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Review
. 2021 Jun 14;22(12):6355.
doi: 10.3390/ijms22126355.

Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer's Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression

Martin Tolar  1 , John Hey  1 , Aidan Power  1 , Susan Abushakra  1
Affiliations
Review

Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer's Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression

Martin Tolar et al. Int J Mol Sci. .

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.

Keywords: ALZ-801; Alzheimer’s disease; aducanumab; beta amyloid oligomers; donanemab; gantenerumab; lecanemab; tramiprosate; ε4 allele of apolipoprotein E (APOE4).

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Conflict of interest statement

Martin Tolar serves as the Founder, President & Chief Executive Officer of Alzheon, Inc. and holds stock and stock options of Alzheon, Inc. John Hey serves as the Chief Scientific Officer of Alzheon, Inc. and holds stock and stock options of Alzheon, Inc. Aidan Power serves as the Chief Development Officer of Alzheon, Inc. and holds stock and stock options of Alzheon, Inc. Susan Abushakra serves as the Chief Medical Officer of Alzheon, Inc. and holds stock and stock options of Alzheon, Inc.

Figures

Figure 1
Figure 1
Beta amyloid species in brains of Alzheimer’s patients. Cleavage of amyloid precursor protein in neuronal membranes produces amyloid monomers. Misfolded beta amyloid (Aβ) monomers aggregate into soluble oligomers of various lengths (dimers to dodecamers) and soluble protofibrils (large oligomers). Oligomers further aggregate into insoluble fibrils and plaque. Soluble Aβ oligomers, which are highly toxic to neurons and synapses, are considered upstream triggers of Alzheimer’s disease (AD) pathology.
Figure 2
Figure 2
Mechanisms mediating neurotoxicity of amyloid oligomers. Beta amyloid (Aβ) oligomers mediate multiple pathogenic mechanisms in Alzheimer’s disease (AD) that lead to neuronal cell dysfunction and death, including direct synaptic and cell toxicity, neuronal hyperactivation, inhibition of long-term potentiation (LTP), tau hyperphosphorylation, microglial activation, and neuroinflammation.
Figure 3
Figure 3
Fluid and imaging biomarkers detect and track progression of pathological processes in Alzheimer’s disease (AD). The core pathologies of AD can now be detected in patients using validated cerebrospinal fluid (CSF) assays for Aβ42, Aβ40, and several isoforms of p-tau. These CSF biomarkers of soluble amyloid and p-tau species indicate a pathological state, while the positron emission tomography (PET) scans show the actual accumulation of insoluble amyloid and tau over time. The toxic downstream effects of amyloid oligomers can be assessed using CSF and plasma biomarkers of neurodegeneration (neurofilament light chain protein (NfL) and total tau) and a biomarker of synaptic injury (neurogranin). Neuroinflammation can be assessed in CSF using the microglial marker (sTREM-2) and astrocytic marker (YKL-40), and in plasma using the astrocytic marker glial fibrillary acidic protein (GFAP) [43]. Insoluble fibrillar amyloid and aggregated tau in NFTs can be visualized and evaluated quantitatively by amyloid and tau PET imaging [8,9,10]. The use of volumetric magnetic resonance imaging (MRI) is well established in AD, accurately detects hippocampal and cortical atrophy reflecting neuronal cell loss and gliosis, and correlates with progression of disease.
Figure 4
Figure 4
Clinical diagnosis of Alzheimer’s disease (AD) in patients with the APOE4/4 genotype shows high accuracy. The ε4 allele of apolipoprotein E (APOE4) genotype can aid in diagnosis of AD and APOE4/4 subjects show particularly high accuracy of clinical diagnosis. The figure shows rates of positive amyloid positron emission tomography (PET) scans in AD patients by APOE4 genotype. Amyloid PET imaging in APOE4 non-carriers and APOE4 heterozygotes was positive in 65% and 88% of subjects, respectively, increasing to >95% positivity in APOE4/4 homozygotes, based on data from a solanezumab clinical trial in Mild to Moderate AD [57].
Figure 5
Figure 5
Only agents that target amyloid oligomers show efficacy in Alzheimer’s disease (AD) trials. Among dozens of failures, only four anti-amyloid agents showed positive clinical results in late-stage clinical trials. All four of these agents either selectively inhibit formation of amyloid oligomers or remove oligomers from the brain: the oral tablet ALZ-801 and the intravenously (IV) infused anti-amyloid antibodies aducanumab, donanemab, and lecanemab. Agents that remove or inhibit formation of beta amyloid (Aβ) monomers or clear amyloid plaques failed to show efficacy in AD trials [16,17].
Figure 6
Figure 6
Carriers of ε4 allele of apolipoprotein E (APOE4) drive the overall efficacy of aducanumab in the EMERGE Phase 3 study. Only a single EMERGE Phase 3 trial showed clinical efficacy of aducanumab. Diagrams adapted from the FDA Advisory Committee Briefing Book illustrate point estimate effects of aducanumab in the EMERGE trial on a functional (Alzheimer’s Disease Cooperative Study—instrumental Activities of Daily Living Inventory (ADCSADL)), cognitive (Alzheimer’s Disease Assessment Scale—Cognitive subscale (ADAS-Cog) and Mini-Mental State Examination (MMSE)), and a composite clinical outcome (Clinical Dementia Rating—Sum of Boxes (CDRSB)). Panels (A) and (B) show effects of high and low doses in APOE4 carriers, and panels (C) and (D) show effects in APOE4 non-carriers, suggesting that the overall efficacy of aducanumab is derived from the APOE4 carrier population with minimal clinical benefits observed in APOE4 non-carriers [68].
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