Associations between structural neuroimaging markers and neuropathology of Alzheimer’s Disease

Structural MRI is widely used for assessing the progression of Alzheimer's disease (AD). However, postmortem pathological examination remains the gold standard for confirming the diagnosis. We systematically investigated associations of structural MRI markers with AD neuropathology in well-characterized cohorts from Alzheimer's Disease Research Centres and the Alzheimer's Disease Neuroimaging Initiative. Data of 805 individuals who died between 2006 and 2024 were included. Markers of medial temporal lobe (MTL) and whole brain atrophy were determined from T1-weighted images acquired shortly before death. Two aggregate indices of AD-related brain atrophy (FSAD) and brain ageing (brainageR) were also included. Associations with neuropathology ratings were examined using ordinal logistic regression with proportional odds. At the time of MRI, median age was 78.5 years and 61 % had dementia. The median time between MRI and death was 4.6 years. At autopsy, 52 % had high Alzheimer's disease neuropathologic change (ADNC). In unadjusted analyses, ADNC most strongly correlated with volume of the MTL and the FSAD score (Spearman's ρ=-0.28 and 0.43). In adjusted analyses, the odds ratio associating low MTL volume with ADNC was 5.0 (95 % CI: 3.0-8.3); for a high FSAD score it was 11.0 (95 % CI: 6.6-18.0). MRI markers of AD generally were more strongly associated with tau than with amyloid beta pathology. AD neuropathology was associated with a distinct pattern of atrophy most pronounced in - but not restricted to - the MTL, differing from patterns seen in normal ageing. These results support the use of aggregate indices of AD-related atrophy over single-region morphometric characteristics for sample enrichment or as secondary outcomes in clinical trials.