{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T11:09:23Z","timestamp":1778324963875,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,6]]},"group-title":"Neurology","reference-count":41,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Hippocampal atrophy is a core marker of neurodegeneration in dementia, particularly in Alzheimer\u2019s disease (AD). However, most studies focus on total hippocampal volume loss and overlook hemispheric asymmetry, which may reflect distinct biological processes. While tau pathology is closely linked to medial temporal lobe degeneration, it remains unclear whether tau is associated with asymmetric patterns of hippocampal atrophy.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We analyzed 483 cognitively unimpaired participants from the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI) with baseline cerebrospinal fluid (CSF) phosphorylated tau (p-tau181) and amyloid-\u03b2 (A\u03b242) measurements and longitudinal structural MRI data over 10 years of follow-up. Total hippocampal volume and hemispheric asymmetry, defined as the absolute difference between left and right hippocampal volumes (|L\u2212R|), were quantified at each visit. Linear mixed-effects models assessed associations between baseline CSF biomarkers and longitudinal changes in hippocampal asymmetry, adjusting for demographic factors, APOE \u03b54 status, and baseline hippocampal volume.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Higher baseline CSF p-tau181 was associated with greater increases in hippocampal asymmetry over time (\u03b2 = 1.20, SE = 0.43, p = 0.006). This association remained significant after additional adjustment for total hippocampal volume and baseline CSF A\u03b242. CSF total tau was highly correlated with p-tau181 (Spearman\u2019s \u03c1 =0.98, p &lt; 0.001) and showed comparable associations with hippocampal measures. In contrast, baseline A\u03b242 was not associated with subsequent changes in hippocampal asymmetry. Both p-tau181 and A\u03b242 were associated with faster decline in total hippocampal volume. In amyloid-stratified analyses, p-tau181 was associated with increasing hippocampal asymmetry only among amyloid-negative individuals, whereas its association with total hippocampal atrophy was observed primarily in amyloid-positive individuals.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>CSF p-tau181 is associated not only with overall hippocampal atrophy but also with progressive hemispheric asymmetry, suggesting that tau-related neurodegeneration may manifest as both magnitude and imbalance of tissue loss. These findings support hippocampal asymmetry as a complementary neuroimaging marker that may capture non-amyloid-related medial temporal lobe degeneration in cognitively unimpaired older adults.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.04.26352391","type":"posted-content","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T17:10:14Z","timestamp":1778087414000},"source":"Crossref","is-referenced-by-count":0,"title":["CSF p-tau Predicts Asymmetric Hippocampal Atrophy in Cognitively Unimpaired Older Adults"],"prefix":"10.64898","author":[{"given":"Elham","family":"Ghanbarian","sequence":"first","affiliation":[{"name":"Department of Neurology, University of California, Irvine, CA, USA"},{"name":"Center for Design, Discovery, and Data Analytics (3D Center) in Neurological Disorders, University of California, Irvine, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1328-2791","authenticated-orcid":false,"given":"Lukai","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of California, Irvine, CA, USA"},{"name":"Center for Design, Discovery, and Data Analytics (3D Center) in Neurological Disorders, University of California, Irvine, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianchen","family":"Qian","sequence":"additional","affiliation":[{"name":"Department of Statistics, University of California, Irvine, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Crystal M.","family":"Glover","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of California, Irvine, CA, USA"},{"name":"Alzheimer\u2019s Disease Research Center, Institute for Memory Impairments and Neurological Disorders (UCI MIND), University of California, Irvine, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S. Ahmad","family":"Sajjadi","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of California, Irvine, CA, USA"},{"name":"Center for Design, Discovery, and Data Analytics (3D Center) in Neurological Disorders, University of California, Irvine, CA, USA"},{"name":"Alzheimer\u2019s Disease Research Center, Institute for Memory Impairments and Neurological Disorders (UCI MIND), University of California, Irvine, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria M.","family":"Corrada","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of California, Irvine, CA, USA"},{"name":"Alzheimer\u2019s Disease Research Center, Institute for Memory Impairments and Neurological Disorders (UCI MIND), University of California, Irvine, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua D.","family":"Grill","sequence":"additional","affiliation":[{"name":"Alzheimer\u2019s Disease Research Center, Institute for Memory Impairments and Neurological Disorders (UCI MIND), University of California, Irvine, CA, USA"},{"name":"Department of Psychiatry and Human Behavior, University of California, Irvine, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali","family":"Ezzati","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of California, Irvine, CA, USA"},{"name":"Center for Design, Discovery, and Data Analytics (3D Center) in Neurological Disorders, University of California, Irvine, CA, USA"},{"name":"Alzheimer\u2019s Disease Research Center, Institute for Memory Impairments and Neurological Disorders (UCI MIND), University of California, Irvine, CA, USA"},{"name":"Department of Epidemiology and Biostatistics, University of California, Irvine, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026050903100604000_2026.05.04.26352391v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2009.215"},{"key":"2026050903100604000_2026.05.04.26352391v1.2","first-page":"476","article-title":"Risk factors for predicting progression from mild cognitive impairment to Alzheimer\u2019s disease: a systematic review and meta-analysis of cohort studies","volume":"87","year":"2015","journal-title":"Journal of Neurology, Neurosurgery & Psychiatry"},{"key":"2026050903100604000_2026.05.04.26352391v1.3","doi-asserted-by":"crossref","first-page":"e70005","DOI":"10.1002\/alz.70005","article-title":"Associations of hippocampal volumes, brain hypometabolism, and plasma NfL with amyloid, tau, and cognitive decline","volume":"21","year":"2025","journal-title":"Alzheimer\u2019s & Dementia"},{"key":"2026050903100604000_2026.05.04.26352391v1.4","doi-asserted-by":"crossref","unstructured":"Wisse L , Ravikumar S , Ittyerah R , et al. Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions. Acta Neuropathologica Communications 2021;9.","DOI":"10.1186\/s40478-021-01225-3"},{"key":"2026050903100604000_2026.05.04.26352391v1.5","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.25151"},{"key":"2026050903100604000_2026.05.04.26352391v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2017.05.058"},{"key":"2026050903100604000_2026.05.04.26352391v1.7","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab114"},{"key":"2026050903100604000_2026.05.04.26352391v1.8","doi-asserted-by":"crossref","unstructured":"Denning A , Ittyerah R , Levorse L , et al. Association of quantitative histopathology measurements with antemortem medial temporal lobe cortical thickness in the Alzheimer\u2019s disease continuum. Acta Neuropathologica 2024;148.","DOI":"10.1007\/s00401-024-02789-9"},{"key":"2026050903100604000_2026.05.04.26352391v1.9","doi-asserted-by":"crossref","unstructured":"Bouwman M , Frigerio I , Lin C-P , Reijner N , Van De Berg W , Jonkman L. Hippocampal subfields: volume, neuropathological vulnerability and cognitive decline in Alzheimer\u2019s and Parkinson\u2019s disease. Alzheimer\u2019s Research & Therapy 2025;17.","DOI":"10.1186\/s13195-025-01768-w"},{"key":"2026050903100604000_2026.05.04.26352391v1.10","doi-asserted-by":"crossref","unstructured":"Pusparani Y , Lin C-Y , Jan Y-K , et al. Hippocampal volume asymmetry in Alzheimer disease: A systematic review and meta-analysis. Medicine 2025;104.","DOI":"10.1097\/MD.0000000000041662"},{"key":"2026050903100604000_2026.05.04.26352391v1.11","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000009058"},{"key":"2026050903100604000_2026.05.04.26352391v1.12","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1016\/S1474-4422(12)70200-4","article-title":"Neuroimaging correlates of pathologically defined subtypes of Alzheimer\u2019s disease: a case-control study","volume":"11","year":"2012","journal-title":"The Lancet Neurology"},{"key":"2026050903100604000_2026.05.04.26352391v1.13","doi-asserted-by":"crossref","first-page":"2400","DOI":"10.1093\/brain\/awae118","article-title":"A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings","volume":"147","year":"2024","journal-title":"Brain"},{"key":"2026050903100604000_2026.05.04.26352391v1.14","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.16543"},{"key":"2026050903100604000_2026.05.04.26352391v1.15","doi-asserted-by":"crossref","unstructured":"Ghanbarian E , Khorsand B , Zheng L , et al. Hippocampal Asymmetry Captures Non-Amyloid-Related Risk of Memory Decline and Clinical Progression. medRxiv 2026.","DOI":"10.64898\/2026.01.06.26343553"},{"key":"2026050903100604000_2026.05.04.26352391v1.16","doi-asserted-by":"crossref","first-page":"e090878","DOI":"10.1002\/alz.090878","article-title":"Asymmetrical hippocampal atrophy: an arrow in the quiver of imaging markers for LATE-NC","volume":"20","year":"2024","journal-title":"Alzheimer\u2019s & Dementia"},{"key":"2026050903100604000_2026.05.04.26352391v1.17","doi-asserted-by":"crossref","first-page":"2400","DOI":"10.1093\/brain\/awaf158","article-title":"Common neuropathologic change drivers of hippocampal sclerosis of ageing","volume":"148","year":"2025","journal-title":"Brain"},{"key":"2026050903100604000_2026.05.04.26352391v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2021.09.017"},{"key":"2026050903100604000_2026.05.04.26352391v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(02)00569-X"},{"key":"2026050903100604000_2026.05.04.26352391v1.20","first-page":"19","article-title":"PENN biomarker core of the Alzheimer\u2019s disease Neuroimaging Initiative","volume":"16","year":"2007","journal-title":"Neurosignals"},{"key":"2026050903100604000_2026.05.04.26352391v1.21","doi-asserted-by":"crossref","first-page":"19024","DOI":"10.1038\/s41598-019-54204-z","article-title":"Predicting clinical decline and conversion to Alzheimer\u2019s disease or dementia using novel Elecsys A\u03b2(1\u201342), pTau and tTau CSF immunoassays","volume":"9","year":"2019","journal-title":"Scientific Reports"},{"key":"2026050903100604000_2026.05.04.26352391v1.22","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1001\/jamaneurol.2019.4749","article-title":"Characterization of Alzheimer Disease Biomarker Discrepancies Using Cerebrospinal Fluid Phosphorylated Tau and AV1451 Positron Emission Tomography","volume":"77","year":"2020","journal-title":"JAMA Neurology"},{"key":"2026050903100604000_2026.05.04.26352391v1.23","first-page":"21","article-title":"Amyloid-\u03b2-independent regulators of tau pathology in Alzheimer disease","volume":"21","year":"2019","journal-title":"Nature Reviews Neuroscience"},{"key":"2026050903100604000_2026.05.04.26352391v1.24","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx243"},{"key":"2026050903100604000_2026.05.04.26352391v1.25","doi-asserted-by":"crossref","unstructured":"Janelidze S , Stomrud E , Smith R , et al. Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer\u2019s disease. Nature Communications 2020;11.","DOI":"10.1038\/s41467-020-15436-0"},{"key":"2026050903100604000_2026.05.04.26352391v1.26","first-page":"188","article-title":"Association of Phosphorylated Tau Biomarkers With Amyloid Positron Emission Tomography vs Tau Positron Emission Tomography","volume":"80","year":"2022","journal-title":"JAMA Neurology"},{"key":"2026050903100604000_2026.05.04.26352391v1.27","doi-asserted-by":"crossref","unstructured":"Kurihara M , Matsubara T , Morimoto S , et al. Neuropathological changes associated with aberrant cerebrospinal fluid p-tau181 and A\u03b242 in Alzheimer\u2019s disease and other neurodegenerative diseases. Acta Neuropathologica Communications 2024;12.","DOI":"10.1186\/s40478-024-01758-3"},{"key":"2026050903100604000_2026.05.04.26352391v1.28","doi-asserted-by":"crossref","unstructured":"Liu E , Zhang Y , Wang J-Z. Updates in Alzheimer\u2019s disease: from basic research to diagnosis and therapies. Translational Neurodegeneration 2024;13.","DOI":"10.1186\/s40035-024-00432-x"},{"key":"2026050903100604000_2026.05.04.26352391v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2011.02.022"},{"key":"2026050903100604000_2026.05.04.26352391v1.30","doi-asserted-by":"crossref","unstructured":"Lan G , Cai Y , Li A , Liu Z , Shaohua, Guo T. Association of Presynaptic Loss with Alzheimer\u2019s Disease and Cognitive Decline. Annals of Neurology 2022;92.","DOI":"10.1002\/ana.26492"},{"key":"2026050903100604000_2026.05.04.26352391v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2010.05.003"},{"key":"2026050903100604000_2026.05.04.26352391v1.32","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s11682-012-9171-6","article-title":"CSF biomarker associations with change in hippocampal volume and precuneus thickness: implications for the Alzheimer\u2019s pathological cascade","volume":"6","year":"2012","journal-title":"Brain Imaging and Behavior"},{"key":"2026050903100604000_2026.05.04.26352391v1.33","doi-asserted-by":"crossref","unstructured":"Seidu N , Kern S , Sacuiu S , et al. Association of CSF biomarkers with MRI brain changes in Alzheimer\u2019s disease. Alzheimer\u2019s & Dementia : Diagnosis, Assessment & Disease Monitoring 2024;16.","DOI":"10.1002\/dad2.12556"},{"key":"2026050903100604000_2026.05.04.26352391v1.34","first-page":"135","article-title":"Tau pathology mediates age effects on medial temporal lobe structure","volume":"109","year":"2021","journal-title":"Neurobiology of Aging"},{"key":"2026050903100604000_2026.05.04.26352391v1.35","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-014-1349-0"},{"key":"2026050903100604000_2026.05.04.26352391v1.36","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-017-1681-2"},{"key":"2026050903100604000_2026.05.04.26352391v1.37","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.3233\/JAD-230022","article-title":"Cognitive and Neuropsychological Profiles in Alzheimer\u2019s Disease and Primary Age-Related Tauopathy and the Influence of Comorbid Neuropathologies","volume":"92","year":"2023","journal-title":"Journal of Alzheimer\u2019s Disease"},{"key":"2026050903100604000_2026.05.04.26352391v1.38","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14582"},{"key":"2026050903100604000_2026.05.04.26352391v1.39","doi-asserted-by":"crossref","unstructured":"Smirnov D , Salmon D , Galasko D , et al. TDP-43 Pathology Exacerbates Cognitive Decline in Primary Age-Related Tauopathy. Annals of Neurology 2022;92.","DOI":"10.1002\/ana.26438"},{"key":"2026050903100604000_2026.05.04.26352391v1.40","doi-asserted-by":"crossref","unstructured":"Zhao T , Cui X , Zhang X , et al. Hippocampal sclerosis: A review on current research status and its mechanisms. Ageing Research Reviews 2025;108.","DOI":"10.1016\/j.arr.2025.102716"},{"key":"2026050903100604000_2026.05.04.26352391v1.41","doi-asserted-by":"crossref","unstructured":"Richardson T , Walker J , Farrell K , Oliveira TG , White C , Crary J. Primary age-related tauopathy. Acta Neuropathologica 2025;150.","DOI":"10.1007\/s00401-025-02943-x"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.04.26352391","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T10:10:20Z","timestamp":1778321420000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.05.04.26352391"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,6]]},"references-count":41,"URL":"https:\/\/doi.org\/10.64898\/2026.05.04.26352391","relation":{},"subject":[],"published":{"date-parts":[[2026,5,6]]},"subtype":"preprint"}}