Clinical and MRI Correlates of β-Amyloid Load Inconsistent With Its Presumed Neurotoxicity in Cognitively Healthy Ageing

Abstract

Cognitively healthy ageing and its conceptual counterpart, dementia, have long garnered much interest in the research community, the broader public and regulatory bodies alike. Although β-amyloid deposition is widely regarded as the principal neuropathological hallmark of Alzheimer's disease, its precise role in the causal chain of cognitive decline remains under debate. Applying strict criteria to define neurocognitive health, a selection of 35 participants aged over 60 years was drawn from the Human Connectome Project-Ageing. The evaluation of both cognitive and physical fitness, and comprehensive magnetic resonance imaging (MRI) protocol, encompassing diffusion-weighted imaging, T1w/T2w ratio, resting-state functional MRI and arterial spin labelling, were combined with an additional 18F-florbetaben scan to evaluate β-amyloid load. Strikingly, β-amyloid load failed to adhere to the transcription patterns of amyloid precursor protein in all surveyed areas but the entorhinal cortex. Moreover, it was associated with either higher cognitive performance, general fitness, cerebral tissue integrity and cerebral perfusion, or had no discernible impact. This pilot study adds to the growing body of evidence that questions the significance attributed to β-amyloid build-up and the mechanisms of its accumulation in the ageing brain. The results invite a re-evaluation of established theories on β-amyloid build-up neurotoxicity at low concentrations as observed in this cohort. Future investigations should focus on recruiting larger populations to ascertain whether a specific threshold of β-amyloid build-up precipitates cognitive decline or whether β-amyloid accumulation, in fact, serves as a protective mechanism that ultimately fails.

Keywords: APP; cognition; general fitness; healthy ageing; quantitative MRI; β‐amyloid.