Recent translational studies have led to a model of Alzheimer’s disease (AD) pathophysiology that focuses on the accumulation of amyloid-beta (Aβ) plaques between 20-30 years prior to the spread of tau, neuronal loss, and appearance of clinical symptoms. These findings have enabled the current research landscape to evolve to include preclinical stages of AD, when treatment success is predicted to be higher. There are a number of contributing factors that lead to a person developing AD. However, the multifactorial nature of AD largely plays into the reasoning researchers are focusing on Aβ accumulation for potential therapeutic interventions for early AD.
Toxicity within the Aβ pathway is believed to play a crucial role in the progression of AD. Studies have suggested a temporal progression of Aβ pathophysiology from the spread of Aβ aggregation to the formation of plaques in the brain. While the causal effect is not fully established, evidence suggests that Aβ aggregation may facilitate and have a synergistic effect on other pathophysiological pathways, triggering downstream effects such as tau misfolding, tangle formation, and eventual neurodegeneration. Understanding this relationship is crucial for unraveling the pathogenesis of AD.
In summary, the central role of Aβ in AD pathophysiology demonstrates why it is a viable target for early treatment options. Aβ accumulation during preclinical stages presents a critical time period for intervention. Imbalances in Aβ production and clearance contribute to plaque formation, while genetic risk factors can trigger further disruption of Aβ homeostasis. When microglia fail to effectively limit Aβ accumulation, Aβ aggregation is accelerated. The resulting toxicity is thought to start a cascade of events, causing disease progression. Continued research holds potential for the development of effective therapies targeting Aβ in the early stages of AD, potentially improving treatment outcomes for individuals affected by this devastating disease.
The Amyloid-β Pathway in Alzheimer’s Disease
Hampel H; Hardy J; Blennow K; Chen C; Perry G; Kim SH; Villemagne VL; Aisen P; Vendruscolo M; Iwatsubo T; Masters CL; Cho M; Lannfelt L; Cummings JL; Vergallo A