{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:01:57Z","timestamp":1785402117088,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,6]]},"group-title":"Neuroscience","reference-count":91,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T00:00:00Z","timestamp":1775433600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"award":["T32AG082631-01"],"award-info":[{"award-number":["T32AG082631-01"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01AG079280"],"award-info":[{"award-number":["R01AG079280"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U24 NS072026"],"award-info":[{"award-number":["U24 NS072026"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30 AG019610"],"award-info":[{"award-number":["P30 AG019610"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30AG072980"],"award-info":[{"award-number":["P30AG072980"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Cognitive decline in Alzheimer\u2019s disease (AD) reflects progressive disruption of cellular and microstructural organization, yet the biological specificity of MRI signals remains incompletely understood. Multidimensional diffusion\u2013relaxation 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\u2013relaxation space and generate spatially organized imaging signatures linked to cognitive impairment.<\/jats:p>\n                <jats:p>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\u03b2, pTau, microglia and myelin burden from the multidimensional diffusion\u2013relaxation 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.<\/jats:p>\n                <jats:p>Distinct diffusion\u2013relaxation components were preferentially associated with different pathological markers, indicating separable microstructural signatures. Voxelwise MRI-derived predictions were significantly associated with histological measures of myelin (\u03c1 = 0.77), pTau (\u03c1 = 0.62), and microglia (\u03c1 = 0.61), with weaker correspondence for A\u03b2 (\u03c1 = 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 &lt; 0.0001). Importantly, higher predicted pTau density in the hippocampus was strongly associated with worse cognitive performance (\u03c1 = \u22120.88, p = 0.0014), with a moderate association in white matter (\u03c1 = \u22120.66, p = 0.036), suggesting that tau-related microstructural alterations within both gray and white matter contribute to cognitive impairment.<\/jats:p>\n                <jats:p>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\u2013relaxation 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.<\/jats:p>","DOI":"10.64898\/2026.04.02.716156","type":"posted-content","created":{"date-parts":[[2026,4,6]],"date-time":"2026-04-06T22:10:12Z","timestamp":1775513412000},"source":"Crossref","is-referenced-by-count":1,"title":["Separable multidimensional MRI signatures of cellular and structural pathology in Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"given":"Eppu","family":"Manninen","sequence":"first","affiliation":[{"name":"Multiscale Imaging and Integrative Biophysics Unit, Laboratory of Behavioral Neuroscience, National Institute on Aging, NIH, Baltimore, MD, 21224, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Courtney J.","family":"Comrie","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Arizona, Tucson, AZ, 85721, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9527-2011","authenticated-orcid":false,"given":"Geidy E.","family":"Serrano","sequence":"additional","affiliation":[{"name":"Banner Sun Health Research Institute, Sun City, AZ, 85351, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas G.","family":"Beach","sequence":"additional","affiliation":[{"name":"Banner Sun Health Research Institute, Sun City, AZ, 85351, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth B.","family":"Hutchinson","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Arizona, Tucson, AZ, 85721, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Benjamini","sequence":"additional","affiliation":[{"name":"Multiscale Imaging and Integrative Biophysics Unit, Laboratory of 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