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While familial AD is caused by specific mutations, the sporadic disease is more common and appears to result from a complex chronic brain neuroinflammation with mitochondriopathies, inducing free radicals\u2019 accumulation. In aged brain, mutations in DNA and several unfolded proteins participate in a chronic amyloidosis response with a toxic effect on myelin sheath and axons, leading to cognitive deficits and dementia. \u0391\u03b2 peptides are the most frequent form of toxic amyloid oligomers. Accumulations of misfolded proteins during several years alters different metabolic mechanisms, induce chronic inflammatory and immune responses with toxic consequences on neuronal cells. Myelin composition and architecture may appear to be an early target for the toxic activity of A\u03b2 peptides and others hydrophobic misfolded proteins. In this work, we describe the possible role of early myelin alterations in the genesis of neuronal alterations and the onset of symptomatology. We propose that some pathophysiological and clinical forms of the disease may arise from structural and metabolic disorders in the processes of myelination\/demyelination of brain regions where the accumulation of non-functional toxic proteins is important. In these forms, the primacy of the deleterious role of amyloid peptides would be a matter of questioning and the initiating role of neuropathology would be primarily the fact of dysmyelination.<\/jats:p>","DOI":"10.1186\/s40478-023-01554-5","type":"journal-article","created":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T19:03:40Z","timestamp":1680289420000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":72,"title":["Myelin in Alzheimer\u2019s disease: culprit or bystander?"],"prefix":"10.1186","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1478-4806","authenticated-orcid":false,"given":"Michel","family":"Maitre","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3630-7242","authenticated-orcid":false,"given":"H\u00e9l\u00e8ne","family":"Jeltsch-David","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8678-0850","authenticated-orcid":false,"given":"Nwife Getrude","family":"Okechukwu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7580-8536","authenticated-orcid":false,"given":"Christian","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9970-8214","authenticated-orcid":false,"given":"Christine","family":"Patte-Mensah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4454-511X","authenticated-orcid":false,"given":"Ayikoe-Guy","family":"Mensah-Nyagan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,3,31]]},"reference":[{"key":"1554_CR1","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1186\/s13041-016-0272-9","volume":"9","author":"SS Adav","year":"2016","unstructured":"Adav SS, Sze SK (2016) Insight of brain degenerative protein modifications in the pathology of neurodegeneration and dementia by proteomic profiling. 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