{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:36:53Z","timestamp":1790660213249,"version":"4.1.0"},"reference-count":87,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T00:00:00Z","timestamp":1776902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universiti Kebangsaan Malaysia Faculty of Medicine Fundamental Grants","award":["FF-2025-443"],"award-info":[{"award-number":["FF-2025-443"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a progressive neurodegenerative disorder classically defined by cerebral amyloid \u03b2 (A\u03b2) plaque deposition and tau pathology. In recent years, AD has increasingly been recognized as a multisystem disorder rather than a purely brain-restricted condition, as mounting evidence indicates that A\u03b2 metabolism is a dynamic, bidirectional process involving both central and peripheral compartments. Peripheral tissues, particularly platelets, liver, kidneys, and the gastrointestinal tract, contribute substantially to circulating A\u03b2 levels and influence cerebral amyloid burden. Platelets are now considered the predominant source of peripheral A\u03b2, accounting for the majority of plasma A\u03b2 under physiological and pathological conditions, while the liver and kidneys play critical roles in A\u03b2 clearance through receptor-mediated uptake, enzymatic degradation and excretion. Disruption of these peripheral clearance pathways elevates circulating A\u03b2, increasing its transport into the brain via blood\u2013brain barrier (BBB) mechanisms by enhanced RAGE-mediated influx and impaired LRP1-dependent efflux in AD. Peripheral A\u03b2 entry into the central nervous system exacerbates neuroinflammation, mitochondrial dysfunction, and oxidative stress, thereby accelerating neuronal damage and disease progression. This review synthesizes updated evidence on peripheral sources of A\u03b2, differences between central and peripheral A\u03b2 pools, mechanisms of A\u03b2 transport across the BBB, pathological consequences of peripheral A\u03b2 on the brain and emerging therapeutic strategies targeting peripheral A\u03b2 metabolism, highlighting the importance of a systemic perspective in AD pathogenesis and treatment.<\/jats:p>","DOI":"10.3390\/cimb48050438","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T12:04:42Z","timestamp":1776945882000},"page":"438","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Review of the Effect of Peripheral Amyloid \u03b2 on the Central Nervous System"],"prefix":"10.3390","volume":"48","author":[{"given":"Zulaikha Elia","family":"Zamzuri","sequence":"first","affiliation":[{"name":"Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4163-2234","authenticated-orcid":false,"given":"Mohd Amir","family":"Kamaruzzaman","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9733-8072","authenticated-orcid":false,"given":"Seong Lin","family":"Teoh","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad Fairuz","family":"Yahaya","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur 56000, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Abubakar, M.B., Sanusi, K.O., Ugusman, A., Mohamed, W., Kamal, H., Ibrahim, N.H., Khoo, C.S., and Kumar, J. 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