{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T20:23:56Z","timestamp":1793132636907,"version":"4.5.0"},"reference-count":266,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T00:00:00Z","timestamp":1699920000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Neurological Disorders and Stroke","award":["R21NS130503"],"award-info":[{"award-number":["R21NS130503"]}]},{"name":"National Institute of Neurological Disorders and Stroke","award":["R61NS126622"],"award-info":[{"award-number":["R61NS126622"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The blood\u2013brain barrier (BBB) is a unique and selective feature of the central nervous system\u2019s vasculature. BBB dysfunction has been observed as an early sign of Alzheimer\u2019s Disease (AD) before the onset of dementia or neurodegeneration. The intricate relationship between the BBB and the pathogenesis of AD, especially in the context of neurovascular coupling and the overlap of pathophysiology in neurodegenerative and cerebrovascular diseases, underscores the urgency to understand the BBB\u2019s role more deeply. Preserving or restoring the BBB function emerges as a potentially promising strategy for mitigating the progression and severity of AD. Molecular and genetic changes, such as the isoform \u03b54 of apolipoprotein E (ApoE\u03b54), a significant genetic risk factor and a promoter of the BBB dysfunction, have been shown to mediate the BBB disruption. Additionally, receptors and transporters like the low-density lipoprotein receptor-related protein 1 (LRP1), P-glycoprotein (P-gp), and the receptor for advanced glycation end products (RAGEs) have been implicated in AD\u2019s pathogenesis. In this comprehensive review, we endeavor to shed light on the intricate pathogenic and therapeutic connections between AD and the BBB. We also delve into the latest developments and pioneering strategies targeting the BBB for therapeutic interventions, addressing its potential as a barrier and a carrier. By providing an integrative perspective, we anticipate paving the way for future research and treatments focused on exploiting the BBB\u2019s role in AD pathogenesis and therapy.<\/jats:p>","DOI":"10.3390\/ijms242216288","type":"journal-article","created":{"date-parts":[[2023,11,14]],"date-time":"2023-11-14T02:20:37Z","timestamp":1699928437000},"page":"16288","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":216,"title":["Blood\u2013Brain Barrier Breakdown in Alzheimer\u2019s Disease: Mechanisms and Targeted Strategies"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6872-4780","authenticated-orcid":false,"given":"Amer E.","family":"Alkhalifa","sequence":"first","affiliation":[{"name":"Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, 720 S. Donahue Dr., Auburn, AL 36849, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nour F.","family":"Al-Ghraiybah","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, 720 S. Donahue Dr., Auburn, AL 36849, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Odum","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, 720 S. Donahue Dr., Auburn, AL 36849, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G.","family":"Shunnarah","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, 720 S. Donahue Dr., Auburn, AL 36849, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nataleigh","family":"Austin","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, 720 S. Donahue Dr., Auburn, AL 36849, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9792-7766","authenticated-orcid":false,"given":"Amal","family":"Kaddoumi","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, 720 S. 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