I have researched this topic and found conflicting opinions towards the amyloid hypothesis in causing Alzheimer's disease. How valid is it?

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It is now widely accepted that Alzheimer's disease is a form of cerebral amyloidosis (in fact the most common form of amyloidosis).

The amyloidoses and prionoses are examples of protein misfloding diseases.

Amyloidosis: Abnormal proteins (amyloid fibrils) build up in tissues when they form incorrectly and are not completely broken down by protease enzymes. There are multiple types and they can be hereditary or acquired (e.g. due to inflammation, multiple myeloma and others).

Prionosis: An abnormally folded protein is able to transmit its abnormal folding to a normal version of the same protein. Examples include kuru and Creutzfeldt-Jacob Disease (CJD).

Alzheimer's Disease (AD)

The type of amyloid protein found causing neuronal damage in Alzheimer's disease is known as amyloid beta / amyloid precursor protein.

There are several hypotheses about the aetiology:

  • Cholinergic hypothesis - This states that AD is due to reduction of the neurotransmitter acetylcholine. Most current drug therapies are based on this. The lack of efficacy of these treatments is one of the reasons why support for this hypothesis is falling.

  • Amyloid hypothesis - First postulated in 1991 that extracellular amyloid beta deposits are the fundamental cause of the disease. Support for this postulate comes from the location of the gene for the amyloid precursor protein (APP) on chromosome 21, together with the fact that people with trisomy 21 (Down Syndrome) who have an extra gene copy almost universally exhibit at least the earliest symptoms of AD by 40 years of age. Also, a specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. While apolipoproteins enhance the breakdown of beta amyloid, some isoforms are not very effective at this task (such as APOE4), leading to excess amyloid buildup in the brain. A vaccination was developed and found to clear the amyloid plaques, but did not improve the dementia, leading researchers to believe that non-plaque oligomers of amyloid beta disrupt neuronal communication by binding to a receptor and altering the surface of the synapse.

  • Tau hypothesis - This proposes that a hyperphosphorylated protein causes the neurofibrillary tangles.

  • Inflammation hypothesis - This links AD to an inflammatory process, with links to chronic periodontal infection and problems with gut microbiome.

  • Neurovascular hypothesis - AD due to problems with the blood-brain barrier.

  • Other hypotheses - These suggest a role for smoking, air pollution and oligodendrocyte dysfunction.

The amyloid plaques and neurofibrillary tangles can be seen clearly by microscopy at autopsy, so they are known to be present. My main source (noted below) summarises this complex disease process and goes into some detail on the pathogenesis. It seems likely that there is a combination of factors interacting, including both amyloid and tau proteins causing neuronal damage and the resulting dementia.


Ghiso et al. Amyloidosis and Alzheimer's disease. Advanced Drug Delivery Reviews, 2002.

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