{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T22:00:13Z","timestamp":1781820013183,"version":"3.54.5"},"reference-count":43,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T00:00:00Z","timestamp":1683590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kaohsiung Municipal Ta-Tung Hospital","award":["KMTTH-110-056"],"award-info":[{"award-number":["KMTTH-110-056"]}]},{"name":"Kaohsiung Municipal Ta-Tung Hospital","award":["KMTTH-111-041"],"award-info":[{"award-number":["KMTTH-111-041"]}]},{"name":"Kaohsiung Municipal Ta-Tung Hospital","award":["MOST-101-2314-B-037-055"],"award-info":[{"award-number":["MOST-101-2314-B-037-055"]}]},{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["KMTTH-110-056"],"award-info":[{"award-number":["KMTTH-110-056"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["KMTTH-111-041"],"award-info":[{"award-number":["KMTTH-111-041"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["MOST-101-2314-B-037-055"],"award-info":[{"award-number":["MOST-101-2314-B-037-055"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a neurodegenerative disorder characterized by memory decline and cognitive impairment. Research on biomarkers can aid in early diagnosis, monitoring disease progression, evaluating treatment efficacy, and advancing fundamental research. We conducted a cross-sectional longitudinal study to see if there is an association between AD patients and age-matched healthy controls for their physiologic skin characteristics, such as pH, hydration, transepidermal water loss (TEWL), elasticity, microcirculation, and ApoE genotyping. The study used the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of the Boxes (CDR-SB) scales as references to quantify the presence of disease, if any. Our findings demonstrate that AD patients have a dominantly neutral pH, greater skin hydration, and less elasticity compared to the control subjects. At baseline, the tortuous capillary percentage negatively correlated with MMSE scores in AD patients. However, AD patients who carry the ApoE E4 allele and exhibit a high percentage of tortuous capillaries and capillary tortuous numbers have shown better treatment outcomes at six months. Therefore, we believe that physiologic skin testing is a rapid and effective way to screen, monitor progression, and ultimately guide the most appropriate treatment for AD patients.<\/jats:p>","DOI":"10.3390\/ijms24108478","type":"journal-article","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T03:32:27Z","timestamp":1683689547000},"page":"8478","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Developing Biomarkers for the Skin: Biomarkers for the Diagnosis and Prediction of Treatment Outcomes of Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"24","author":[{"given":"Ching-Ying","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Dermatology, College of Medicine and Post Baccalaureat Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Department of Cosmetic Science, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1046-0959","authenticated-orcid":false,"given":"Chih-Yi","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Dermatology, College of Medicine and Post Baccalaureat Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1918-9021","authenticated-orcid":false,"given":"Yuan-Han","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurology, College of Post Baccalaureat Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/s40120-022-00338-8","article-title":"Alzheimer\u2019s Disease: Epidemiology and Clinical Progression","volume":"11","author":"Byrnes","year":"2022","journal-title":"Neurol. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1212\/WNL.56.9.1143","article-title":"Practice parameter: Diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology","volume":"56","author":"Knopman","year":"2001","journal-title":"Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1002\/ana.20009","article-title":"Imaging brain amyloid in Alzheimer\u2019s disease with Pittsburgh Compound-B","volume":"55","author":"Klunk","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/S1474-4422(06)70355-6","article-title":"Association between CSF biomarkers and incipient Alzheimer\u2019s disease in patients with mild cognitive impairment: A follow-up study","volume":"5","author":"Hansson","year":"2006","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1212\/01.WNL.0000091890.32140.8F","article-title":"Plasma A\u03b240 and A\u03b242 and Alzheimer\u2019s disease: Relation to age, mortality, and risk","volume":"61","author":"Mayeux","year":"2003","journal-title":"Neurology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/S1474-4422(06)70501-4","article-title":"Plasma A\u03b2(1\u201340) and A\u03b2(1\u201342) and the risk of dementia: A prospective case-cohort study","volume":"5","author":"Hofman","year":"2006","journal-title":"Lancet Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1602\/neurorx.1.2.226","article-title":"Biomarkers of Alzheimer disease in plasma","volume":"1","author":"Irizarry","year":"2004","journal-title":"NeuroRx"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1212\/01.wnl.0000256043.50901.e3","article-title":"Fluctuations of CSF amyloid-beta levels: Implications for a diagnostic and therapeutic biomarker","volume":"68","author":"Bateman","year":"2007","journal-title":"Neurology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1002\/gps.609","article-title":"Decreased cutaneous vasodilatation to isometric handgrip exercise in Alzheimer\u2019s disease","volume":"17","author":"Rudas","year":"2002","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3233\/JAD-2007-11106","article-title":"Impaired peripheral endothelial microvascular responsiveness in Alzheimer\u2019s disease","volume":"11","author":"Khalil","year":"2007","journal-title":"J. Alzheimers Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"31504","DOI":"10.1074\/jbc.M704273200","article-title":"Presenilin 1 regulates epidermal growth factor receptor turnover and signaling in the endosomal-lysosomal pathway","volume":"282","author":"Repetto","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1093\/hmg\/ddh151","article-title":"Partial loss of presenilins causes seborrheic keratosis and autoimmune disease in mice","volume":"13","author":"Tournoy","year":"2004","journal-title":"Hum. Mol. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1016\/S0891-5849(02)01049-3","article-title":"Oxidative stress and reduced antioxidant defenses in peripheral cells from familial Alzheimer\u2019s patients","volume":"33","author":"Cecchi","year":"2002","journal-title":"Free Radic. Biol. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.1096\/fj.02-1147fje","article-title":"Alzheimer\u2019s disease skin fibroblasts selectively express a bradykinin signaling pathway mediating tau protein Ser phosphorylation","volume":"17","author":"Jong","year":"2003","journal-title":"FASEB J."},{"key":"ref_15","first-page":"55","article-title":"Expression of amyloid beta-protein precursor mRNAs in cultured skin fibroblasts taken from patients with dementia of the Alzheimer type","volume":"5","author":"Okada","year":"1994","journal-title":"Dementia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"829","DOI":"10.3233\/JAD-2009-1193","article-title":"Altered cholesterol ester cycle in skin fibroblasts from patients with Alzheimer\u2019s disease","volume":"18","author":"Pani","year":"2009","journal-title":"J. Alzheimers Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7999","DOI":"10.1073\/pnas.83.20.7999","article-title":"Cytosolic free calcium and cell spreading decrease in fibroblasts from aged and Alzheimer donors","volume":"83","author":"Peterson","year":"1986","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/j.neurobiolaging.2004.07.006","article-title":"Enhanced GM1 ganglioside catabolism in cultured fibroblasts from Alzheimer patients","volume":"26","author":"Pitto","year":"2005","journal-title":"Neurobiol. Aging."},{"key":"ref_19","first-page":"36","article-title":"Expression of beta-amyloid and tau-protein in mastocytes in Alzheimer disease","volume":"65","author":"Kvetnaia","year":"2003","journal-title":"Arkh. Patol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/0140-6736(92)90046-6","article-title":"Amyloid beta-protein deposition in skin of patients with dementia","volume":"339","author":"Soininen","year":"1992","journal-title":"Lancet"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1007\/BF00293394","article-title":"Presence of non-fibrillar amyloid beta protein in skin biopsies of Alzheimer\u2019s disease (AD), Down\u2019s syndrome and non-AD normal persons","volume":"88","author":"Wen","year":"1994","journal-title":"Acta Neuropathol"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2581","DOI":"10.1212\/WNL.43.12.2581","article-title":"Cytosol protein kinase C downregulation in fibroblasts from Alzheimer\u2019s disease patients","volume":"43","author":"Govoni","year":"1993","journal-title":"Neurology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1161\/01.STR.0000014421.15948.67","article-title":"Alzheimer disease as a vascular disorder: Nosological evidence","volume":"33","year":"2002","journal-title":"Stroke"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"247","DOI":"10.3233\/JAD-2003-5308","article-title":"Is Alzheimer\u2019s disease a vascular disorder?","volume":"5","author":"Jellinger","year":"2003","journal-title":"J. Alzheimers Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/j.jacc.2019.10.062","article-title":"Alzheimer\u2019s Disease and Vascular Aging: JACC Focus Seminar","volume":"75","author":"Iadecola","year":"2020","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1002\/gps.5527","article-title":"Correlation between cerebral blood flow and olfactory function in mild cognitive impairment and Alzheimer\u2019s disease","volume":"36","author":"Kashibayashi","year":"2021","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1159\/000448176","article-title":"Aortic Stiffness, Cerebrovascular Dysfunction, and Memory","volume":"4","author":"Cooper","year":"2016","journal-title":"Pulse"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3233\/CH-2009-1174","article-title":"Whole blood viscosity and microvascular abnormalities in Alzheimer\u2019s Disease","volume":"41","author":"Smith","year":"2009","journal-title":"Clin. Hemorheol. Microcirc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"599","DOI":"10.2147\/VHRM.S34874","article-title":"Cerebral blood flow in Alzheimer\u2019s disease","volume":"8","author":"Roher","year":"2012","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/341226a0","article-title":"Amyloid beta-protein deposition in tissues other than brain in Alzheimer\u2019s disease","volume":"341","author":"Joachim","year":"1989","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"729","DOI":"10.3233\/JAD-142262","article-title":"Peripheral biomarkers of Alzheimer\u2019s disease","volume":"44","author":"Khan","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.nbd.2009.02.003","article-title":"A cellular model of Alzheimer\u2019s disease therapeutic efficacy: PKC activation reverses Abeta-induced biomarker abnormality on cultured fibroblasts","volume":"34","author":"Khan","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"463","DOI":"10.3233\/JAD-181191","article-title":"Neurodegenerative Disease-Related Proteins within the Epidermal Layer of the Human Skin","volume":"69","author":"Akerman","year":"2019","journal-title":"J. Alzheimers Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1159\/000501145","article-title":"Fibroblast Growth Factors: A Controlling Mechanism of Skin Aging","volume":"32","author":"Trindade","year":"2019","journal-title":"Ski. Pharm. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Shin, J.W., Kwon, S.H., Choi, J.Y., Na, J.I., Huh, C.H., Choi, H.R., and Park, K.C. (2019). Molecular Mechanisms of Dermal Aging and Antiaging Approaches. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092126"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e22090","DOI":"10.1002\/jcla.22090","article-title":"Association between malnutrition and hyperhomocysteine in Alzheimer\u2019s disease patients and diet intervention of betaine","volume":"31","author":"Sun","year":"2017","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_37","first-page":"450","article-title":"Implications of protein malnutrition and inflammatory disorders in the pathophysiology of Alzheimer\u2019s disease","volume":"29","author":"Ingenbleek","year":"2020","journal-title":"Asia Pac. J. Clin. Nutr."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.jshs.2020.01.004","article-title":"Physical exercise in the prevention and treatment of Alzheimer\u2019s disease","volume":"9","author":"Millan","year":"2020","journal-title":"J. Sport Health Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1016\/j.neuron.2022.03.004","article-title":"ApoE Cascade Hypothesis in the pathogenesis of Alzheimer\u2019s disease and related dementias","volume":"110","author":"Martens","year":"2022","journal-title":"Neuron"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.2174\/1567205014666170203125942","article-title":"Biomarkers for Alzheimer\u2019s Disease Diagnosis","volume":"14","author":"Mantzavinos","year":"2017","journal-title":"Curr. Alzheimer Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1097\/MOL.0000000000000604","article-title":"HDL from an Alzheimer\u2019s disease perspective","volume":"30","author":"Button","year":"2019","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"10","DOI":"10.5483\/BMBRep.2020.53.1.309","article-title":"Peripheral inflammatory biomarkers in Alzheimer\u2019s disease: A brief review","volume":"53","author":"Park","year":"2020","journal-title":"BMB Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"984786","DOI":"10.5402\/2012\/984786","article-title":"Biomarkers in Alzheimer\u2019s disease: A review","volume":"2012","author":"Chintamaneni","year":"2012","journal-title":"ISRN Pharm."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8478\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:32:00Z","timestamp":1760124720000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/10\/8478"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,9]]},"references-count":43,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24108478"],"URL":"https:\/\/doi.org\/10.3390\/ijms24108478","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,9]]}}}