期刊
ACTA NEUROPATHOLOGICA COMMUNICATIONS
卷 2, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s40478-014-0135-5
关键词
Alzheimer's disease; Amyloid hypothesis; Amyloid beta; Neurofibrilliary tangles; Tau; Synapse; Microglia; Astrocytes; Neuroinflammation; TNF; Neurodegeneration; Amyloid precursor protein; Plaque
资金
- Stanley
- Henry Roth Foundation
- ISG Foundation
- Amadeus Energy Ltd.
- Gleneagle Securities
- Patricia A. Quick Foundation
The amyloid hypothesis has driven drug development strategies for Alzheimer's disease for over 20 years. We review why accumulation of amyloid-beta (A beta) oligomers is generally considered causal for synaptic loss and neurodegeneration in AD. We elaborate on and update arguments for and against the amyloid hypothesis with new data and interpretations, and consider why the amyloid hypothesis may be failing therapeutically. We note several unresolved issues in the field including the presence of A beta deposition in cognitively normal individuals, the weak correlation between plaque load and cognition, questions regarding the biochemical nature, presence and role of A beta oligomeric assemblies in vivo, the bias of pre-clinical AD models toward the amyloid hypothesis and the poorly explained pathological heterogeneity and comorbidities associated with AD. We also illustrate how extensive data cited in support of the amyloid hypothesis, including genetic links to disease, can be interpreted independently of a role for A beta in AD. We conclude it is essential to expand our view of pathogenesis beyond A beta and tau pathology and suggest several future directions for AD research, which we argue will be critical to understanding AD pathogenesis.
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