The path forward in Alzheimer's disease therapeutics: Reevaluating the amyloid cascade hypothesis

Abstract

Development of disease-modifying treatments for Alzheimer's disease (AD) has been challenging, with no drugs approved to date. The failures of several amyloid-targeted programs have led many to dismiss the amyloid beta (A) hypothesis of AD. An antiamyloid antibody aducanumab recently showed modest but significant efficacy in a phase 3 trial, providing important validation of amyloid as a therapeutic target. However, the inconsistent results observed with aducanumab may be explained by the limited brain penetration and lack of selectivity for the soluble A oligomers, which are implicated as upstream drivers of neurodegeneration by multiple studies. Development of agents that can effectively inhibit A oligomer formation or block their toxicity is therefore warranted. An ideal drug would cross the blood-brain barrier efficiently and achieve sustained brain levels that can continuously prevent oligomer formation or inhibit their toxicity. A late-stage candidate with these attributes is ALZ-801, an oral drug with a favorable safety profile and high brain penetration that can robustly inhibit A oligomer formation. An upcoming phase 3 trial with ALZ-801 in APOE4/4 homozygous patients with early AD will effectively test this amyloid oligomer hypothesis.

Alzheimer’s disease: targeting the glutamatergic system

“…Associated neurotoxic events include generation of ROS, loss of mitochondrial function (Reddy and Beal 2008), disruption of calcium homestasis together with neuroinflammation due to microglia activation by Ab (Cai et al 2014). Decades of clinical trials dedicated to target Ab processing have failed to generate a treatment for AD (Tolar et al 2019). The most recent trial with Aducanumab (BIIB037), a monoclonal antibody that targets Ab, failed to reach primary endpoint targets in March, 2019, where an indepdendent data monitoring committee determined that there was insufficient evidence to support drug efficacy.…”

Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval

“…The central and early role of beta amyloid (Aβ) in the pathogenesis of Alzheimer's disease (AD) is supported by numerous genetic, biomarker, and genome-wide association studies in both familial (early-onset) and sporadic (late-onset) AD [1]. The brain amyloid species consistently shown to be associated with acute neuronal toxicity and neurodegeneration in AD are the soluble amyloid oligomers, formed by the aggregation of misfolded Aβ monomers [1][2][3].…”

TheAppNL-G-Fmouse retina is a site for preclinical Alzheimer’s disease diagnosis and research

“…Notably, an explanation for the diverging and more severe phenotype of many other transgenic AD mouse models may be sought in the fact that those models are far removed from the human disease state, with nonendogenous promotors, overexpression of APP byproducts, PS1 mutation and/or abnormal APP and Aβ expression levels. This study is pioneering in that it is the first-time retinal phenotyping study of the App NL- As such, these do not always provide information about oligomeric Aβ, which may be the more relevant Aβ species to target 41,42 . Our data substantiate that hyperspectral imaging is a highly sensitive technique that can be used to quantify Aβ burden in the earliest stages of disease.…”