who carry APOE4. JAMA Neurol. 77, 849–862 (2020).

    PubMed  PubMed Central  Google Scholar 

  187. Satoh, J.-I. et al. TMEM106B expression is reduced in Alzheimer’s disease brains. Alzheimers. Res. Ther. 6, 17 (2014).

    PubMed  PubMed Central  Google Scholar 

  188. Hohman, T. J., Koran, M. E. I. & Thornton-Wells, T. A. Genetic modification of the relationship between phosphorylated tau and neurodegeneration. Alzheimers Dement. 10, 637–645.e1 (2014).

    PubMed  PubMed Central  Google Scholar 

  189. Licher, S. et al. Genetic predisposition, modifiable-risk-factor profile and long-term dementia risk in the general population. Nat. Med. 25, 1364–1369 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Lourida, I. et al. Association of lifestyle and genetic risk with incidence of dementia. JAMA 322, 430–437 (2019).

    PubMed  PubMed Central  Google Scholar 

  191. Solomon, A. et al. Effect of the apolipoprotein E genotype on cognitive change during a multidomain lifestyle intervention a subgroup analysis of a randomized clinical trial. JAMA Neurol. 75, 462–470 (2018).

    PubMed  PubMed Central  Google Scholar 

  192. Bostanciklioğlu, M. The role of gut microbiota in pathogenesis of Alzheimer’s disease. J. Appl. Microbiol. 127, 954–967 (2019).

    PubMed  Google Scholar 

  193. Marizzoni, M., Provasi, S., Cattaneo, A. & Frisoni, G. B. Microbiota and neurodegenerative diseases. Curr. Opin. Neurol. 30, 630–638 (2017).

    PubMed  Google Scholar 

  194. Cryan, J. F., O’Riordan, K. J., Sandhu, K., Peterson, V. & Dinan, T. G. The gut microbiome in neurological disorders. Lancet Neurol. 19, 179–194 (2020).

    CAS  PubMed  Google Scholar 

  195. Arenaza-Urquijo, E. M. & Vemuri, P. Resistance vs resilience to Alzheimer disease. Neurology 90, 695–703 (2018).

    PubMed  PubMed Central  Google Scholar 

  196. Dumitrescu, L. et al. Genetic variants and functional pathways associated with resilience to Alzheimer’s disease. Brain 143, 2561–2575 (2020).

    PubMed  PubMed Central  Google Scholar 

  197. Gladyshev, V. N. Aging: progressive decline in fitness due to the rising deleteriome adjusted by genetic, environmental, and stochastic processes. Aging Cell 15, 594–602 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Partridge, L., Deelen, J. & Slagboom, P. E. Facing up to the global challenges of ageing. Nature 561, 45–56 (2018).

    CAS  PubMed  Google Scholar 

  199. Herndon, L. A. et al. Stochastic and genetic factors influence tissue-specific decline in ageing C. Elegans. Nature 419, 808–814 (2002).

    CAS  PubMed  Google Scholar 

  200. Williams, G. C. Pleiotropy, natural selection, and the evolution of senescence. Evolution 11, 398–411 (1957).

    Google Scholar 

  201. Altmann, A., Tian, L., Henderson, V. W. & Greicius, M. D. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann. Neurol. 75, 563–573 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Fisher, D. W., Bennett, D. A. & Dong, H. Sexual dimorphism in predisposition to Alzheimer’s disease. Neurobiol. Aging 70, 308–324 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Shen, S., Zhou, W., Chen, X. & Zhang, J. Sex differences in the association of APOE ε4 genotype with longitudinal hippocampal atrophy in cognitively normal older people. Eur. J. Neurol. 26, 1362–1369 (2019).

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  205. Williams, T., Borchelt, D. R. & Chakrabarty, P. Therapeutic approaches targeting Apolipoprotein e function in Alzheimer’s disease. Mol. Neurodegener. 15, 8 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Xiong, M. et al. APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function. Sci. Transl. Med. 13, eabd7522 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Langa, K. M. & Burke, J. F. Preclinical Alzheimer disease - early diagnosis or overdiagnosis? JAMA Intern. Med. 179, 1161–1162 (2019).

    PubMed  Google Scholar 

  208. Jicha, G. A. & Rentz, D. M. Cognitive and brain reserve and the diagnosis and treatment of preclinical Alzheimer disease. Neurology 80, 1180–1181 (2013).

    PubMed  Google Scholar 

  209. Frisoni, G. B. et al. Re-aligning scientific and lay narratives of Alzheimer’s disease. Lancet Neurol. 18, 918–919 (2019).

    PubMed  Google Scholar 

  210. Frisoni, G. B. et al. Precision prevention of Alzheimer’s and other dementias: anticipating future needs in the control of risk factors and implementation of disease-modifying therapies. Alzheimers Dement. https://doi.org/10.1002/alz.12132 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  211. Tavana, J. P. et al. RAB10: an Alzheimer’s disease resilience locus and potential drug target. Clin. Interv. Aging 14, 73–79 (2019).

    CAS  PubMed  Google Scholar 

  212. Barroeta-Espar, I. et al. Distinct cytokine profiles in human brains resilient to Alzheimer’s pathology. Neurobiol. Dis. 121, 327–337 (2019).

    CAS  PubMed  Google Scholar 

  213. Cummings, J., Lee, G., Ritter, A., Sabbagh, M. & Zhong, K. Alzheimer’s disease drug development pipeline: 2020. Alzheimers Dement. Transl. Res. Clin. Interv. 6, e12050 (2020).

    Google Scholar 

  214. Ballard, C. et al. Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis: a phase 2, randomised, placebo-controlled, double-blind study. Lancet Neurol. 17, 213–222 (2018).

    CAS  PubMed  Google Scholar 

  215. Iqbal, K. & Grundke-Iqbal, I. Alzheimer neurofibrillary degeneration: significance, etiopathogenesis, therapeutics and prevention. J. Cell. Mol. Med. 12, 38–55 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Veitch, D. P. et al. Understanding disease progression and improving Alzheimer’s disease clinical trials: recent highlights from the Alzheimer’s Disease Neuroimaging Initiative. Alzheimers Dement. 15, 106–152 (2019).

    PubMed  Google Scholar 

  217. Derry, P. J. et al. Revisiting the intersection of amyloid, pathologically modified tau and iron in Alzheimer’s disease from a ferroptosis perspective. Prog. Neurobiol. 184, 101716 (2020).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This Perspective was the result of a workshop funded by the Swiss National Science Foundation entitled “How many roads lead to Rome? Insights in Alzheimer disease pathophysiology to lead future drug development” (grant number IZSEZ0_192840). G.B.F. received funding from the following sources: European Prevention of Alzheimer’s Dementia - EPAD (grant agreement number 115736) and Amyloid Imaging to Prevent Alzheimer’s Disease - AMYPED (grant agreement number 115952) funded by the EU–EFPIA Innovative Medicines Initiatives 2 Joint Undertaking; the Swiss National Science Foundation (“Brain connectivity and metacognition in persons with subjective cognitive decline (COSCODE): correlation with clinical features and in vivo neuropathology” (grant number 320030_182772)); Association Suisse pour la Recherche sur la Maladie d’Alzheimer, Geneva; Fondation Segré, Geneva; I. Pictet, Geneva; Fondazione Agusta, Lugano; Fondation Chmielewski, Geneva; and the VELUX Foundation. D.R.T. received funding from Fonds Wetenschappelijk Onderzoek Vlaanderen (FWO-G0F8516N Odysseus). R.v.d.K. was supported by an Alzheimer Nederland pilot grant (WE.03-2017-08) and a grant from the Selfridges Group Foundation (NR170059). K.B. is supported by the Swedish Research Council (2017-00915), the Swedish Alzheimer Foundation (AF-742881), Hjärnfonden, Sweden (FO2017-0243), and the Swedish state under an agreement between the Swedish government and the county councils, the ALF agreement (ALFGBG-715986). J.C. is supported by Keep Memory Alive, NIGMS grant P20GM109025, NINDS grant U01NS093334 and NIA grant R01AG053798.

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The authors all researched data for the article, provided substantial contributions to discussion of its content and reviewed/edited the manuscript before submission. G.B.F., D.A., D.R.T., F.R., R.v.d.K., R.O., P.M.N., P.-Y.D., P.S. and B.D. wrote the article.

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Correspondence to Giovanni B. Frisoni.

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Competing interests

G.B.F. has received grants from Avid Radiopharmaceuticals, Biogen, GE International, Guerbert, IXICO, Merz Pharma, Nestlé, Novartis, Eisai, Piramal, Roche, Siemens, Teva Pharmaceutical Industries and Vifor Pharma. He has received personal fees from AstraZeneca, Avid Radiopharmaceuticals, Biogen, Roche, Diadem, Neurodiem, Elan Pharmaceuticals, GE International, Lundbeck, Pfizer and TauRx Therapeutics. D.R.T. has received speaker honoraria from Novartis Pharma Basel (Switzerland) and Biogen (USA), has received travel reimbursement from GE Healthcare (UK), and UCB (Belgium) and has collaborated with GE Healthcare (UK), Novartis Pharma Basel (Switzerland), Probiodrug (Germany) and Janssen Pharmaceuticals (Belgium). K.B. has served as a consultant, on advisory boards or on data monitoring committees for Abcam, Axon, Biogen, Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is part of the GU Ventures incubator programme. J.C. has acted as a consultant for Acadia, Actinogen, Alkahest, Alzheon, Annovis, Avanir, Axsome, Biogen, Cassava, Cerecin, Cerevel, Cortexyme, Cytox, EIP Pharma, Eisai, Foresight, GemVax, Genentech, Green Valley, Grifols, Karuna, Merck, Novo Nordisk, Otsuka, Resverlogix, Roche, Samumed, Samus, Signant Health, Suven and United Neuroscience. J.C. also has stock options in ADAMAS, AnnovisBio, MedAvante and BiOasis, and owns the copyright of the Neuropsychiatric Inventory. P.S. has received consultancy fees (paid to Amsterdam UMC) from AC Immune, Brainstorm Cell, EIP, ImmunoBrain Checkpoint, Genentech, Novartis, and Novo Noridisk. He is a principal investigator on studies with AC Immune, FUJIFILM Toyama, UCB, and Vivoryon. He is a part-time employee of Life Sciences Partners Amsterdam. B.D. has received research funding (paid to the institution) from Merck-Avenir Foundation and Roche and consultancy fees from Biogen, Neurodiem, Green Valley, Cytox and Brainstorm. He is a principal investigator on clinical trials with Eisai, Genentech, Novartis, Biogen and Roche. D.A., F.R., R.v.d.K., R.O., C.v.D., P.M.N. and P.-Y.D. declare no competing interests.

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Glossary

Alzheimer disease

(AD). The co-occurrence of brain Aβ and tau pathology. AD dementia is the final stage of AD, in which cognitive impairment and loss of daily function are also present.

Amyloid

In the brain, a 37–49-amino-acid polypeptide (amyloid-β (Aβ)) produced by the metabolism of the synaptic membrane protein amyloid precursor protein (APP). The amyloid fibrillar form is made mainly of the 42-amino-acid variant (Aβ42) and is the primary component of amyloid plaques found in the brains of individuals with Alzheimer disease. Soluble Aβ42 can be found in plasma and the cerebrospinal fluid and can give rise to soluble oligomers, thought to be the toxic form of Aβ.

Braak stage

Braak stage denotes the degree of tau pathology in Alzheimer disease and assumes progressive spread of such pathology from the transentorhinal region of the brain. Braak stages I and II denote neurofibrillary tangle involvement confined mainly to the transentorhinal region, stages III and IV when there is also involvement of limbic regions such as the hippocampus, and stages V and VI when there is extensive neocortical involvement.

Mild cognitive impairment

(MCI). A syndrome featuring cognitive impairment and no loss of daily function; Alzheimer disease is the underlying pathology in 60–80% of MCI cases. In these cases, the condition is also called prodromal Alzheimer disease or MCI due to Alzheimer disease.

Neurodegeneration

Progressive loss of the structure or function of neurons, which may ultimately involve cell death. The earliest detectable event is thought to be synaptic loss, followed by neuronal loss. Neurodegeneration can be detected in vivo with volumetric MRI and positron emission tomography with 18F-labelled deoxyglucose.

Tau

A protein whose primary role is in maintaining the stability of microtubules in axons. In the course of Alzheimer disease, tau becomes hyperphosphorylated, leading to axonal and synaptic dysfunction and aggregation of tau into intracellular neurofibrillary tangles.

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Frisoni, G.B., Altomare, D., Thal, D.R. et al. The probabilistic model of Alzheimer disease: the amyloid hypothesis revised. Nat Rev Neurosci 23, 53–66 (2022). https://doi.org/10.1038/s41583-021-00533-w

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