{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:17:47Z","timestamp":1791897467464,"version":"4.3.4"},"reference-count":70,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Serpero Foundation"},{"name":"Golgi Cenci Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD), the leading cause of dementia, is expected to markedly increase in prevalence in the coming decades. Beyond amyloid and tau pathologies, accumulating evidence suggests that mitochondrial dysfunction and impaired protein homeostasis play crucial roles in AD onset and progression. Building on our previous identification of molecular signatures associated with disease progression, this study investigated whether epigenetic alterations of mitochondrial DNA (mtDNA) contribute to cognitive decline. Specifically, we analyzed the methylation status of the mtDNA regulatory D-loop region and mtDNA copy number in blood-derived DNA samples from 75 participants who we followed longitudinally over eight years. Subjects were classified into four groups according to clinical progression from healthy cognition to mild cognitive impairment (MCI) and AD. Using a linear mixed-effects model, we observed significant differences in methylation dynamics and mtDNA copy number across groups and time points. Healthy controls showed a progressive increase in D-loop methylation, whereas individuals converting to AD exhibited a marked decrease in its level. An opposite trend was evidenced for mtDNA copy number. These findings suggest that reduced D-loop methylation and increased mtDNA are associated with mitochondrial dysfunction and disease progression, whereas increased methylation may represent a possible protective mechanism.<\/jats:p>","DOI":"10.3390\/ijms27031477","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T12:49:44Z","timestamp":1770036584000},"page":"1477","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Longitudinal Analysis of Mitochondrial D-Loop Methylation and Copy Number in Peripheral Blood: Epigenetic Signatures of Alzheimer\u2019s Disease Progression and Aging"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5799-7732","authenticated-orcid":false,"given":"Bartolo","family":"Rizzo","sequence":"first","affiliation":[{"name":"Golgi Cenci Foundation, 20081 Abbiategrasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1532-0002","authenticated-orcid":false,"given":"Michele","family":"Rossi","sequence":"additional","affiliation":[{"name":"Golgi Cenci Foundation, 20081 Abbiategrasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7314-5046","authenticated-orcid":false,"given":"Riccardo Rocco","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Golgi Cenci Foundation, 20081 Abbiategrasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Pellegrini","sequence":"additional","affiliation":[{"name":"Golgi Cenci Foundation, 20081 Abbiategrasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7608-3306","authenticated-orcid":false,"given":"Francesca","family":"Dragoni","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7834-0342","authenticated-orcid":false,"given":"Rosalinda","family":"Di Gerlando","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2689-1592","authenticated-orcid":false,"given":"Evelyne","family":"Minucchi","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3954-5932","authenticated-orcid":false,"given":"Antonio","family":"Guaita","sequence":"additional","affiliation":[{"name":"Golgi Cenci Foundation, 20081 Abbiategrasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8463-6879","authenticated-orcid":false,"given":"Tino Emanuele","family":"Poloni","sequence":"additional","affiliation":[{"name":"Golgi Cenci Foundation, 20081 Abbiategrasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6589-6907","authenticated-orcid":false,"given":"Stella","family":"Gagliardi","sequence":"additional","affiliation":[{"name":"IRCCS Mondino Foundation, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5597-7586","authenticated-orcid":false,"given":"Annalisa","family":"Davin","sequence":"additional","affiliation":[{"name":"Golgi Cenci Foundation, 20081 Abbiategrasso, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s disease","volume":"397","author":"Scheltens","year":"2021","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"112001","DOI":"10.1016\/j.mad.2024.112001","article-title":"Convergence between brain aging and Alzheimer\u2019s disease: Focus on mitochondria","volume":"222","author":"Vaiasicca","year":"2024","journal-title":"Mech. 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