Could changing the course of Alzheimer's disease pathology with immunotherapy prevent dementia?

Abstract

This scientific commentary refers to ‘Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer’s disease’ by Nicoll et al. (doi:10.1093/brain/awz142).

Figure 1

Diagrammatic representation of the alignment between stages of Alzheimer’s disease, immunotherapy clinical trials targeting amyloid-β protein and the potential pathogenic mechanisms involved. Anti-amyloid immunotherapy trials such as the AN1792 active immunization study from which the neuropathological study by Nicoll et al. (2019) originated, were conducted in symptomatic participants with mild to moderate Alzheimer’s disease. At this stage there is extensive amyloid-β protein deposition, and tau, α-synuclein and TDP-43 also begin to accumulate. Further complicating the picture is the contribution by other processes such as inflammation, alterations in lipid metabolism and vasculature and the development of co-morbidities such as obesity, diabetes mellitus (DM), arterial hypertension (HTA) and trauma. A number of passive immunotherapy trials that showed amyloid removal but no clinical improvement were conducted at the mild to moderate stage, including studies with bapineuzumab (AAB-001) and solanezumab (EXPEDITION I, II, III). More recent trials conducted at earlier stages of the Alzheimer’s disease continuum with monoclonal antibodies against higher order multimers (crenezumab and aducanumab) failed to show clinical improvement in spite of demonstrable effects on amyloid biomarkers. Even at the MCI stage, tau pathology and neurodegenerative pathology characterized by synapse loss are already developing. Current trials with anti-amyloid antibodies are being performed in asymptomatic participants who are positive for amyloid. Examples of such secondary prevention trials include A4 (solanezumab) and API-APOE4 [active vaccination with CD106 versus a BACE inhibitor (CNP520)] in sporadic preclinical Alzheimer’s disease and API-ADAD (crenezumab) and DIAN-TU (solanezumab and gantenerumab) in familial Alzheimer’s disease. The antibody to be used in the A3 trial in asymptomatic cases has yet to be decided. Overall, this diagram suggests that anti-amyloid immunotherapy might be best suited for preclinical stages, while in symptomatic stages other targets including tau, α-synuclein, TDP-43, inflammation, lipid metabolism, vascular and ageing-related comorbidities might need to be included in the context of combinatorial therapy. Amyl = amyloid; Neuro = neurodegeneration.