Alzheimer’s Disease and the Amyloid Hypothesis

According to the NHS, 1 in 20 people below the age of 65 are diagnosed with Alzheimer’s Disease (AD). (1) 

With over 25 years of research into the amyloid hypothesis, this progressive disorder of the brain has highlighted the role of a peptide, amyloid-b, in causing the disease. 

The amyloid hypothesis- whereby the accumulation of amyloid-b is the root of the disease- has produced several drug trials for AD. However, at present, none has brought forward any drugs with promising results and AD remains incurable. While amyloid-b is a normal product of b-amyloid precursor protein (APP) found in the body, mutations in the APP gene result in abnormally cleaved protein and an imbalance between the amyloid-b produced and cleared. Mutated amyloid-b self-aggregates into sticky clusters characteristic to AD. (2) Looking at preventative targets, the clearance of increased amyloid-b in APP transgenic mice bears success without side effects. 

The same approach in AD patients, however, results in a transient inflammatory reaction. Excess amyloid-b plaques also seem to be normal in many healthy humans not showing any symptoms of AD. But it is argued that these plaques could effectively be an early indication of AD developing down the line. (3)(4)

Decades of research show amyloid-b plaques are an initial step to the cascade of events leading to AD. The abundance of research into drugs targeting amyloid-b but the lack of successful clinical trials is a potential indication of another downstream change playing a greater role in causing AD. 

However, little research looking at anti-amyloid agents has been carried out. Until ongoing studies produce an alternative target with broader evidential support than the amyloid hypothesis, the current model seems to remain the guide for potential treatments for AD.

(1) NHS (2021). Overview - Alzheimer’s Disease. [online] NHS. Available at: https://www.nhs.uk/conditions/alzheimers-disease/.

(2) Makin, S. (2018). The amyloid hypothesis on trial. [online] Nature.com. Available at: https://www.nature.com/articles/d41586-018-05719-4.

(3) Hardy, J. and Selkoe, D.J. (2002). The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science (New York, N.Y.), [online] 297(5580), pp.353–6. doi:10.1126/science.1072994.

(4) Selkoe, D.J. and Hardy, J. (2016). The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO molecular medicine, [online] 8(6), pp.595–608. doi:10.15252/emmm.201606210.