The amyloid puzzle: current concepts and controversies in Alzheimer’s disease

23 Aug 2021

Amyloid-β remains an important therapeutic target in Alzheimer’s disease (AD), experts say

While amyloid has been shown to play a key role in the pathogenesis of AD, clinical trials of therapies targeting amyloid have been largely disappointing to date. This has led experts to consider the need for treatment earlier within the disease process before irreversible damage has occurred.

In ‘The Amyloid Puzzle’, a podcast in the MindChangers series hosted on the recently launched ADBioHub, Professor Colin Masters (Laboratory Head of the Neuropathology and Neurodegeneration Laboratory at the Florey Institute of Neuroscience and Mental Health) and Associate Professor David Darby (Behavioural and Cognitive Neurologist at Melbourne Cognitive Services and the Florey Institute) share their insights into the current concepts and controversies in the neuropathology of AD.

Amyloid-β: an overview

Accumulation of amyloid-β outside neurons in the brain is a hallmark pathology of AD.1,2  In the AD brain, abnormal levels of amyloid-β, a naturally occurring protein, form plaques that accumulate between neurons and disrupt cell function.1,2 Deposition of amyloid-β in the brain has been proposed as the initiating step of AD pathogenesis, leading to subsequent tau deposition, neuron and synaptic loss and cognitive decline.1,2 While healthy individuals exhibit good amyloid-β clearance potential, this naturally declines with age and becomes significantly impaired in people with AD.2,3

Prof Masters, who in 1984 with German biologist Prof Konrad Beyruther purified and sequenced the amyloid constituent of the plaque in Alzheimer’s disease, explains that amyloid-β is sometimes referred to as the “peptide from hell” because it is very difficult to work with in the laboratory. “It is 42 amino acids in length but two-thirds of it is very insoluble…so in the test tube it aggregates like crazy – and this is part of the problem with Alzheimer’s disease. As it is being generated in the brain, it aggregates and gets stuck so you have to have a very efficient clearance mechanism in the brain and that is the mechanism that fails as we get older,” he says.

Current understanding of the role of amyloid-β in AD

As amyloid-β builds up in people with AD, it causes the synapses in the brain to malfunction. This loss of normal synaptic function is eventually expressed as the development of cognitive impairment. Prof Masters explains, “This is a molecule that is most heavily used in those parts of the brain involved in memory and learning… and it is those areas of the brain that are affected first in Alzheimer’s disease, because those areas are the ones that experience the build-up first.”

Significant progress has been made in the last 5 years in our understanding of the role of amyloid-β in AD, including imaging techniques that now allow for the identification of AD earlier in the disease process – many years before any cognitive impairment can be detected.4 There has been a revolution in the field in the last 5 to 10 years. For the first time now during life we can watch the build-up of amyloid in the brain using PET scans or biomarkers in cerebrospinal fluid – and now in the blood,” says Prof Masters. He adds that this This allows for the identification of patients in the preclinical stages of AD.

Potential future therapeutic approaches in AD

While the role of amyloid-β in AD is now well-established, demonstrating clinical benefit with amyloid-β-targeted therapies has been challenging.  There are many novel ways of slowing the build-up of amyloid-β in the brain, such as monoclonal antibodies as well as passive and active immunisation, but there is a need to understand how and when these treatments might be used to benefit patients.2

In particular, addressing the build-up of amyloid-β very early in the disease process, potentially years before any symptoms of cognitive decline occur, may represent a key strategy moving forward.

A/Prof David Darby, a leading behavioural and cognitive neurologist with research interests in early detection and early treatment trials, notes, “Unfortunately, by the time patients come to us with symptoms, usually it is not just the amyloid that is present. They often have multiple other consequences of the amyloid present as well, for example, tau deposition.” He suggests that future approaches to management will need to consider earlier detection and treatment. “We know that amyloid deposits for many decades before there are significant symptoms, so that would be the time to remove the amyloid,” he says.

Learn more about the current challenges and controversies surrounding amyloid-β in AD in the ADBioHub Mind Changers podcast ‘The Amyloid Puzzle’.


  1. Alzheimer’s Dement 2021;17:327–406.
  2. Long JM, Holtzman DM. Cell 2019;179:312–39.
  3. Behl T et al. Int J Mol Sci2020;21:7443.
  4. Dubois B et al. Lancet Neurol 2021;20:484–96.

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