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

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 beta) 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 beta oligomers, which are implicated as upstream drivers of neurodegeneration by multiple studies. Development of agents that can effectively inhibit A beta 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 beta 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.