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Cited by 183Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Alzheimer's Disease Puzzle: Delving into Pathogenesis Hypotheses

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Mohammad Nasb, Weichu Tao, Ning Chen·2024·aging and disease
DOI 10.14336/ad.2023.0608PMC PMC10796101
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Abstract

Alzheimer's disease (AD) is a prevalent neurodegenerative disease characterized by both amnestic and non-amnestic clinical manifestations. It accounts for approximately 60-70% of all dementia cases worldwide. With the increasing number of AD patients, elucidating underlying mechanisms and developing corresponding interventional strategies are necessary. Hypotheses about AD such as amyloid cascade, Tau hyper-phosphorylation, neuroinflammation, oxidative stress, mitochondrial dysfunction, cholinergic, and vascular hypotheses are not mutually exclusive, and all of them play a certain role in the development of AD. The amyloid cascade hypothesis is currently the most widely studied; however, other hypotheses are also gaining support. This article summarizes the recent evidence regarding major pathological hypotheses of AD and their potential interplay, as well as the strengths and weaknesses of each hypothesis and their implications for the development of effective treatments. This could stimulate further studies and promote the development of more effective therapeutic strategies for AD.

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  • Chronic or repeated infections overwhelm clearance mechanisms, resulting in persistent protein aggregation and neuroinflammation that ultimately drive neurodegeneration.

    “While protective in the short term, chronic or repeated infections overwhelm clearance mechanisms, resulting in persistent protein aggregation and neuroinflammation that ultimately drive neurodegeneration [165].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [165]

    The sections on the intersection of AD hypotheses and pro-inflammatory cytokines describe impaired Aβ clearance, accumulating aggregates, self-perpetuating neuroinflammation, and neuronal damage (page not provided). They do not say that chronic or repeated infections overwhelm clearance mechanisms, nor do they establish the claimed short-term protective response. The paper also notes in “Role of inflammation in AD” that whether inflammation is a cause or consequence remains unclear. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Aβ and tau may function as antimicrobial peptides, part of an innate immune response intended to neutralize or sequester infectious agents.

    “The second proposes that Aβ and tau function as antimicrobial peptides, part of an innate immune response intended to neutralize or sequester infectious agents.”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [165]

    The section “Current studies on inflammation in AD” says innate immunity has an important role in AD, but does not describe Aβ or tau as antimicrobial peptides. Searches for “antimicrobial” and for infectious-agent sequestration found no passage in our copy addressing that proposed function. (LLM, conf=0.73)

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Authors
Nasb, M., Tao, W., & Chen, N.
Affiliations
Wuhan Sports University (CN)
Corresponding author
Ning Chen
ORCID
Venue
aging and disease
Publisher
Aging and Disease
Published
2024
Volume
15
Issue
1
Pages
43-73
ISSN
2152-5250 (ISSN-L)
DOI
10.14336/ad.2023.0608
PMC
PMC10796101
OpenAlex
W4384401187
Cited by
183
References
57
Citations by year
2026: 48 · 2025: 94 · 2024: 35 · 2023: 6
FWCI
6.13
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Aging and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Hubei Provincial Department of Education
  • National Natural Science Foundation of China (31771318)
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, pathogenesis, amyloid hypothesis, tau hyperphosphorylation, neuroinflammation, oxidative stress, mitochondrial dysfunction, cholinergic hypothesis, vascular hypothesis, dementia, treatment options
MeSH terms
Alzheimer Disease, Amyloid, Humans, Phosphorylation, Oxidative Stress, Neurodegenerative Diseases

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