Summary
The finding of amyloid-beta (Aβ) deposition in AD brains after death led to the so-called “amyloid hypothesis”. We have extensively reviewed the literature which claims that AD is caused by the deposition of Aβ within structures called senile plaques that invade AD brains and that such plaque formation then leads to further abnormalities within the nerve cells, eventually killing them.
Analysis
We have found little evidence to support this claim and ample evidence to question it. For example, the amyloid hypothesis has been criticized because its research findings up to now have not generated any benefits in the clinical management and treatment of AD patients nor to an understanding of how the elderly are preferentially affected. The three main flaws of the amyloid hypothesis appear to be that: 1) Aβ deposition has not been found to be toxic or cause damage and death of nerve cells in human or animal brain; (2) the brains of many cognitively normal aged individuals show abundant Aβ containing senile plaques but no clinical signs of Alzheimer disease, 3) and since there is general agreement that senile plaques containing Aβ are the products of degenerating neurons, they can not be the cause, since it is axiomatic that a product is the result not the cause of some activity. By contrast, there is now considerable and still growing evidence from the fields of epidemiology, pharmacology, neuroimaging, clinical medicine, microscopic anatomy, and molecular biology which indicate that non-genetic AD is a vascular disorder whose underlying cause is impaired blood flow to the brain during advanced aging. This evidence can be summarized as follows: (1) numerous epidemiologic studies link AD risk factors such as stroke, heart disease, hypertension and atherosclerosis to reduced cerebral blood flow; (2) evidence that AD and vascular dementia (VaD), an acknowledged vascular disorder, share practically all the same risk factors and may benefit from the same treatments; (3) drug therapy reported to improve AD symptoms (including prescriptive drugs now available for AD) all increase blood flow to the brain; (4) people who are likely to develop AD but do not yet show dementia symptoms can be identified by using brain blood flow measurements and brain PET scans; (5) the clinical symptoms are very similar in most AD and VaD patients; (6) parallel abnormalities occur in brain vessels and brain tissue including Aβ laden plaques in AD and VaD patients; (7) low levels of brain blood flow in aged humans and animals can lead to abnormal cell metabolism, tissue damage and memory problems independent of Aβ; (8) mild cognitive impairment (a term used to describe a preliminary stage leading to AD) can convert equally to AD or VaD; (9) and small vessel damage (including the subcellular organelles such as mitochondria) is present in the majority of AD brains after death.
For these reasons, it is suggested that AD be re-classified as a oxidative stress induced vascular disorder and described as a “vasocognopathy” with the mitochondrial failure. The term aptly describes the origin of the disease , its primary effect on a system (-cogno: relating to mental ability) and its clinical course (-pathy: disorder). Re-classification of AD from a neurodegenerative to a vascular disorder would speed the development of truly beneficial treatments or a cure, improve patient management, provide earlier diagnosis, and reduce the number of AD cases in the future by aggressively treating the risk factors that can turn on this dementia. In conclusion, a bare-bones examination of the literature reveals no compelling evidence that Aβ deposition causes AD or that it results in significant damage to brain cells. By contrast, the findings that support AD as a primary oxidative stress induced mitochondrial failure (e.g., which induces the cellular and subcellular hypoperfusion) vascular disorder appear substantially more convincing.
Moreover, the recent failure in the vaccine trials for Alzheimer patients also appears to not only indicate that this type of work does not provide any concrete evidence and/or new and more effective treatment strategies for the AD patients but in addition might block new and perspective treatment strategies for this devastating disease. Therefore, in my judgment imaging Amyloid deposit in the brain of Alzheimer patients has nothing to do with the treatment or benefits for AD patients.
This author consults with leading institutions through GLG
Analyses are solely the work of the authors and have not been edited or endorsed by GLG.
