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bioRxiv · 10.64898/2026.04.02.716156

Separable multidimensional MRI signatures of cellular and structural pathology in Alzheimer's disease

Manninen, E.·Comrie, C. J.·Serrano, G. E.·Beach, T.·Hutchinson, E. B.·Benjamini, D.
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Abstract

Cognitive decline in Alzheimers disease (AD) reflects progressive disruption of cellular and microstructural organization, yet the biological specificity of MRI signals remains incompletely understood. Multidimensional diffusion-relaxation MRI (MD-MRI) resolves sub-voxel tissue heterogeneity, offering a potential framework to link imaging signals to underlying pathology. We tested the hypothesis that neuronal, glial and white matter pathologies in AD occupy separable regions of diffusion-relaxation space and generate spatially organized imaging signatures linked to cognitive impairment. We integrated ex vivo MD-MRI with co-registered histology from 12 human donors spanning a range of Braak stages and pathological severity. Using nested cross-validated elastic net modeling, we predicted voxelwise A{beta}, pTau, microglia and myelin burden from the multidimensional diffusion-relaxation density distribution. Regional associations were assessed across hippocampal subfields and white matter, and clinical relevance was evaluated by relating MRI-predicted pathology to Mini-Mental State Examination (MMSE) scores. Distinct diffusion-relaxation components were preferentially associated with different pathological markers, indicating separable microstructural signatures. Voxelwise MRI-derived predictions were significantly associated with histological measures of myelin ({rho} = 0.77), pTau ({rho} = 0.62), and microglia ({rho} = 0.61), with weaker correspondence for A{beta} ({rho} = 0.45). Regionally, predicted pathology recapitulated known patterns of selective vulnerability, with elevated pTau and microglial signal in hippocampal subfields and dominant myelin-associated signal in white matter (p < 0.0001). Importantly, higher predicted pTau density in the hippocampus was strongly associated with worse cognitive performance ({rho} = -0.88, p = 0.0014), with a moderate association in white matter ({rho} = -0.66, p = 0.036), suggesting that tau-related microstructural alterations within both gray and white matter contribute to cognitive impairment. By directly linking multidimensional MRI signatures to histologically verified cellular pathology, this study demonstrates that AD-related processes manifest as distinct and spatially organized diffusion-relaxation signatures. These findings provide mechanistic insight into the microstructural basis of MRI contrasts and support the potential of MD-MRI to map regionally specific neuropathological processes in AD. As clinically feasible MD-MRI acquisition protocols continue to emerge, translation of these spectral signatures to in vivo imaging may enable more mechanistically informed assessment of aging and dementia.

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Manninen, E., Comrie, C. J., Serrano, G. E., Beach, T., Hutchinson, E. B., Benjamini, D.. 2026-04-06. Separable multidimensional MRI signatures of cellular and structural pathology in Alzheimer's disease. https://doi.org/10.64898/2026.04.02.716156

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