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Alzheimer disease

Abstract

Alzheimer disease (AD) is biologically defined by the presence of β-amyloid-containing plaques and tau-containing neurofibrillary tangles. AD is a genetic and sporadic neurodegenerative disease that causes an amnestic cognitive impairment in its prototypical presentation and non-amnestic cognitive impairment in its less common variants. AD is a common cause of cognitive impairment acquired in midlife and late-life but its clinical impact is modified by other neurodegenerative and cerebrovascular conditions. This Primer conceives of AD biology as the brain disorder that results from a complex interplay of loss of synaptic homeostasis and dysfunction in the highly interrelated endosomal/lysosomal clearance pathways in which the precursors, aggregated species and post-translationally modified products of Aβ and tau play important roles. Therapeutic endeavours are still struggling to find targets within this framework that substantially change the clinical course in persons with AD.

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Fig. 1: Neuropathological diagnoses that cause cognitive impairment across the age spectrum.
Fig. 2: APP cleavage pathways.
Fig. 3: ApoE and Aβ interaction.
Fig. 4: Consequences of the endosomal–lysosomal network and autophagy dysfunction in AD.
Fig. 5: Terminologies for characterizing cognitive impairment.
Fig. 6: Conceptualizing the A-T-N scheme.
Fig. 7: Aβ-PET scans closely approximate neuropathology.
Fig. 8: Tau-PET and FDG-PET patterns in different clinical syndromes in persons with high β-amyloid-PET.

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Acknowledgements

The authors acknowledge research support from NIH (D.S.K. and R.C.P, P30 AG062677 and U01 AG006786; B.T.H., P30AG062421; R.A.N. P01 AG017617 and R01 AG062376).

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Authors and Affiliations

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Contributions

Introduction (D.S.K.); Epidemiology (H.A.); Mechanisms/pathophysiology (D.T.J., R.A.N., B.T.H. and D.M.H.); Diagnosis, screening and prevention (G.C., R.C.P. and D.S.K.); Management (R.C.P. and D.S.K.); Quality of life (D.S.K.); Outlook (D.S.K.); Overview of Primer (D.S.K.).

Corresponding author

Correspondence to David S. Knopman.

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Competing interests

D.S.K. served on a Data Safety Monitoring Board for the DIAN study. He serves on a Data Safety Monitoring Board for a tau therapeutic for Biogen but receives no personal compensation. He is a site investigator in a Biogen aducanumab trial. He is an investigator in a clinical trial sponsored by Lilly Pharmaceuticals and the University of Southern California. He serves as a consultant for Samus Therapeutics, Third Rock, Roche and Alzeca Biosciences but receives no personal compensation. He receives research support from the NIH. G.C. serves on the Scientific Advisory Board of the Fondation Vaincre Alzheimer but receives no personal compensation. She receives personal fees from Fondation d’entreprise MMA des Entrepreneurs du Futur and from Fondation Alzheimer as she serves in the Operational Committee. She receives research support from European Union Horizon 2020 research and innovation programme (grant agreement number 667696), Inserm, Fondation d’entreprise MMA des Entrepreneurs du Futur, Fondation Alzheimer, Programme Hospitalier de Recherche Clinique, Région Normandie, Association France Alzheimer et maladies apparentées and Fondation Vaincre Alzheimer. R.C.P. is a consultant for Biogen, Inc., Roche, Inc., Merck, Inc., Genentech Inc. and Eisai, Inc., has given educational lectures for GE Healthcare, receives publishing royalties from Mild Cognitive Impairment (Oxford University Press, 2003), UpToDate, and receives research support from the NIH. B.T.H. has a family member who works at Novartis and owns stock in Novartis; he serves on the SAB of Dewpoint and owns stock. He serves on a scientific advisory board or is a consultant for Biogen, Novartis, Cell Signalling, the US Dept of Justice, Takeda, Vigil, W20 group and Seer. His laboratory is supported by sponsored research agreements with Abbvie, F Prim, and research grants from the National Institutes of Health, Cure Alzheimer’s Fund, Tau Consortium, Brightfocus and the JPB Foundation. H.A. serves on the Scientific Advisory Board of the Observatoire des Mémoires but receives no personal compensation. She receives research support from Spoelberch Foundation, Association France Alzheimer et maladies apparentées, the Regional Health Agency of Aquitaine and National Research Agency. D.M.H. reports being a Co-founder for C2N Diagnostics LLC and participating in scientific advisory boards/consulting for Genentech, C2N Diagnostics, Denali, Merck and Idorsia. He is an inventor on patents licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies (this anti-tau antibody programme is licensed to Abbvie) and to Eli Lilly on the therapeutic use of an anti-amyloid-β antibody. His laboratory receives research grants from the National Institutes of Health, Cure Alzheimer’s Fund, Tau Consortium, the JPB Foundation, Good Ventures, Centene, BrightFocus and C2N Diagnostics. All other authors declare no competing interests.

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Knopman, D.S., Amieva, H., Petersen, R.C. et al. Alzheimer disease. Nat Rev Dis Primers 7, 33 (2021). https://doi.org/10.1038/s41572-021-00269-y

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