The Amyloid Cascade Hypothesis in Alzheimer's Disease: Should We Change Our Thinking?

Abstract

Old age increases the risk of Alzheimer's disease (AD), the most common neurodegenerative disease, a devastating disorder of the human mind and the leading cause of dementia. Worldwide, 50 million people have the disease, and it is estimated that there will be 150 million by 2050. Today, healthcare for AD patients consumes 1% of the global economy. According to the amyloid cascade hypothesis, AD begins in the brain by accumulating and aggregating Aβ peptides and forming β-amyloid fibrils (Aβ42). However, in clinical trials, reducing Aβ peptide production and amyloid formation in the brain did not slow cognitive decline or improve daily life in AD patients. Prevention studies in cognitively unimpaired people at high risk or genetically destined to develop AD also have not slowed cognitive decline. These observations argue against the amyloid hypothesis of AD etiology, its development, and disease mechanisms. Here, we look at other avenues in the research of AD, such as the presenilin hypothesis, synaptic glutamate signaling, and the role of astrocytes and the glutamate transporter EAAT2 in the development of AD.

Keywords: E280A; EAAT2; amyloid hypothesis; astrocyte; dementia; presenilin.

Figure 1

The comparison between amyloid and presenilin hypotheses. The amyloid hypothesis proposed that mutation in PSEN1 results in presenilin dysfunction, thus change in γ-secretase activity resulting in relative increase of the Aβ42/Aβ40 ratio, which is significantly increased in AD pathologies. The presenilin hypothesis does not exclude the amyloid hypothesis but complements it. It presents theory that PSEN1 mutation and following loss of presenilin normal activity in brain triggers neurodegeneration and dementia also without coexisting amyloid formation. Created with BioRender.com.