Abstract
A large body of clinical and nonclinical evidence supports the role of neurotoxic soluble beta amyloid (amyloid, Aβ) oligomers as upstream pathogenic drivers of Alzheimer’s disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species of Aβ provide compelling evidence that inhibition of Aβ oligomer toxicity represents an effective approach to slow or stop disease progression: (1) only agents that target soluble Aβ oligomers show clinical efficacy in AD patients; (2) clearance of amyloid plaque does not correlate with clinical improvements; (3) agents that predominantly target amyloid monomers or plaque failed to show clinical effects; and (4) in positive trials, efficacy is greater in carriers of the ε4 allele of apolipoprotein E (APOE4), who are known to have higher brain concentrations of Aβ oligomers. These trials also show that inhibiting Aβ neurotoxicity leads to a reduction in tau pathology, suggesting a pathogenic sequence of events where amyloid toxicity drives an increase in tau formation and deposition. The late-stage agents with positive clinical or biomarker data include four antibodies that engage Aβ oligomers (aducanumab, lecanemab, gantenerumab, and donanemab) and ALZ-801, an oral agent that fully blocks the formation of Aβ oligomers at the clinical dose.
Highlights
The neuropathological diagnosis of Alzheimer’s disease (AD) requires the presence of two core pathologies: extracellular beta amyloid plaques and aggregated tau protein forming intra-neuronal neurofibrillary tangles [1,2]
The development of highly specific positron emission tomography (PET) imaging tools that enable detection and quantitation of the insoluble forms of deposited amyloid and tau have led to ground-breaking longitudinal clinical studies that defined the temporal relationship between the appearance of brain amyloid deposits and the later stages of disease, which are characterized by extensive tau pathology and progressive neurodegeneration [3]
Anti-amyloid agents that target Aβ oligomers with various degrees of selectivity have reported statistically significant clinical efficacy in late-stage trials. These include the anti-amyloid antibodies aducanumab, donanemab, and lecanemab, and a small molecule agent, ALZ-801, that fully blocks the formation of Aβ oligomers at the target clinical dose (Figure 5)
Summary
The neuropathological diagnosis of Alzheimer’s disease (AD) requires the presence of two core pathologies: extracellular beta amyloid (amyloid, Aβ) plaques and aggregated tau protein forming intra-neuronal neurofibrillary tangles (tau, NFT) [1,2]. Recently have clinical, imaging, and biomarker studies in AD patients firmly established the central role of amyloid in disease initiation and progression, and in triggering the spread of tau pathology and neurodegeneration. These include the anti-amyloid antibodies aducanumab, donanemab, and lecanemab, and a small molecule agent, ALZ-801, that fully blocks the formation of Aβ oligomers at the target clinical dose (Figure 5).
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