Alzheimer's disease: From immunotherapy to immunoprevention

Abstract

Recent Aβ-immunotherapy trials have yielded the first clear evidence that removing aggregated Aβ from the brains of symptomatic patients can slow the progression of Alzheimer's disease. The clinical benefit achieved in these trials has been modest, however, highlighting the need for both a deeper understanding of disease mechanisms and the importance of intervening early in the pathogenic cascade. An immunoprevention strategy for Alzheimer's disease is required that will integrate the findings from clinical trials with mechanistic insights from preclinical disease models to select promising antibodies, optimize the timing of intervention, identify early biomarkers, and mitigate potential side effects.

Keywords: ARIA; Tau; aducanumab; aduhelm; cerebral amyloid antipathy; dementia; donanemab; lecanemab; neurofilament; β-amyloid.

Figure 1.. The pathologic progression of AD, immunoprevention, and the impact of immunotherapy in symptomatic patients.

(A, B) Immunohistochemical detection of Aβ deposition in AD brain as plaques (A) and cerebral β-amyloid angiopathy (CAA; black asterisk in B); the affected vessel is surrounded by diffuse parenchymal Aβ deposits, and a dense-core plaque is in the upper right. CAA is moderate-to-severe in nearly half of all AD cases, and CAA has been linked to the side effects of Aβ-immunotherapy; antibody 4G8, Nissl counterstain; scale bars are 50 μm. (C) Representative Aβ-PET images (left to right) from a control person (non-mutation carrier), a mutation carrier about 10 years before symptom onset, and two mutation carriers that are symptomatic (Pittsburgh compound B [PiB] tracer; shown are participants with familial AD). The increase in PiB retention primarily occurs in the presymptomatic phase. (D) In the two-stage model of AD,^– the first stage is dominated by Aβ deposition. The second stage commences approximately 10 years before symptom onset and becomes partly independent of Aβ deposition with the emergence of clear signs of neurodegeneration (as assessed, e.g., by NfL levels in CSF or blood) and, eventually, behavioral impairments. Targeting aberrant Aβ as immunoprevention (prevention of the disease) is likely to be most successful when initiated during or prior to the first stage. Given the growing pathologic complexity of the disease, it is not clear how much clinical benefit can be expected from Aβ-removing therapies alone beyond this time point. Indeed, Aβ-immunotherapy trials for 18 months with aducanumab, lecanemab, or donanemab removed >60% of the deposited Aβ, but NfL continued to rise (albeit at a reduced pace), paralleling the slowed - but not stopped - cognitive decline in treated subjects.

Figure 2.. Aβ aggregation and the epitopes recognized by therapeutic antibodies.

(A) Aβ aggregation starts with a slow nucleation phase during which Aβ assumes an alternative conformation that converts and binds to other Aβ molecules to form the initial segment of the amyloid fibril. With increasing length, the growing fibril eventually breaks and releases seeding-active Aβ multimers, at which stage the process becomes self-propagating (based on Jucker and Walker). As deposition progresses, Aβ comprises a mixture of multimers, ranging from small soluble oligomers to long amyloid fibrils, which differ in their cytotoxicity and ability to seed further aggregation.^,,, The growing amyloid fibril schematically depicted here consists of two twisted protofilaments (based on Yang et al. for brain-derived Aβ42 fibrils). Note that the N-terminal amino acids (orange) are exposed from the hydrophobic amyloid core (blue). (B) Diagram of Aβ42 showing the amino acid epitopes that therapeutic antibodies are thought to recognize (based on Plotkin and Cashman). Common to the antibodies that cleared Aβ deposits in clinical trials (gantenerumab, aducanumab, donanemab, lecanemab) is that they recognize N-terminal amino acids (orange), i.e., epitopes that are exposed on mature amyloid fibrils. In contrast, solanezumab and crenezumab only recognize mid-sequence epitopes that are buried within the amyloid fibril; hence, these antibodies mainly recognize monomeric Aβ. (C) Schematic illustration of the binding strength of five different antibodies to Aβ that was derived from native amyloid-laden brain samples (AD and mouse models) and fractionated according to size. The two antibodies that most effectively remove Aβ from the brain (donanemab, aducanumab) recognize predominantly large amyloid aggregates (based on Uhlmann et al.).