Alzheimer disease: Aβ-independent processes-rethinking preclinical AD

Abstract

The amyloid cascade hypothesis, which posits that amyloid-β accumulation is the key event in Alzheimer disease neurodegeneration, has dominated the field for 20 years. Recent findings, however, show that neuronal-injury biomarkers are independent of amyloid-β, calling for reconsideration of the pathological cascade and assessment of alternative therapeutic strategies.

Figure 1. Possible mechanisms for AD considering Aβ deposition and neuronal injury as (partly) independent events

Aβ and tau-related pathologies may occur in parallel, their onset and rate being under the influence of a series of genetic and environmental risk factors. These pathologies result in brain alterations that are then represented in neuroimaging measures classically used as biomarkers for AD. Abbreviations: Aβ, amyloid β; CSF, cerebrospinal fluid; FDG, ¹⁸F-fluorodeoxyglucose; fMRI, functional MRI; sMRI, structural MRI; WMH, white matter hyperintensities.