Alzheimer’s: Why the β-amyloid hypothesis is under attack

The amyloid hypothesis of Alzheimer’s disease (AD) posits that accumulation of β-amyloid (Aβ) in the brain – whether through overproduction, inadequate clearance, or both – is the primary pathophysiological event leading to the progressive dementia that dominates the clinical picture many years later. The identification of genetically determined Aβ metabolism abnormalities in the rare familial form of AD has strengthened this concept. Thus, for the last 20 years this hypothesis has virtually monopolized the search for a disease-modifying therapeutic, and vast amounts of financial and clinical resource have been consumed by drugs targeting either Aβ production (e.g., β- and ϒ-secretase inhibitors) or clearance (e.g., Aβ-directed monoclonal antibodies).

However, the last few years have seen the repeated failure of drugs targeting Aβ – firstly in patients with established AD, then in those with prodromal cognitive impairment, and latterly in subjects deemed at high risk of the disease.  Analyses on possible reasons for this have highlighted issues with selection of patients, trial design and endpoints, but improvements in these areas have not helped.  Finally, it is clear that despite successfully reducing Aβ load, many anti-Aβ drugs appear to worsen cognitive function – a finding that has led to the early termination of several recent studies.

Ongoing research indicates that Aβ has many physiological roles within the CNS, including modulation of synaptic function, facilitation of neuronal growth and survival, protection against oxidative stress, and surveillance against neuroactive compounds, toxins and pathogens; brain Aβ levels have also been shown to rise in traumatic brain injury, encephalopathy, cerebral ischemia and other acute causes of CNS stress. These findings suggest that Aβ accumulation in AD may not be causative, but may actually be a protective adaptation.

Thus, a consensus is now developing that research efforts should be directed towards other areas of interest, such as neuroinflammation, microglial dysfunction, microbial infection and metabolic derangement (oxidative, cholesterol, glucose) – especially if the current round of anti-tau products meets the same fate as the anti-Aβ products…

Further reading

Panza F, Lozupone M, Watling M, Imbimbo BP. Do BACE inhibitor failures in Alzheimer patients challenge the amyloid hypothesis of the disease? Expert Rev Neurother. 2019; 19(7): 599-602. (PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31112433)