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Cited by 106Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

The Beta Amyloid Dysfunction (BAD) Hypothesis for Alzheimer’s Disease

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Hillen, Heinz·2019·Frontiers in Neuroscience
DOI 10.3389/fnins.2019.01154PMC PMC6853841
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Abstract

Beta amyloid, Aβ 1-42, originally named as Amyloid A4 protein is one of the most investigated peptides in Neuroscience and has attracted substantial interest since its discovery as the main insoluble fibril type protein in cerebrovascular plaques (Glenner and Wong, 1984, Masters et al.,1985) of Alzheimer`s Disease (AD). Since its discovery, Aβ was regarded per se as a „bad molecule“ from the very beginning, triggering the so called „beta amyloid cascade hypothesis“ (Hardy and Higgins, 1992). This hypothesis ignored any physiological function for steadily generated Aß monomer with normal production and turnover rate (Bateman, R., 2006). Accordingly, pan-Aβ related therapeutic approaches were designed to eliminate or lower all three structural isoforms in parallel: 1. the pre-amyloid monomer, 2. the misfolded oligomer and 3. the final fibril. While we already knew about poor correlations between plaques and cognitive decline quite early (Terry et al., 1991), more importantly, also data for an essential benign physiological role for Aβ monomer at low concentrations were surprisingly not considered to be relevant. Here I describe a different Beta Amyloid Hypothesis, the so called „Beta Amyloid Dysfunction Hypothesis“, which in contrast to the „Beta Amyloid Cascade Hypothesis“ builds on an important physiological role of nascent Aβ monomer in accelerated synaptic trafficking in the vesicle budding process. Disease relevant early Aß pathology starts when the control of the folding process is disturbed leading then to misfolded Aß oligomers. These early species compete with the physiological Aβ monomer and exert their neurotoxicity through promiscuous receptors for sticky oligomer type Aß aggregates. The Beta Amyloid Dysfunction (BAD) Hypothesis is introduced and shown to explain negative clinical results of Gamma secretase - and BACE inhibitors as well as pan-Aβ isotype unselective immunotherapies. This new hypothesis also gives clear guidance to what really needs to be done therapeutically to bring this genetically validated target back into successful clinical testing in Alzheimer`s disease. The BAD hypothesis will need further refinement in particular through more detailed exploration for the role of physiological Aβ monomer.

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  • Under healthy conditions, soluble monomeric Aβ contributes to synaptic regulation, neuronal signaling, and neuroprotection through modulation of calcium homeostasis, metal ion binding, and antimicrobial defense.

    “Under healthy conditions, soluble monomeric Aβ contributes to synaptic regulation, neuronal signaling, and neuroprotection through modulation of calcium homeostasis, metal ion binding, and antimicrobial defense [41–43].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [41]

    In “Aβ Monomer Homeostasis Is Essential for Synaptic Function” (page unavailable), the paper describes a physiological role for Aβ monomer in synaptic regulation, and Table 1 reports that it is neuroprotective. The passages do not support the claimed mechanisms of calcium-homeostasis modulation, metal-ion binding, or antimicrobial defense. (LLM, conf=0.86)

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Authors
Hillen, H.
Corresponding author
Hillen, Heinz
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2019-11-07
Volume
13
Pages
1154-1154
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2019.01154
PMC
PMC6853841
OpenAlex
W2987379711
Cited by
106
References
13
Citations by year
2026: 12 · 2025: 14 · 2024: 6 · 2023: 20 · 2022: 20 · 2021: 16 · 2020: 18
FWCI
9.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
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-beta, amyloid-beta oligomers, vesicle budding, amyloid plaques, gamma-secretase inhibitors, BACE inhibitors, anti-amyloid therapy, neurotoxicity, protein folding

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