Structural progression of Alzheimer’s disease over decades: the MRI staging scheme

The chronological progression of brain atrophy over decades, from pre-symptomatic to dementia stages, has never been formally depicted in Alzheimer’s disease. This is mainly due to the lack of cohorts with long enough MRI follow-ups in cognitively unimpaired young participants at baseline. To describe a spatiotemporal atrophy staging of Alzheimer’s disease at the whole-brain level, we built extrapolated lifetime volumetric models of healthy and Alzheimer’s disease brain structures by combining multiple large-scale databases (n = 3512 quality controlled MRI from 9 cohorts of subjects covering the entire lifespan, including 415 MRI from ADNI1, ADNI2 and AIBL for Alzheimer’s disease patients). Then, we validated dynamic models based on cross-sectional data using external longitudinal data. Finally, we assessed the sequential divergence between normal aging and Alzheimer’s disease volumetric trajectories and described the following staging of brain atrophy progression in Alzheimer’s disease: (i) hippocampus and amygdala; (ii) middle temporal gyrus; (iii) entorhinal cortex, parahippocampal cortex and other temporal areas; (iv) striatum and thalamus and (v) middle frontal, cingular, parietal, insular cortices and pallidum. We concluded that this MRI scheme of atrophy progression in Alzheimer’s disease was close but did not entirely overlap with Braak staging of tauopathy, with a ‘reverse chronology’ between limbic and entorhinal stages. Alzheimer’s disease structural progression may be associated with local tau accumulation but may also be related to axonal degeneration in remote sites and other limbic-predominant associated proteinopathies.