{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T14:28:12Z","timestamp":1781188092141,"version":"3.54.1"},"reference-count":78,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2017,12,9]],"date-time":"2017-12-09T00:00:00Z","timestamp":1512777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) represents the most common form of dementia among older age subjects, and despite decades of studies, the underlying mechanisms remain unresolved. The definition of AD has changed over the past 100 years, and while early-onset AD is commonly related to genetic mutations, late-onset AD is more likely due to a gradual accumulation of age-related modifications. \u201cNormal brain aging\u201d and AD may represent different pathways of successful or failed capability to adapt brain structures and cerebral functions. Cellular senescence and age-related changes (ARCs) affecting the brain may be considered as biologic manifestations of increasing entropy, a measure of disorder. Late-onset AD may be regarded as the final effect of a reduced energy production, due to exhausted mitochondria, and an increased entropy in the brain. This unique trajectory enables a bioenergetics-centered strategy targeting disease-stage specific profile of brain metabolism for disease prevention and treatment.<\/jats:p>","DOI":"10.3390\/ijms18122672","type":"journal-article","created":{"date-parts":[[2017,12,11]],"date-time":"2017-12-11T12:26:37Z","timestamp":1512995197000},"page":"2672","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Of Energy and Entropy: The Ineluctable Impact of Aging in Old Age Dementia"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2134-1122","authenticated-orcid":false,"given":"Virginia","family":"Boccardi","sequence":"first","affiliation":[{"name":"Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Comanducci","sequence":"additional","affiliation":[{"name":"Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Baroni","sequence":"additional","affiliation":[{"name":"Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0729-5246","authenticated-orcid":false,"given":"Patrizia","family":"Mecocci","sequence":"additional","affiliation":[{"name":"Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"148","DOI":"10.3389\/fgene.2012.00148","article-title":"A new definition of aging?","volume":"3","author":"Flatt","year":"2012","journal-title":"Front. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/nrn1323","article-title":"Insights into the aging mind: A view from cognitive neuroscience","volume":"5","author":"Hedden","year":"2004","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.ncl.2017.01.006","article-title":"Late-Onset Alzheimer Disease","volume":"35","author":"Pierce","year":"2017","journal-title":"Neurol. Clin."},{"key":"ref_4","first-page":"33","article-title":"Epidemiology of cognitive aging in the oldest old","volume":"68","author":"Giulioli","year":"2016","journal-title":"Rev. Investig. Clin."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1002\/ana.21915","article-title":"Incidence continues to increase with age in the oldest old: The 90+ study","volume":"67","author":"Corrada","year":"2010","journal-title":"Ann. Neurol."},{"key":"ref_6","unstructured":"(2017, July 15). National Institute of Aging, Available online: https:\/\/www.nia.nih.gov\/sites\/default\/files\/2017-06\/WPAM."},{"key":"ref_7","unstructured":"(2017, July 15). National Population Projections, Available online: http:\/\/www.census.gov\/population\/www\/projections\/summarytables.html."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1212\/WNL.0b013e31828726f5","article-title":"Alzheimer disease in the United States (2010\u20132050) estimated using the 2010 census","volume":"80","author":"Hebert","year":"2013","journal-title":"Neurology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1212\/WNL.44.9.1563","article-title":"If we live long enough, will we all be demented?","volume":"44","author":"Drachman","year":"1994","journal-title":"Neurology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1001\/archneur.1976.00500040001001","article-title":"The prevalence and malignancy of Alzheimer\u2019s disease: A major killer","volume":"3","author":"Katzman","year":"1976","journal-title":"Arch. Neurol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/nm0896-864","article-title":"Secreted amyloid \u03b2-protein similar to that in the senile plaques of Alzheimer\u2019s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer\u2019s disease","volume":"8","author":"Scheuner","year":"1996","journal-title":"Nat. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1212\/01.wnl.0000240127.89601.83","article-title":"Aging of the brain, entropy, and Alzheimer disease","volume":"67","author":"Drachman","year":"2006","journal-title":"Neurology"},{"key":"ref_13","first-page":"457","article-title":"Dementia in the oldest old","volume":"19","author":"Bullain","year":"2013","journal-title":"Continuum"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/alzrt181","article-title":"Dementia in the oldest old: A multi-factorial and growing public health issue","volume":"5","author":"Gardner","year":"2013","journal-title":"Alzheimers Res. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1111\/jgs.14224","article-title":"Sound body sound mind? Physical performance and the risk of dementia in the oldest-old: The 901 Study","volume":"4","author":"Bullain","year":"2016","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1001\/jama.1997.03550160069041","article-title":"Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: A meta analysis","volume":"278","author":"Farrer","year":"1997","journal-title":"JAMA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1111\/j.1532-5415.2009.02264.x","article-title":"The effect of age on the association between blood pressure and cognitive function later in life","volume":"57","author":"Euser","year":"2009","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"239","DOI":"10.3233\/JAD-160904","article-title":"Short-Term Response is not Predictive of Long-Term Response to Acetylcholinesterase Inhibitors in Old Age Subjects with Alzheimer\u2019s Disease: A \u201cReal World\u201d Study","volume":"56","author":"Boccardi","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"323","DOI":"10.3233\/JAD-161127","article-title":"Biomarkers for Early Diagnosis of Alzheimer\u2019s Disease in the Oldest Old: Yes or No?","volume":"58","author":"Paolacci","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.jalz.2011.03.004","article-title":"Introduction to the recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"Jack","year":"2011","journal-title":"Alzheimers Dement."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0197-4580(97)00056-0","article-title":"Frequency of stages of Alzheimer-related lesions in different age categories","volume":"18","author":"Braak","year":"1997","journal-title":"Neurobiol. Aging"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2302","DOI":"10.1056\/NEJMoa0806142","article-title":"Age, neuropathology, and dementia","volume":"360","author":"Savva","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.maturitas.2011.07.008","article-title":"Diagnosing dementia in the oldest-old","volume":"70","author":"Balasubramanian","year":"2011","journal-title":"Maturitas"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1002\/ana.23654","article-title":"Relation of neuropathology to cognition in persons without cognitive impairment","volume":"72","author":"Bennett","year":"2012","journal-title":"Ann. Neurol."},{"key":"ref_25","unstructured":"(2012). The 90+ study. Curr. Alzheimer Res., 9, 709\u2013717."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s13195-015-0104-7","article-title":"Clinical and imaging features of mixed Alzheimer and vascular pathologies","volume":"7","author":"Chui","year":"2015","journal-title":"Alzheimers Res. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1002\/ana.24125","article-title":"Mild to moderate Alzheimer dementia with insufficient neuropathological changes","volume":"75","author":"Qian","year":"2014","journal-title":"Ann. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/0197-4580(93)90096-T","article-title":"Beta A4 deposits are constant in the brain of the oldest old: An immunocytochemical study of 20 French centenarians","volume":"14","author":"Delaere","year":"1993","journal-title":"Neurobiol. Aging"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1097\/00005072-199612000-00004","article-title":"Distinct patterns of neuronal loss and Alzheimer\u2019s disease lesion distribution in elderly individuals older than 90 years","volume":"55","author":"Giannakopoulos","year":"1996","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/s00401-010-0654-5","article-title":"Prevalence of dementia disorders in the oldest-old: An autopsy study","volume":"119","author":"Jellinger","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1007\/s00401-011-0826-y","article-title":"Alzheimer\u2019s disease is not \u201cbrain aging\u201d: Neuropathological, genetic, and epidemiological human studies","volume":"121","author":"Nelson","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/nrneurol.2013.105","article-title":"Dementia in oldest old","volume":"9","author":"Yang","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1212\/WNL.58.11.1629","article-title":"Cerebral amyloid angiopathy and cognitive function: The HAAS autopsy study","volume":"58","author":"Pfeifer","year":"2002","journal-title":"Neurology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1097\/NEN.0b013e318232a379","article-title":"Stages of the pathologic process in Alzheimer disease: Age categories from 1 to100 years","volume":"70","author":"Braak","year":"2011","journal-title":"J Neuropathol Exp Neurol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"713","DOI":"10.3233\/JAD-2009-1178","article-title":"Brain lesions at autopsy in older Japanese\u2013American men as related to cognitive impairment and dementia in the final years of life: A summary report from the Honolulu\u2013Asia Aging Study","volume":"18","author":"White","year":"2009","journal-title":"J. Alzheimers Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1093\/jnen\/nlw002","article-title":"Altered proteins in the aging brain","volume":"75","author":"Elobeid","year":"2016","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. Med."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Velickaite, V., Giedraitis, V., Str\u00f6m, K., Alafuzoff, I., Zetterberg, H., Lannfelt, L., Kilander, L., Larsson, E.M., and Ingelsson, M. (2017). Cognitive function in very old men does not correlate to biomarkers of Alzheimer\u2019s disease. BMC Geriatr., 17.","DOI":"10.1186\/s12877-017-0601-6"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1126\/science.278.5337.412","article-title":"Life and death of neurons in the aging brain","volume":"278","author":"Morrison","year":"1997","journal-title":"Science"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.arr.2004.05.001","article-title":"Cognitive reserve and the neurobiology of cognitive aging","volume":"3","author":"Whalley","year":"2004","journal-title":"Ageing Res. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1212\/01.wnl.0000176053.98907.3f","article-title":"Dementia incidence may increase more slowly after age 90: Results from the Bronx Aging Study","volume":"65","author":"Hall","year":"2005","journal-title":"Neurology"},{"key":"ref_42","first-page":"1933","article-title":"Abnormal expression of the cell cycle regulators P16 and CDK4 in Alzheimer\u2019s disease","volume":"150","author":"McShea","year":"1997","journal-title":"Am. J. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/clpt.2012.193","article-title":"Senescent cells: A novel therapeutic target for aging and age-related diseases","volume":"93","author":"Naylor","year":"2013","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1007\/s10522-014-9532-1","article-title":"Are there roles for brain cell senescence in aging and neurodegenerative disorders?","volume":"15","author":"Tan","year":"2014","journal-title":"Biogerontology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1146\/annurev-pathol-121808-102144","article-title":"The senescence-associated secretory phenotype: The dark side of tumor suppression","volume":"5","author":"Desprez","year":"2010","journal-title":"Ann. Rev. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.arr.2015.04.003","article-title":"From cellular senescence to Alzheimer\u2019s disease: The role of telomere shortening","volume":"22","author":"Boccardi","year":"2015","journal-title":"Ageing Res. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1101\/gad.235184.113","article-title":"Cellular senescence and its effector programs","volume":"28","author":"Salama","year":"2014","journal-title":"Genes Dev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/978-1-62703-239-1_4","article-title":"Markers of cellular senescence","volume":"965","author":"Carnero","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1111\/j.1474-9726.2012.00870.x","article-title":"Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response","volume":"11","author":"Jurk","year":"2012","journal-title":"Aging Cell"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/978-3-662-05073-6_2","article-title":"Microglia and the Response to Brain Injury","volume":"39","author":"Streit","year":"2002","journal-title":"Neuroinflamm. Bench Bedside"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1016\/j.neurobiolaging.2007.04.013","article-title":"Neocortical glial cell numbers in human brains","volume":"29","author":"Pelvig","year":"2008","journal-title":"Neurobiol. Aging"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.neurobiolaging.2012.06.009","article-title":"Effect of age on neocortical brain cells in 90+ year old human females, a cell counting study","volume":"34","author":"Fabricius","year":"2013","journal-title":"Neurobiol. Aging"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1002\/ana.410420602","article-title":"Aging and the brain: A new frontier","volume":"42","author":"Drachman","year":"1997","journal-title":"Ann. Neurol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1001\/archneur.60.7.989","article-title":"A longitudinal study of brain volume changes in normal ageing using serial registered magnetic resonance imaging","volume":"60","author":"Scahill","year":"2003","journal-title":"Arch. Neurol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1016\/S0028-3932(03)00129-5","article-title":"Neuroanatomical correlates of selected executive functions in middle aged and older adults: A prospective MRI study","volume":"41","author":"Raz","year":"2003","journal-title":"Neuropsychologia"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1023\/A:1025731309829","article-title":"The effects of normal aging on myelin and nerve fibers: A review","volume":"31","author":"Peters","year":"2002","journal-title":"J. Neurocytol."},{"key":"ref_57","first-page":"4524","article-title":"The cell biology of aging","volume":"15","author":"Murphy","year":"2015","journal-title":"Mol. Biol. Cell."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/0047-6374(91)90006-L","article-title":"Aging as multistep process characterized by lowering of entropy production leading the cell to a sequence of defined stages","volume":"15","author":"Toussaint","year":"1991","journal-title":"Mech. Ageing Dev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/S0047-6374(02)00031-3","article-title":"Approach of evolutionary theories of ageing, stress, senescence-like phenotypes, calorie restriction and hormesis from the view point of far-from-equilibrium thermodynamics","volume":"30","author":"Toussaint","year":"2002","journal-title":"Mech. Ageing Dev."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/BF02153597","article-title":"Biologie et thermodynamique des phenomenes irr\u00e9versibles","volume":"2","author":"Prigogine","year":"1946","journal-title":"Experientia"},{"key":"ref_61","first-page":"322","article-title":"The Thermodynamics of the Steady State","volume":"29","author":"Denbeigh","year":"1951","journal-title":"J. Chem. Educ."},{"key":"ref_62","unstructured":"Navratil, V. (2017, July 15). Health, Ageing and Entropy. Available online: http:\/\/www.ped.muni.cz\/z21\/knihy\/2011\/39\/texty\/eng\/34_navratil_eng.pdf."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0022-5193(05)80333-9","article-title":"Entropy principle for human development, growth and aging","volume":"21","author":"Aoki","year":"1991","journal-title":"J. Theor. Biol."},{"key":"ref_64","unstructured":"Alberts, B., Johnson, A., and Lewis, J. (2002). Catalysis and the Use of Energy by Cells. Molecular Biology of the Cell, Garland Science."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1002\/pmic.201400277","article-title":"Proteomic analysis and functional characterization of mouse brain mitochondria during aging reveal alterations in energy metabolism","volume":"15","author":"Stauch","year":"2015","journal-title":"Proteomics"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1542\/pedsv47is1fullF","article-title":"Metabolic rate and organ size during growth from infancy to maturity and during late gastation and early infancy","volume":"47","author":"Holliday","year":"1971","journal-title":"Pediatrics"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1023\/A:1022534709672","article-title":"Energetics of functional activation in neural tissues","volume":"24","author":"Sokoloff","year":"1999","journal-title":"Neurochem. Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/0006-8993(91)90926-M","article-title":"Glucose transport is reduced in the blood-brain barrier of aged rats","volume":"14","author":"Mooradian","year":"1991","journal-title":"Brain Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1172\/JCI105650","article-title":"Brain Metabolism during Fasting","volume":"46","author":"Owen","year":"1967","journal-title":"J. Clin. Investig."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.nut.2010.07.021","article-title":"Brain fuel metabolism, aging, and Alzheimer\u2019s disease","volume":"27","author":"Cunnane","year":"2011","journal-title":"Nutrition"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.18632\/aging.101131","article-title":"Proteomic profiling of mitochondria: What does it tell us about the ageing brain?","volume":"8","author":"Ingram","year":"2016","journal-title":"Aging"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1006\/abbi.1999.1495","article-title":"Age-related changes in activities of mitochondrial electron transport complexes in various tissues of the mouse","volume":"1","author":"Kwong","year":"2000","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.freeradbiomed.2016.04.200","article-title":"Energy metabolism and inflammation in brain aging and Alzheimer\u2019s disease","volume":"100","author":"Yin","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"320","DOI":"10.18632\/aging.100657","article-title":"Aging synaptic mitochondria exhibit dynamic proteomic changes while maintaining bioenergetic function","volume":"6","author":"Stauch","year":"2014","journal-title":"Aging"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1002\/ana.410340416","article-title":"Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain","volume":"34","author":"Mecocci","year":"1993","journal-title":"Ann. Neurol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1002\/ana.410360510","article-title":"Oxidative damage to mitochondrial DNA is increased in Alzheimer\u2019s disease","volume":"36","author":"Mecocci","year":"1994","journal-title":"Ann. Neurol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.mehy.2003.12.045","article-title":"A \u201cmitochondrial cascade hypothesis\u201d for sporadic Alzheimer\u2019s disease","volume":"63","author":"Swerdlow","year":"2004","journal-title":"Med. Hypotheses"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1016\/j.bbadis.2011.08.012","article-title":"Brain aging, Alzheimer\u2019s disease, and mitochondria","volume":"1812","author":"Swerdlow","year":"2011","journal-title":"Biochim. Biophys. Acta"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/12\/2672\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:53:18Z","timestamp":1760208798000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/12\/2672"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12,9]]},"references-count":78,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["ijms18122672"],"URL":"https:\/\/doi.org\/10.3390\/ijms18122672","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,12,9]]}}}