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The amyloid hypothesis, time to move on: Amyloid is the downstream result, not cause, of Alzheimer's disease
Author(s) -
Drachman David A.
Publication year - 2014
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.11.003
Subject(s) - amyloid (mycology) , dementia , neuroscience , disease , medicine , mechanism (biology) , angiogenesis , atrophy , alzheimer's disease , biochemistry of alzheimer's disease , amyloidosis , amyloid precursor protein , pathology , psychology , philosophy , epistemology
The “amyloid hypothesis” has dominated Alzheimer research for more than 20 years, and proposes that amyloid is the toxic cause of neural/synaptic damage and dementia. If correct, decreasing the formation or removing amyloid should be therapeutic. Despite discrepancies in the proposed mechanism, and failed clinical trials, amyloid continues to be considered the cause of a degenerative cascade. Alternative hypotheses must explain three features: ( i ) why amyloid toxicity is not the etiology of Alzheimer's disease (AD), ( ii ) what alternative mechanisms cause the degeneration and dementia of AD, and ( iii ) why increased amyloid accumulates in the brain in AD. We propose that AD, which occurs in elderly, already vulnerable brains, with multiple age‐related changes, is precipitated by impaired microvascular function, resulting primarily from decreased Notch‐related angiogenesis. With impaired microvasculature, a lack of vascular endothelial‐derived trophic factors and decreased cerebral blood flow cause the atrophy of neural structures. Therapeutic strategies should focus on supporting normal angiogenesis.