The Relevance of Beta-Amyloid on Markers of Alzheimer’s Disease in Clinically Normal Individuals and Factors That Influence These Associations

Aberrant accumulation of beta-amyloid (Aβ) is thought to be an early event in a biological cascade that eventually leads to Alzheimer’s disease (AD). Along these lines, many clinically normal (CN) older individuals have evidence of beta-amyloid (Aβ) accumulation, which may be indicative of preclinical AD. However, relationships between Aβ and “downstream” AD markers are often inconsistent across studies. These inconsistencies may be due to the presence of other age-related processes that also influence AD markers, as well as additional risk factors that interact with Aβ to influence downstream changes. For instance, it is possible that the effect of Aβ is modified by neurodegeneration, genetics, sex-differences and cognitive reserve. Thus, a multivariate approach to determining risk of AD within CN participants may be more appropriate than reliance on Aβ status alone. An understanding of how additional risk factors interact with Aβ to influence an individual’s trajectory towards AD is essential for characterizing preclinical AD and has implications for prevention trials.     

Lifespan brain activity, β-amyloid, and Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of progressive cognitive decline and dementia in adults. While the amyloid cascade hypothesis of AD posits an initiating role for the β-amyloid (Aβ) protein, there is limited understanding of why Aβ is deposited. A growing body of evidence based on in vitro, animal studies and human imaging work suggests that synaptic activity increases Aβ, which is deposited preferentially in multimodal brain regions that show continuous levels of heightened activation and plasticity across the lifespan. Imaging studies of people with genetic predispositions to AD are consistent with these findings, suggesting a mechanism whereby neural efficiency or cognitive reserve may diminish Aβ deposition. The aggregated findings unify observations from cellular and molecular studies with human cognitive neuroscience to reveal potential mechanisms of AD development.