{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T23:45:25Z","timestamp":1785800725564,"version":"3.56.0"},"reference-count":39,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Alzheimer\u2019s disease (AD) involves ongoing neurodegeneration, with phosphorylated tau (PTAU) intracellular accumulation closely associated with cortical shrinking. However, not everyone with high PTAU levels shows the same degree of neurodegeneration, implying that other biological stress factors might influence tau\u2019s harmful effects. This research explores whether cerebrospinal fluid erythrocyte burden (CTRED), a marker indicating vascular\u2013CSF barrier disruption and heme toxicity, affects the link between PTAU181 levels and entorhinal cortex atrophy in AD. Methods: We examined 25 observations from 18 patients with AD using a linear mixed effects model. The dependent variable was entorhinal cortex volume, with fixed effects for PTAU, CTRED, and their interaction. Random intercepts accounted for variability within subjects. A cognitively normal (CN) control group was included for comparison. Results: CTRED is significantly associated with reduced entorhinal volume (p = 0.005). A notable interaction between CTRED and PTAU was also found (p = 0.004), suggesting that higher CTRED enhances PTAU\u2019s atrophic effects. PTAU alone was not a significant predictor. No significant effects were observed in the CN group, which supports the specificity of the disease. Conclusions: CTRED alters the neurotoxic impact of PTAU on the entorhinal cortex in AD, supporting a multi-hit model of degeneration that involves tau pathology and erythrocyte-derived stress. These findings emphasize the clinical importance of vascular\u2013CSF biomarkers in predicting neurodegeneration and guiding targeted treatments.<\/jats:p>","DOI":"10.3390\/biom15091300","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T08:43:54Z","timestamp":1757493834000},"page":"1300","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Cerebrospinal Fluid Erythrocyte Burden Amplifies the Impact of PTAU on Entorhinal Degeneration in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6857-3927","authenticated-orcid":false,"given":"Rafail C.","family":"Christodoulou","sequence":"first","affiliation":[{"name":"Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0002-5513","authenticated-orcid":false,"given":"Georgios","family":"Vamvouras","sequence":"additional","affiliation":[{"name":"Department of Mechanical Engineering, National Technical University of Athens, 15772 Zografou, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasileia","family":"Petrou","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Ioannina, 45110 Ioannina, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6102-3344","authenticated-orcid":false,"given":"Platon S.","family":"Papageorgiou","sequence":"additional","affiliation":[{"name":"2nd Department of Orthopaedic Surgery and Traumatology, Aghia Sophia Pediatric General Hospital, Thivon 3 Street, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Pitsillos","sequence":"additional","affiliation":[{"name":"Neurophysiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludwing","family":"Rivera","sequence":"additional","affiliation":[{"name":"Department of Medicine, American University of Antigua College of Medicine, St. Johns 1451, Antigua and Barbuda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evros","family":"Vassiliou","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Kean University, Union, NJ 07083, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8863-3635","authenticated-orcid":false,"given":"Sokratis G.","family":"Papageorgiou","sequence":"additional","affiliation":[{"name":"1st Department of Neurology, Medical School, National and Kapodistrian University of Athens, Eginition Hospital, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena E.","family":"Solomou","sequence":"additional","affiliation":[{"name":"Internal Medicine-Hematology, University of Patras Medical School, 26500 Rion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.cell.2019.09.001","article-title":"Alzheimer Disease: An Update on Pathobiology and Treatment Strategies","volume":"179","author":"Long","year":"2019","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1046\/j.1440-1819.2001.00779.x","article-title":"Prevalence of Alzheimer\u2019s disease, vascular dementia and dementia with Lewy bodies in a Japanese population","volume":"55","author":"Yamada","year":"2001","journal-title":"Psychiatry Clin. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Monteiro, A.R., Barbosa, D.J., Remi\u00e3o, F., and Silva, R. (2023). Alzheimer\u2019s disease: Insights and new prospects in disease pathophysiology, biomarkers and disease-modifying drugs. Biochem. Pharmacol., 211.","DOI":"10.1016\/j.bcp.2023.115522"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2929","DOI":"10.1016\/j.neuron.2022.06.021","article-title":"Molecular signatures underlying neurofibrillary tangle susceptibility in Alzheimer\u2019s disease","volume":"110","author":"Mahajani","year":"2022","journal-title":"Neuron"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"265","DOI":"10.3233\/JAD-170490","article-title":"Cognitive Decline in Preclinical Alzheimer\u2019s Disease: Amyloid-Beta versus Tauopathy","volume":"61","author":"Huber","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s40120-017-0073-9","article-title":"A Review of Fluid Biomarkers for Alzheimer\u2019s Disease: Moving from CSF to Blood","volume":"6","author":"Blennow","year":"2017","journal-title":"Neurol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhang, S., Crossley, C.A., and Yuan, Q. (2024). Neuronal Vulnerability of the Entorhinal Cortex to Tau Pathology in Alzheimer\u2019s Disease. Br. J. Biomed. Sci., 81.","DOI":"10.3389\/bjbs.2024.13169"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13024-020-00395-3","article-title":"Neuroimaging advances regarding subjective cognitive decline in preclinical Alzheimer\u2019s disease","volume":"15","author":"Wang","year":"2020","journal-title":"Mol. Neurodegener."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Karimani, F., Asgari Taei, A., Abolghasemi-Dehaghani, M.R., Safari, M.S., and Dargahi, L. (2024). Impairment of entorhinal cortex network activity in Alzheimer\u2019s disease. Front. Aging Neurosci., 16.","DOI":"10.3389\/fnagi.2024.1402573"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Christodoulou, R., Vamvouras, G., Lorentzen, L., and Vassiliou, E. (2025). Erythrocyte Load in Cerebrospinal Fluid Linked with Hippocampal Atrophy in Alzheimer\u2019s Disease. J. Clin. Med., 14.","DOI":"10.3390\/jcm14134670"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"599","DOI":"10.3233\/JAD-230792","article-title":"Effect of Vascular Risk Factors on Blood-Brain Barrier and Cerebrospinal Fluid Biomarkers Along the Alzheimer\u2019s Disease Continuum: A Retrospective Observational Study","volume":"97","author":"Ricci","year":"2023","journal-title":"J Alzheimers Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.neuroimage.2012.01.021","article-title":"FreeSurfer","volume":"62","author":"Fischl","year":"2012","journal-title":"NeuroImage"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.brainresbull.2022.10.006","article-title":"The central role of tau in Alzheimer\u2019s disease: From neurofibrillary tangle maturation to the induction of cell death","volume":"190","author":"Thal","year":"2022","journal-title":"Brain Res. Bull."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/s00401-020-02195-x","article-title":"Plasma p-tau181 accurately predicts Alzheimer\u2019s disease pathology at least 8 years prior to post-mortem and improves the clinical characterisation of cognitive decline","volume":"140","author":"Karikari","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e1681","DOI":"10.1212\/WNL.0000000000012727","article-title":"Comparing the Clinical Utility and Diagnostic Performance of CSF P-Tau181, P-Tau217, and P-Tau231 Assays","volume":"97","author":"Leuzy","year":"2021","journal-title":"Neurology"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lombardi, G., Pancani, S., Manca, R., Mitolo, M., Baiardi, S., Massa, F., Coppola, L., Franzese, M., Nicolai, E., and Guerini, F.R. (2024). Role of Blood P-Tau Isoforms (181, 217, 231) in Predicting Conversion from MCI to Dementia Due to Alzheimer\u2019s Disease: A Review and Meta-Analysis. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms252312916"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s13024-023-00605-8","article-title":"Plasma phospho-tau in Alzheimer\u2019s disease: Towards diagnostic and therapeutic trial applications","volume":"18","author":"Kac","year":"2023","journal-title":"Mol. Neurodegener."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7918","DOI":"10.1038\/s41467-024-52297-3","article-title":"Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology","volume":"15","author":"Goettemoeller","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1111\/j.1750-3639.2009.00266.x","article-title":"Mitochondrial ATP-synthase in the entorhinal cortex is a target of oxidative stress at stages I\/II of Alzheimer\u2019s disease pathology","volume":"20","author":"Terni","year":"2010","journal-title":"Brain Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Zhang, M., Cheng, Y., Zhai, Y., Yuan, Y., Hu, H., Meng, X., Fan, X., Sun, H., and Li, S. (2022). Attenuated iron stress and oxidative stress may participate in anti-seizure and neuroprotective roles of xenon in pentylenetetrazole-induced epileptogenesis. Front. Cell Neurosci., 16.","DOI":"10.3389\/fncel.2022.1007458"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Canepa, E., and Fossati, S. (2020). Impact of Tau on Neurovascular Pathology in Alzheimer\u2019s Disease. Front. Neurol., 11.","DOI":"10.3389\/fneur.2020.573324"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2612","DOI":"10.1038\/s41467-020-15701-2","article-title":"Spread of pathological tau proteins through communicating neurons in human Alzheimer\u2019s disease","volume":"11","author":"Vogel","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez-Frausto, M., and Vivar, C. (2024). Entorhinal cortex\u2013hippocampal circuit connectivity in health and disease. Front. Hum. Neurosci., 18.","DOI":"10.3389\/fnhum.2024.1448791"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1016\/j.cub.2015.02.045","article-title":"Repeating spatial activations in human entorhinal cortex","volume":"25","author":"Miller","year":"2015","journal-title":"Curr. Biol."},{"key":"ref_25","first-page":"S111","article-title":"Cerebral amyloid angiopathy and Alzheimer\u2019s disease","volume":"61","author":"Ghiso","year":"2010","journal-title":"Hirosaki Med. J."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Dutra, F.F., and Bozza, M.T. (2014). Heme on innate immunity and inflammation. Front. Pharmacol., 5.","DOI":"10.3389\/fphar.2014.00115"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2609","DOI":"10.1172\/JCI78443","article-title":"Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1","volume":"125","author":"Schallner","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s10571-021-01175-3","article-title":"The Critical Role of Erythrolysis and Microglia\/Macrophages in Clot Resolution After Intracerebral Hemorrhage: A Review of the Mechanisms and Potential Therapeutic Targets","volume":"43","author":"Zheng","year":"2023","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1139\/bcb-2020-0116","article-title":"Lactoferrin and hematoma detoxification after intracerebral hemorrhage","volume":"99","author":"Zhao","year":"2021","journal-title":"Biochem. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.expneurol.2015.08.018","article-title":"Microglia in the TBI brain: The good, the bad, and the dysregulated","volume":"275","author":"Loane","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s12975-012-0245-y","article-title":"Nrf2 to pre-condition the brain against injury caused by products of hemolysis after ICH","volume":"4","author":"Zhao","year":"2013","journal-title":"Transl. Stroke Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wei, C., Chen, C., Li, S., Ding, Y., Zhou, Y., Mai, F., Hong, S., Wu, J., Yang, Y., and Zhu, Z. (2025). TRIOL attenuates intracerebral hemorrhage injury by bidirectionally modulating microglia- and neuron-mediated hematoma clearance. Redox Biol., 80.","DOI":"10.1016\/j.redox.2024.103487"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1083\/jcb.201709069","article-title":"Microglia in Alzheimer\u2019s disease","volume":"217","author":"Hansen","year":"2018","journal-title":"J. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Wang, F., Wang, J., Shen, Y., Li, H., Rausch, W.D., and Huang, X. (2022). Iron Dyshomeostasis and Ferroptosis: A New Alzheimer\u2019s Disease Hypothesis?. Front. Aging Neurosci., 14.","DOI":"10.3389\/fnagi.2022.830569"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Tran, D., DiGiacomo, P., Born, D.E., Georgiadis, M., and Zeineh, M. (2022). Iron and Alzheimer\u2019s Disease: From Pathology to Imaging. Front. Hum. Neurosci., 16.","DOI":"10.3389\/fnhum.2022.838692"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1038\/s41419-024-07152-0","article-title":"The link between amyloid \u03b2 and ferroptosis pathway in Alzheimer\u2019s disease progression","volume":"15","author":"Salinas","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"eaau5732","DOI":"10.1126\/scitranslmed.aau5732","article-title":"Prospective longitudinal atrophy in Alzheimer\u2019s disease correlates with the intensity and topography of baseline tau-PET","volume":"12","author":"Salinas","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e045733","DOI":"10.1002\/alz.045733","article-title":"Longitudinal hippocampal atrophy is associated with an amyloid-independent entorhinal tauopathy and an amyloid-dependent neocortical tauopathy","volume":"16","author":"Hanseeuw","year":"2020","journal-title":"Alzheimers Dement."},{"key":"ref_39","first-page":"e70068","article-title":"Blood phosphorylated Tau181 reliably differentiates amyloid-positive from amyloid-negative subjects in the Alzheimer\u2019s disease continuum: A systematic review and meta-analysis","volume":"17","author":"Antonioni","year":"2025","journal-title":"Alzheimers Dement."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/9\/1300\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:42:59Z","timestamp":1760035379000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/9\/1300"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,10]]},"references-count":39,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["biom15091300"],"URL":"https:\/\/doi.org\/10.3390\/biom15091300","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,10]]}}}