{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T01:29:22Z","timestamp":1791336562683,"version":"4.3.1"},"reference-count":38,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T00:00:00Z","timestamp":1767052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kuen Lau Research Foundation"},{"DOI":"10.13039\/100000002","name":"National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health","doi-asserted-by":"publisher","award":["UL1 TR001872"],"award-info":[{"award-number":["UL1 TR001872"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background\/Objectives: Alzheimer\u2019s disease (AD) is the leading cause of dementia, which is an inevitable consequence of aging. Early detection of AD, or detection during the pre-AD stage, is beneficial, as it enables timely intervention to reduce modifiable risk factors, which may help prevent or delay the progression to dementia. On the one hand, plasma biomarkers have demonstrated great promise in predicting cognitive decline. On the other hand, in recent years, ocular imaging features, particularly the thickness of retinal layers measured by spectral-domain optical coherence tomography (SD-OCT), are emerging as possible non-invasive, non-contact surrogate markers for early detection and monitoring of neurodegeneration. This pilot study aims to identify retinal layer thickness changes across the entire retina linked to plasma AD biomarkers in cognitively healthy (CH) elderly individuals at risk for AD. Methods: Eleven CH individuals (20 eyes total) were classified in the pre-AD stage by plasma \u03b2-amyloid (A\u03b2)42\/40 ratio &lt; 0.10 and underwent SD-OCT. A deep-learning-derived automated algorithm was used to segment retinal layers on OCT (with manual correction when needed). Multiple layer thicknesses throughout the entire retina (including the inner retina, the outer retina, and the choroid) were measured in the inner ring (1\u20133 mm) and outer ring (3\u20136 mm) of the Early Treatment Diabetic Retinopathy Study (ETDRS). Relationships between retinal layers and plasma biomarkers were analyzed by ridge regression\/bootstrapping. Results: Results showed that photoreceptor inner segment (PR-IS) thinning had the largest size effect with neurofilament light chain. Additional findings revealed thinning or thickening of the other retinal layers in association with increasing levels of glial fibrillary acidic protein and phosphorylated tau at threonine 181 and 217 (p-tau181 and p-tau217). Conclusions: This pilot study suggests that retinal layer-specific signatures exist, with PR-IS thinning as the largest effect, indicating neurodegeneration in pre-AD. Further research is needed to confirm the findings of this pilot study using larger longitudinal pre-AD cohorts and comparative analyses with healthy aging adults.<\/jats:p>","DOI":"10.3390\/jcm15010275","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T15:05:01Z","timestamp":1767193501000},"page":"275","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Emerging Oculomic Signatures: Linking Thickness of Entire Retinal Layers with Plasma Biomarkers in Preclinical Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"15","author":[{"given":"Ibrahim","family":"Abboud","sequence":"first","affiliation":[{"name":"Doheny Image Analysis Laboratory, Doheny Eye Institute, 150 N. Orange Grove Blvd., Pasadena, CA 91103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2194-342X","authenticated-orcid":false,"given":"Emily","family":"Xu","sequence":"additional","affiliation":[{"name":"Doheny Image Analysis Laboratory, Doheny Eye Institute, 150 N. Orange Grove Blvd., Pasadena, CA 91103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0496-2509","authenticated-orcid":false,"given":"Sophia","family":"Xu","sequence":"additional","affiliation":[{"name":"Doheny Image Analysis Laboratory, Doheny Eye Institute, 150 N. Orange Grove Blvd., Pasadena, CA 91103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Alhasany","sequence":"additional","affiliation":[{"name":"Doheny Image Analysis Laboratory, Doheny Eye Institute, 150 N. Orange Grove Blvd., Pasadena, CA 91103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Doheny Image Analysis Laboratory, Doheny Eye Institute, 150 N. Orange Grove Blvd., Pasadena, CA 91103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Analytical Biochemistry Core Laboratory, Huntington Medical Research Institute, 686 S. Fair Oaks Avenue, Pasadena, CA 91105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6623-9763","authenticated-orcid":false,"given":"Natalie","family":"Astraea","sequence":"additional","affiliation":[{"name":"Analytical Biochemistry Core Laboratory, Huntington Medical Research Institute, 686 S. Fair Oaks Avenue, Pasadena, CA 91105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, University of California, San Francisco, 50 16th Street, #2538, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8307-0298","authenticated-orcid":false,"given":"Zhihong Jewel","family":"Hu","sequence":"additional","affiliation":[{"name":"Doheny Image Analysis Laboratory, Doheny Eye Institute, 150 N. Orange Grove Blvd., Pasadena, CA 91103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7120-521X","authenticated-orcid":false,"given":"Jane W.","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of California, Los Angeles, 100 Stein Plaza Driveway, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1038\/s41398-020-01137-1","article-title":"Plasma glial fibrillary acidic protein is elevated in cognitively normal older adults at risk of Alzheimer\u2019s disease","volume":"11","author":"Chatterjee","year":"2021","journal-title":"Transl. Psychiatry"},{"key":"ref_2","first-page":"66","article-title":"Long-term course of neurofilament light chain in blood across the Alzheimer\u2019s disease continuum","volume":"13","author":"Preische","year":"2021","journal-title":"Alzheimers Res. Ther."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1002\/alz.12751","article-title":"An accurate fully automated panel of plasma biomarkers for Alzheimer\u2019s disease","volume":"19","author":"Palmqvist","year":"2023","journal-title":"Alzheimers Dement."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1001\/jamaneurol.2023.5319","article-title":"Diagnostic Accuracy of a Plasma Phosphorylated Tau 217 Immunoassay for Alzheimer Disease Pathology","volume":"81","author":"Ashton","year":"2024","journal-title":"JAMA Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e14526","DOI":"10.1002\/alz.14526","article-title":"Differential roles of Alzheimer\u2019s disease plasma biomarkers in stepwise biomarker-guided diagnostics","volume":"21","author":"Jang","year":"2025","journal-title":"Alzheimers Dement."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1002\/alz.12614","article-title":"Association of plasma biomarkers, p-tau181, glial fibrillary acidic protein, and neurofilament light, with intermediate and long-term clinical Alzheimer\u2019s disease risk: Results from a prospective cohort followed over 17 years","volume":"19","author":"Stocker","year":"2022","journal-title":"Alzheimers Dement."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1002\/alz.13560","article-title":"Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative","volume":"20","author":"Sanchez","year":"2023","journal-title":"Alzheimers Dement."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1002\/kjm2.12870","article-title":"Advances in blood biomarkers for Alzheimer\u2019s disease (AD): A review","volume":"40","author":"Assfaw","year":"2024","journal-title":"Kaohsiung J. Med. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.ophtha.2018.08.009","article-title":"Spectral-domain OCT measurements in preclinical Alzheimer\u2019s disease","volume":"126","author":"Chan","year":"2019","journal-title":"Ophthalmology"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Asanad, S., Fantini, M., Sultan, W., Nassisi, M., Felix, C.M., Wu, J., Karanjia, R., Ross-Cisneros, F.N., Sagare, A.P., and Zlokovic, B.V. (2020). Retinal nerve fiber layer thickness predicts CSF amyloid\/tau before cognitive decline. PLoS ONE, 15, Correction in PLoS ONE 2020, 15, e0236379. https:\/\/doi.org\/10.1371\/journal.pone.0236379.","DOI":"10.1371\/journal.pone.0236379"},{"key":"ref_11","first-page":"196","article-title":"Change in retinal structural anatomy during the preclinical stage of Alzheimer\u2019s disease","volume":"10","author":"Santos","year":"2018","journal-title":"Alzheimer\u2019s Dement. Diagn. Assess. Dis. Monit."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s13195-022-00998-6","article-title":"The retinal ganglion cell layer reflects neurodegenerative changes in cognitively unimpaired individuals","volume":"14","author":"Lage","year":"2022","journal-title":"Alzheimers Res. Ther."},{"key":"ref_13","first-page":"743","article-title":"The Alzheimer\u2019s Disease Fluid Biomarker Study: Design and baseline cohort","volume":"9","author":"Harrington","year":"2013","journal-title":"Alzheimers Dement."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.1161\/STR.0b013e3182299496","article-title":"Vascular contributions to cognitive impairment and dementia","volume":"42","author":"Gorelick","year":"2011","journal-title":"Stroke"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.neuron.2013.10.008","article-title":"The pathobiology of vascular dementia","volume":"80","author":"Iadecola","year":"2013","journal-title":"Neuron"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9541","DOI":"10.1038\/s41598-020-66355-5","article-title":"Automated Retinal Layer Segmentation Using Graph-based Algorithm Incorporating Deep-learning-derived Information","volume":"10","author":"Mishra","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"076006","DOI":"10.1117\/1.JBO.18.7.076006","article-title":"Multiple layer segmentation and analysis in three-dimensional spectral-domain optical coherence tomography volume scans","volume":"18","author":"Hu","year":"2013","journal-title":"J. Biomed. Opt."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1167\/tvst.10.4.24","article-title":"Automatic Segmentation in Multiple OCT Layers For Stargardt Disease Characterization via Deep Learning","volume":"10","author":"Mishra","year":"2021","journal-title":"Transl. Vis. Sci. Technol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1002\/acn3.51522","article-title":"Neurofilament light chain and retinal layers\u2019 determinants and association: A population-based study","volume":"9","author":"Garzone","year":"2022","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Garc\u00eda-Berm\u00fadez, M.Y., Vohra, R., Freude, K., Wijngaarden, P.v., Martin, K., Thomsen, M.S., Aldana, B.I., and Kolko, M. (2023). Potential Retinal Biomarkers in Alzheimer\u2019s Disease. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242115834"},{"key":"ref_21","first-page":"3117","article-title":"Metabolic dependence of photoreceptors on the choroid in the normal and detached retina","volume":"41","author":"Linsenmeier","year":"2000","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e11170","DOI":"10.15252\/emmm.201911170","article-title":"Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer\u2019s disease","volume":"11","author":"Palmqvist","year":"2019","journal-title":"EMBO Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1111\/ene.15762","article-title":"Blood biomarkers in mild cognitive impairment patients: Relationship between analytes and progression to Alzheimer\u2019s disease dementia","volume":"30","author":"Bernardes","year":"2023","journal-title":"Eur. J. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.neurobiolaging.2023.01.015","article-title":"Retinal photoreceptor layer thickness has disease specificity and distinguishes predicted FTLD-Tau from biomarker-determined Alzheimer\u2019s disease","volume":"125","author":"Kim","year":"2023","journal-title":"Neurobiol. Aging"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s13195-024-01668-5","article-title":"Association and multimodal model of retinal and blood-based biomarkers for detection of preclinical Alzheimer\u2019s disease","volume":"17","author":"Ravichandran","year":"2025","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.optom.2018.07.001","article-title":"Retinal glial changes in Alzheimer\u2019s disease\u2014A review","volume":"12","author":"Salazar","year":"2019","journal-title":"J. Optom."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/0197-4580(96)00009-7","article-title":"Retinal pathology in Alzheimer\u2019s disease. II. Regional neuron loss and glial changes in GCL","volume":"17","author":"Blanks","year":"1996","journal-title":"Neurobiol. Aging"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Nagai, N., Mushiga, Y., and Ozawa, Y. (2023). Retinal Pigment Epithelial Abnormality and Choroidal Large Vascular Flow Imbalance Are Associated with Choriocapillaris Flow Deficits in Age-Related Macular Degeneration in Fellow Eyes. J Clin Med., 12.","DOI":"10.3390\/jcm12041360"},{"key":"ref_29","first-page":"775","article-title":"The retinal choroid as an oculovascular biomarker for Alzheimer\u2019s dementia: A histopathological study in severe disease","volume":"11","author":"Asanad","year":"2019","journal-title":"Alzheimer\u2019s Dement. Diagn. Assess. Dis. Monit."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1038\/s41591-023-02380-x","article-title":"Astrocyte reactivity influences amyloid-\u03b2 effects on tau pathology in preclinical Alzheimer\u2019s disease","volume":"29","author":"Bellaver","year":"2023","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1007\/s00401-021-02275-6","article-title":"Plasma p-tau231: A new biomarker for incipient Alzheimer\u2019s disease pathology","volume":"141","author":"Ashton","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e102036","DOI":"10.1002\/alz70855_102036","article-title":"Basic Science and Pathogenesis","volume":"21","author":"Thal","year":"2025","journal-title":"Alzheimers. Dement."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1186\/s40478-018-0650-x","article-title":"Amyloid-beta and phosphorylated tau in post-mortem Alzheimer\u2019s disease retinas","volume":"6","author":"Morrema","year":"2018","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2732","DOI":"10.1364\/BOE.8.002732","article-title":"Automatic segmentation of nine retinal layer boundaries in OCT images of non-exudative AMD patients using deep learning and graph search","volume":"8","author":"Fang","year":"2017","journal-title":"Biomed. Opt. Express"},{"key":"ref_35","first-page":"364","article-title":"Fully convolutional boundary regression for OCT layer segmentation","volume":"10","author":"He","year":"2019","journal-title":"Biomed. Opt. Express"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1167\/iovs.61.3.20","article-title":"Graph-based deep learning for automated retinal layer segmentation in OCT","volume":"61","author":"Marques","year":"2020","journal-title":"Investig Ophthalmol. Vis. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3555","DOI":"10.1038\/s41467-021-23746-0","article-title":"Plasma biomarkers of Alzheimer\u2019s disease improve prediction of cognitive decline in cognitively unimpaired elderly populations","volume":"12","author":"Cullen","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1001\/jamaneurol.2022.5272","article-title":"Prediction of Longitudinal Cognitive Decline in Preclinical Alzheimer Disease Using Plasma Biomarkers","volume":"80","author":"Ashton","year":"2023","journal-title":"JAMA Neurol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/1\/275\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T15:22:08Z","timestamp":1767194528000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/1\/275"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,30]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["jcm15010275"],"URL":"https:\/\/doi.org\/10.3390\/jcm15010275","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,30]]}}}