The antimicrobial protection hypothesis of Alzheimer’s disease
Abstract
Objective: We explore here a novel model for amyloidogenesis in Alzheimer's disease (AD). This new perspective on AD amyloidosis seeks to provide a rational framework for incorporating recent and seemingly independent findings on the antimicrobial role of β‐amyloid and emerging experimental, genetic, and epidemiological data, suggesting innate immune‐mediated inflammation propagates AD neurodegeneration. Background: AD pathology is characterized by cerebral deposition of amyloid‐β protein (Aβ) as β‐amyloid. Genetic studies have confirmed the key role of Aβ in AD, revealing that mutation‐mediated shifts in the peptides generation lead to early onset familial Alzheimer's disease. However, Aβ generation appears normal for the majority of AD patients, who lack early onset familial Alzheimer's disease mutations. In prevailing models of nonfamilial AD, individual genetics and age‐associated changes in brain milieu promote an intrinsically abnormal propensity of Aβ for self‐association. However, emerging findings are increasingly inconsistent with characterization of Aβ oligomerization as a nonphysiological and exclusively pathological activity. Recent studies suggest Aβ is an ancient, highly conserved effector molecule of innate immunity. Moreover, Aβ oligomerization and β‐amyloid generation appear to be important innate immune pathways that mediate pathogen entrapment and protect against infection. New AD amyloidogenesis model: Recent findings on inflammation‐mediated neurodegeneration and the role of Aβ in immunity have led to emergence of the “Antimicrobial Protection Hypothesis” of AD. In this model, β‐amyloid deposition is an early innate immune response to genuine, or mistakenly perceived, immunochallenge. Aβ first entraps and neutralizes invading pathogens in β‐amyloid. Aβ fibrillization drives neuroinflammatory pathways that help fight the infection and clear β‐amyloid/pathogen deposits. In AD, chronic activation of this pathway leads to sustained inflammation and neurodegeneration. Mounting data link elevated brain microbe levels with AD. The Antimicrobial Protection Hypothesis reveals how increased brain microbial burden may directly exacerbate β‐amyloid deposition, inflammation, and AD progression. Amyloid cascade hypothesis: In the antimicrobial protection model, the modality of Aβ's pathophysiology is shifted from abnormal stochastic behavior toward dysregulated innate immune response. However, β‐amyloid deposition in AD still leads to neurodegeneration. Thus, the new model extends but remains broadly consistent with the Amyloid Cascade Hypothesis and overwhelming data showing the primacy of Aβ in AD pathology.
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Chronic activation of Aβ can cause hyperphosphorylation of tau and the creation of neurofibrillary tangles that lead to AD pathology in aged individuals, due to their reduced efficiency in Aβ and tau clearance.
“Chronic activation of Aβ can cause hyperphosphorylation of tau and the creation of neurofibrillary tangles [109] that lead to AD pathology in aged individuals [104,110], due to their reduced efficiency in Aβ and tau clearance [110].”
From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [104]
Oligomerization of Aβ may be an innate host response to entrap microbial pathogens in the brain.
“Oligomerization of Aβ may be an innate host response to entrap microbial pathogens in the brain [104].”
From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [104]
Aβ has been suggested to be part of an anti-microbial host response.
“Aβ has been suggested to be part of an anti-microbial host response.”
From What would it take to prove that a chronic infection is a causal agent in Alzheimer’s disease? (2025) · cites this paper as [104]
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- Authors
- Moir, R. D., Lathe, R., & Tanzi, R. E.
- Affiliations
- Harvard University (US)
- University of Edinburgh (GB)
- Corresponding author
- Tanzi, Rudolph E.
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2018-10-09
- Volume
- 14
- Issue
- 12
- Pages
- 1602-1614
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- OpenAlex
- W2896921600
- Cited by
- 456
- References
- 10
- Citations by year
- 2026: 51 · 2025: 59 · 2024: 49 · 2023: 48 · 2022: 70 · 2021: 60 · 2020: 77 · 2019: 41 · 2018: 1
- FWCI
- 30.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Leona M. and Harry B. Helmsley Charitable Trust (2012PG‐T1D039)
- National Institutes of Health (1R01AI081990‐01A1)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease
- MeSH terms
- Neuroprotection, Alzheimer Disease, Amyloid, Amyloidosis, Animals, Anti-Infective Agents, Humans, Immunity, Innate, Models, Biological
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