{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T22:38:09Z","timestamp":1792881489344,"version":"4.5.0"},"reference-count":30,"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"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC2406500"],"award-info":[{"award-number":["2022YFC2406500"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"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:title>INTRODUCTION<\/jats:title>\n                    <jats:p>Apolipoprotein E (APOE) \u03b54 is the strongest genetic risk factor for Alzheimer's disease (AD), with homozygous carriers (\u03b54\/\u03b54) experiencing accelerated cognitive decline. While its role in amyloid and tau pathology is established, its impact on retinal and cerebral microvasculature remains underexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      A total of 107 AD (46 non\u2010carriers, 42 heterozygotes, 19 homozygotes) underwent optical coherence tomography angiography (OCTA) to assess retinal microvasculature and magnetic resonance imaging (MRI) \u2010derived peak width of skeletonized mean diffusivity (PSMD) to evaluate cerebral small vessel disease. Plasma biomarkers (A\u03b2\n                      <jats:sub>42<\/jats:sub>\n                      , p\u2010tau217, glial fibrillary acidic protein [GFAP], neurofilament light chain [NfL]) and cognitive scores were also analyzed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Homozygous APOE \u03b54 carriers exhibited the most severe reduction in retinal microvascular density and higher PSMD (\n                      <jats:italic>p<\/jats:italic>\n                      \u00a0&lt;\u00a00.001). Superficial retinal vessels and PSMD partially mediated APOE \u03b54's association with cognitive impairment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>APOE \u03b54 homozygosity exacerbates retinal and cerebral microvascular dysfunction, which partially mediates cognitive impairment in AD.<\/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>Apolipoprotein E (APOE) \u03b54 homozygosity is associated with the most severe reductions in retinal microvascular densities and elevated cerebral small vessel disease (peak width of skeletonized mean diffusivity [PSMD]) in Alzheimer's disease (AD).<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>\n                            Vascular dysfunction (retinal and cerebral) correlates with lower A\u03b242, higher p\u2010tau217\/A\u03b2\n                            <jats:sub>42<\/jats:sub>\n                            , and worse cognitive scores (Mini\u2010Mental State Examination [MMSE], Montreal Cognitive Assessment [MoCA]).\n                          <\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Mediation analysis reveals that retinal (superficial vascular complex [SVC]) and cerebral (PSMD) microvascular changes partially explain the link between APOE \u03b54 and cognitive decline.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Findings highlight vascular pathways as potential therapeutic targets in APOE \u03b54 carriers to mitigate cognitive impairment.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71000","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T11:30:53Z","timestamp":1765798253000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Apolipoprotein E \u03b54 homozygosity exacerbates retinal and cerebral microvascular dysfunction in Alzheimer's disease: A mediation analysis of vascular contributions to cognitive decline"],"prefix":"10.1002","volume":"21","author":[{"given":"Yuntao","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Neurology The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanyu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Neurology Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People's Hospital Quzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youjie","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology West China Hospital, Sichuan University Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqian","family":"Luan","sequence":"additional","affiliation":[{"name":"Department of Geriatrics The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Geriatrics The First Affiliated Hospital of Wenzhou Medical University Wenzhou 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L. Cheung Research Center for Management of Parkinsonism Faculty of Medicine The Chinese University of Hong Kong Hong Kong SAR China"},{"name":"Lau Tat\u2010chuen Research Centre of Brain Degenerative Diseases in Chinese Faculty of Medicine The Chinese University of Hong Kong Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William Robert","family":"Kwapong","sequence":"additional","affiliation":[{"name":"Department of Neurology Xuanwu Hospital, Capital Medical University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Geriatrics The First Affiliated Hospital of Wenzhou Medical University Wenzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(20)30412\u20109"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024\u2010022\u201000574\u20104"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70632"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13871"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00238"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.212780"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.3174\/ajnr.A7042"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14594"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tjpad.2024.100037"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.123.033081"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13859"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24758"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.10062"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mri.2019.05.008"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awac333"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70745"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.62.9.40"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0034823"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000012125"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm12175649"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/dad2.12181"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14302"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41746\u2010024\u201001292\u20105"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp\u20102020\u2010325347"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2020.100878"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469\u20107580.2005.00395.x"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.14433"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awae156"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70535"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.70316"}],"container-title":["Alzheimer's &amp; 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