Rationale for Amyloid-Beta Targeting Therapies for Early AD Treatment

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.

As discussed in previous blogs, Aβ is an enzymatic product of the amyloid precursor protein (APP) gene. An imbalance of Aβ production in the brain and extra-cellular clearance precedes Aβ protein misfolding and aggregation into brain plaques in AD. Mutations in APP can make enzymes involved in processing it bind more tightly to it, causing more of these misfolded Aβ protein fragments to be produced. Additionally, the APP gene can be processed by 3 main proteases: β-secretase and gamma-secretase promote toxic Aβ production, whereas A-secretase produces healthy, soluble Aβ. Dysregulation in these secretases can result in Aβ over production. Although an excess of Aβ proves detrimental, Aβ protein is necessary for normal neurotransmission and synaptic plasticity, so knocking out the APP gene altogether is not a viable solution. Large-scale genome-wide association studies have identified over 50 additional genetic risk factors for AD, and while they do not denote the exact cause of the disease, most are involved in maintaining Aβ homeostasis. For instance, those with early-onset AD often have mutations in at least one of three genes: APP, presenilin 1 (PSEN1), and presenilin 2 (PSEN 2), and have increased Aβ due to genetic driven-dysregulation. This is compared to those with late-onset AD, with Aβ plaques largely attributed to reduced cellular quality control.

Another well-known genetic association with Aβ metabolism and homeostasis is an individual’s apolipoprotein (APOE) genotype. In-vitro and mouse models have shown that APOE moderates the activity of specific enzymes and downstream Aβ production. Those with an APOE E4 genotype were found to have significantly higher Aβ secretion, and those with two copies resulted in a 5-13-fold increase in AD incidence. Although our genes can be important in determining health status, sometimes it’s the downstream events, after protein production, that can initiate dysfunction. These post-translational, or epigenetic, changes further modify gene expression and protein production and degradation, continuing to alter Aβ levels.

In an attempt to protect the brain from Aβ plaques, microglia activate to prevent Aβ plaque spread, help with Aβ clearance, and attempt to limit Aβ accumulation. A dysregulation in these microglia, or a normal regulation under Aβ conditions, can further induce Aβ aggregation in the brain. Transforming growth factor-beta1 (TGFβ-1) is a neuroprotective, anti-inflammatory growth factor that stimulates Aβ clearance. In those with early AD, this growth factor is selectively impaired. The presence of Aβ can induce detrimental microglia activity, causing the release of pro-inflammatory cytokines and interfering with anti-inflammatory cytokine synthesis. For example, the cytokine tumor necrosis factor-alpha (TNF-α) results in increased synthesis of Aβ peptides, and its presence perpetuates more TNF- α in a vicious cycle. Studies have found that TNF-α levels are elevated in both mild cognitive impairment (MCI) and AD. Therefore, Aβ is again a common factor in the culmination of events that can lead to disease progression. Since microglia have both beneficial and detrimental effects on the brain when associated with Aβ, an undiscovered temporal factor may be at play, indicating that only at certain stages can microglia constructively intervene. More research is needed to elucidate this further.

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.

Reference:

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

https://pubmed.ncbi.nlm.nih.gov/34456336/