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Cited by 1,849Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective

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Tanzi, Rudolph E., Bertram, Lars·2005·Cell
DOI 10.1016/j.cell.2005.02.008
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Abstract

From Alois Alzheimer's description of Auguste D.'s brain in 1907 to George Glenner's biochemical dissection of beta-amyloid in 1984, the "amyloid hypothesis" of Alzheimer's disease has continued to gain support over the past two decades, particularly from genetic studies. Here we assess the amyloid hypothesis based on both known and putative Alzheimer's disease genes.

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  • Strong genetic and biochemical evidence suggests that an increase in total Aβ production, an increase in the ratio of Aβ42 to Aβ40, or generation of a mutant form of Aβ with greater amyloidogenic propensity are the main mechanisms for rare early-onset autosomal-dominant familial AD, CAA, or both.

    “Although strong genetic and biochemical evidence suggests that an increase in total A production, an increase in the ratio of Aβ42 to Aβ40, or generation of a mutant form of Aβ with greater amyloidogenic propensity are the main mechanisms for the rare early-onset forms of autosomal-dominant familial AD, cerebral amyloid angiopathy (CAA), or a combination of both disorders, these are”

    From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Tanzi and Bertram, 2005

    The Introduction reports that most early-onset familial AD mutations increase the cerebral Aβ42-to-Aβ40 ratio, and the Conclusion says rare autosomal-dominant mutations primarily affect Aβ generation. The passages do not establish increased total Aβ production or a more amyloidogenic mutant Aβ as the other specified mechanisms, nor do they extend this account to cerebral amyloid angiopathy (CAA). No page numbers are available in our copy. (LLM, conf=0.85)

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  • These early-onset mechanisms are probably not the major pathogenic mechanisms underlying the more common late-onset AD.

    “these are probably not the major pathogenic mechanisms underlying the more common late-onset AD (Haass and Selkoe, 2007; Tanzi and Bertram, 2005).”

    From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Tanzi and Bertram, 2005

    The Conclusion (page unavailable) distinguishes early-onset mutations, which primarily affect Aβ generation, from the established late-onset risk factor APOE-ϵ4, which appears to affect Aβ oligomerization and clearance. The Introduction also says APP and presenilin mutations account for less than 5% of AD cases. These passages support a difference in genetic drivers, but not the broader claim that early-onset pathogenic mechanisms are probably not major mechanisms in late-onset AD; the paper describes an Aβ imbalance as central to AD. (LLM, conf=0.78)

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Cited by

Sorted by citations

Authors
Tanzi, R. E., & Bertram, L.
Affiliations
Harvard University (US)
Corresponding author
Tanzi, Rudolph E.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2005-02
Volume
120
Issue
4
Pages
545-555
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2005.02.008
OpenAlex
W2131819352
Cited by
1,849
References
13
Citations by year
2026: 32 · 2025: 42 · 2024: 83 · 2023: 59 · 2022: 65 · 2021: 85 · 2020: 101 · 2019: 76 · 2018: 86 · 2017: 89 · 2016: 105 · 2015: 96 · 2014: 104 · 2013: 125 · 2012: 118
FWCI
11.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, amyloid hypothesis, amyloid-beta, genetic susceptibility, genetic epidemiology, history of Alzheimer's disease
MeSH terms
Alzheimer Disease, Chromosomes, Human, Pair 21, Humans, Mutation, Endopeptidases, Protein Denaturation, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Amyloid Precursor Protein Secretases

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