A neuroimaging biomarker for disease staging in clinically diagnosed Alzheimer's disease

Precision medicine for Alzheimer's disease (AD) requires the development of a robust management framework grounded in individualized disease staging systems. To date, only a limited number of studies have supplemented the existing AD staging systems.

This retrospective study included 7491 MRI examinations from five independent cohorts. We used a novel pseudo-healthy synthesis method to capture individualized brain atrophy patterns. An individualized brain atrophy score (BAS) was computed from the 30 regions with the most severe brain atrophy and used to stratify participants into distinct disease stages. The Jenks natural breaks optimization method was used to determine an optimal number of disease stages based on the individual BAS.

BAS exhibited a strong biological basis and revealed a synergistic relationship among biomarker-based staging systems. Four stages were delineated based on the BAS for participants with MCI and clinically diagnosed AD. Stage I showed a slight cognitive decline with only mild hippocampal atrophy evident. Stage II showed mild cognitive decline and mild brain atrophy and shrinkage, extending to the temporal and parietal lobes. Stage III showed moderate cognitive decline and more severe brain atrophy in the temporal lobe, amygdala, hippocampus, parietal lobe, and frontal lobe. Stage IV showed severe mental impairment and diffuse atrophy across the whole brain. The disease stages are associated with dementia severity and abnormalities in AD biomarkers, such as cerebrospinal fluid (CSF) Aβ_1-42, CSF total tau, CSF p-tau₁₈₁, and cognitive scores. Furthermore, those MCI participants at higher disease stages at baseline have a higher risk of progressing to clinically diagnosed AD dementia even under the A/T-negative status.

The individualized staging system can accurately assess disease severity, enabling risk stratification at ultra-early pathological stages and facilitating precise AD management.