The conventional view of AD (Alzheimer's disease) is that much of the pathology is driven by an increased load of β-amyloid in the brain of AD patients (the ‘Amyloid Hypothesis’). Yet, many therapeutic strategies based on lowering β-amyloid have so far failed in clinical trials. This failure of β-amyloid-lowering agents has caused many to question the Amyloid Hypothesis itself. However, AD is likely to be a complex disease driven by multiple factors. In addition, it is increasingly clear that β-amyloid processing involves many enzymes and signalling pathways that play a role in a diverse array of cellular processes. Thus the clinical failure of β-amyloid-lowering agents does not mean that the hypothesis itself is incorrect; it may simply mean that manipulating β-amyloid directly is an unrealistic strategy for therapeutic intervention, given the complex role of β-amyloid in neuronal physiology. Another possible problem may be that toxic β-amyloid levels have already caused irreversible damage to downstream cellular pathways by the time dementia sets in. We argue in the present review that a more direct (and possibly simpler) approach to AD therapeutics is to rescue synaptic dysfunction directly, by focusing on the mechanisms by which elevated levels of β-amyloid disrupt synaptic physiology.
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Review Article| August 14 2012
Is the Amyloid Hypothesis of Alzheimer's disease therapeutically relevant?
Andrew F. Teich ;
Andrew F. Teich 1
1Department of Pathology and Cell Biology, Columbia University Medical Center, 630 West 168th Street, PH15-124, New York, NY 10032, U.S.A.
1To whom correspondence should be addressed (email firstname.lastname@example.org).
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Andrew F. Teich, Ottavio Arancio; Is the Amyloid Hypothesis of Alzheimer's disease therapeutically relevant?. Biochem J 1 September 2012; 446 (2): 165–177. doi: https://doi.org/10.1042/BJ20120653
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