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Acta Neuropathol Commun. 2014 Sep 18;2:135. doi: 10.1186/s40478-014-0135-5.

Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer's disease.

Author information

1
Garvan Institute of Medical Research, Neuroscience Department, Neurodegenerative Disorders Laboratory, 384 Victoria Street, Darlinghurst 2010, NSW, Australia. brycevissel@gmail.com.

Abstract

The amyloid hypothesis has driven drug development strategies for Alzheimer's disease for over 20 years. We review why accumulation of amyloid-beta (Aβ) 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 Aβ deposition in cognitively normal individuals, the weak correlation between plaque load and cognition, questions regarding the biochemical nature, presence and role of Aβ 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 Aβ in AD. We conclude it is essential to expand our view of pathogenesis beyond Aβ and tau pathology and suggest several future directions for AD research, which we argue will be critical to understanding AD pathogenesis.

PMID:
25231068
PMCID:
PMC4207354
DOI:
10.1186/s40478-014-0135-5
[Indexed for MEDLINE]
Free PMC Article

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