{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T12:02:21Z","timestamp":1789646541477,"version":"4.0.0"},"reference-count":48,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:label\/>\n                    <jats:p>Alzheimer's disease (AD) is widely recognized as a multifactorial disorder involving neurovascular and glial dysfunction beyond amyloid\u2010\u03b2 and tau pathology. In this Perspective, we synthesize recent evidence to propose a conceptual framework linking transactive response (TAR) DNA\u2010binding protein 43\u00a0kDa (TDP\u201043) to neurovascular unit (NVU) disruption in AD. Traditionally considered a neuronal co\u2010pathology, TDP\u201043 also aggregates in astrocytes and endothelial cells, impairing blood\u2013brain barrier (BBB) integrity, glymphatic clearance, and metabolic homeostasis. Endothelial TDP\u201043 loss disrupts \u03b2\u2010catenin signaling and fibronectin, triggering vascular breakdown and neuroinflammation. Astrocytic perivascular aggregates correlate with reduced aquaporin\u20104 (AQP4) and CD146, further compromising clearance pathways. These vascular\u2013glial mechanisms may accelerate AD progression and help explain clinical heterogeneity and limited therapeutic response in TDP\u201043\u2013positive patients. We argue for the reclassification of TDP\u201043 as a potential upstream driver of disease progression. Such a shift would support the development of integrative biomarkers and precision treatment strategies targeting NVU dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Highlights<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Transactive response (TAR) DNA\u2010binding protein 43\u00a0kDa (TDP\u201043) may act as a driver of neurovascular dysfunction in Alzheimer's disease (AD).<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>We propose reclassifying TDP\u201043 from co\u2010pathology to upstream contributor.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>TDP\u201043 affects endothelial cells and astrocytes, disrupting blood\u2013brain barrier (BBB) and clearance.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Neurovascular unit (NVU) dysfunction links TDP\u201043 to inflammation, hypoperfusion, and cognitive decline.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>A vascular\u2013glial model of AD opens new therapeutic and biomarker opportunities.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.70988","type":"journal-article","created":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T06:51:46Z","timestamp":1765867906000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Reframing TDP\u201043 in Alzheimer's disease: From co\u2010pathology to neurovascular culprit"],"prefix":"10.1002","volume":"21","author":[{"given":"Martina Gaia","family":"Di Donna","sequence":"first","affiliation":[{"name":"Memory Clinic and Neurodegenerative Dementia Research Unit Policlinico Tor Vergata University of Rome \u201cTor Vergata\u201d  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Motta","sequence":"additional","affiliation":[{"name":"Memory Clinic and Neurodegenerative Dementia Research Unit Policlinico Tor Vergata University of Rome \u201cTor Vergata\u201d  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara Giuseppina","family":"Bonomi","sequence":"additional","affiliation":[{"name":"Memory Clinic and Neurodegenerative Dementia Research Unit Policlinico Tor Vergata University of Rome \u201cTor Vergata\u201d  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Bernocchi","sequence":"additional","affiliation":[{"name":"Memory Clinic and Neurodegenerative Dementia Research Unit Policlinico Tor Vergata University of Rome \u201cTor Vergata\u201d  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Ricci","sequence":"additional","affiliation":[{"name":"Memory Clinic and Neurodegenerative Dementia Research Unit Policlinico Tor Vergata University of Rome \u201cTor Vergata\u201d  Rome Italy"},{"name":"Department of Clinical and Behavioral Neurology Santa Lucia Foundation IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Poli","sequence":"additional","affiliation":[{"name":"Memory Clinic and Neurodegenerative Dementia Research Unit Policlinico Tor Vergata University of Rome \u201cTor Vergata\u201d  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Koch","sequence":"additional","affiliation":[{"name":"Department of Clinical and Behavioral Neurology Santa Lucia Foundation IRCCS  Rome Italy"},{"name":"Department of Neuroscience and Rehabilitation University of Ferrara, and Center for Translational Neurophysiology of Speech and Communication (CTNSC) Italian Institute of Technology (IIT)  Ferrara Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8456-4169","authenticated-orcid":false,"given":"Alessandro","family":"Martorana","sequence":"additional","affiliation":[{"name":"Memory Clinic and Neurodegenerative Dementia Research Unit Policlinico Tor Vergata University of Rome \u201cTor Vergata\u201d  Rome 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