The Amyloid Hypothesis, Time to Move On

This paper is one example of numerous varied critiques of the mainstream consensus view that accumulating amyloid in the brain is the proximate cause of Alzheimer's disease pathology. No current consensus in science ever goes unchallenged, especially when working therapies are slow to emerge as a result of that consensus:

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.

Link: http://dx.doi.org/10.1016/j.jalz.2013.11.003


Agreed that the amyloid hypothesis has had its day. After extensive investigated it has given us no effective treatment for AD: while amyloid surely plays some role in neurodegeneration it seems to me that plaques are a protective response to the toxicity of amyloid oligomers but we have no idea why these form. The tau hypothesis seems promising but the question remains - what is the cause of the neurodegeneration? My hunch is that a viral flare-up is the trigger but i'm in a small minority.

This paper contends that cerebral blood circulation impairment is the culprit. Obviously neurons deprived of blood are going to suffer but is there any evidence that AD brains show a significant difference in microvasculature compared to healthy brains of the same age?

Posted by: Richard Wilson at July 19th, 2014 5:39 AM

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