The relationship between amyloid deposition, neurodegeneration, and cognitive decline in dementia

Abstract

Amyloid imaging has been clinically approved for measuring β amyloid plaque load in patients being evaluated for Alzheimer's disease or other causes of cognitive decline. Here we explore a multidimensional approach to cognitive decline, where we situate amyloid plaque burden among a number of other relevant dimensions, such as aging, volume loss, other proteinopathies such as TDP43 and Lewy bodies, and functional reorganisation of cognitive brain systems. The multidimensional model incorporates a 'pure AD' trajectory, corresponding to e.g. monogenic Alzheimer's disease, but leaves room for other combinations of biomarker abnormalities (e.g. volume loss without amyloid positivity) and other trajectories. More tools will become available in the future that allow one to carve out a causal-mechanistic space for explaing cognitive decline in a personalized manner, enhancing progress towards more efficacious interventions.