What Causes Alzheimer’s Disease: The Beta-Amyloid vs. Tau Debate, and Beyond
Scientist Explains with Dr. Wai Haung (Ho) Yu
Originally published September 1, 2022 on Toronto Dementia Research Alliance. Updated and reissued January 15, 2024.
Alzheimer’s disease (AD) dementia is the most common form of dementia. Early signs of AD include mild memory loss that progressively leads to loss of the ability to carry on a conversation and respond to the environment. AD involves parts of the brain that control thought, memory, and language. While the average duration following diagnosis is four to eight years, individuals have lived for two decades post-diagnosis.
What Causes Alzheimer’s Disease?
Alzheimer’s disease, first identified in the early 1900s by Alois Alzheimer, is characterized by the build-up of two proteins in the brain called 'plaques' and 'tangles'. Plaques are formed when a protein outside of a brain cell called beta-amyloid clumps together. Tangles are formed when a protein inside of a brain cell called tau twists together. The formation of these plaques and tangles interferes with the ability of brain cells to communicate with one another, and as a result, causes them to die over time. In addition, the loss of brain cells (called neurons) - due to the buildup of the plaques, tangles and other toxic events - and the increased activity of other cells, specifically microglia and astrocytes, are thought to contribute to the disease process in AD. Microglia and astrocytes normally support brain function but may not be as helpful in aging or disease.
Beta-Amyloid vs. Tau Hypotheses
There has been a long standing debate on what is more important in AD: beta-amyloid (plaques) or tau (tangles). For many years, people have considered beta-amyloid to be the main cause of AD. We know that beta-amyloid can appear in the brain decades before tau. Additionally, gene mutations that cause early onset AD are linked to the production of beta-amyloid in the brain. However, since the late 1990s, clinical trials targeting beta-amyloid have been largely unsuccessful.
Over the past couple of years the Food and Drug Administration (FDA, USA) approved two medications that promote the clearance beta-amyloid from the brain. The antibody therapies, Aduhelm (approved May 2021 – see previous TDRA statement) and Leqembi (approved July 2023), have both been shown to reduce the decline in memory in people with early AD. Notably, these therapies are not approved in Canada, and are not effective in all people with AD, including those who carry the Apolipoprotein E4 gene. Further, these therapies do not necessarily cure AD, so we know that beta-amyloid cannot be the whole story.