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In the present study, samples of the entorhinal cortex (EC) and frontal cortex area 8 (FC) of cases with NFT pathology classified as stages I\u2013II, III\u2013IV, and V\u2013VI without comorbidities, and of middle\u2010aged (MA) individuals with no NFT pathology, were analyzed by conventional label\u2010free and SWATH\u2010MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) to assess the (phospho)proteomes. The total number of identified dysregulated phosphoproteins was 214 in the EC, 65 of which were dysregulated at the first stages (I\u2013II) of NFT pathology; 167 phosphoproteins were dysregulated in the FC, 81 of them at stages I\u2013II of NFT pathology. A large percentage of dysregulated phosphoproteins were identified in the two regions and at different stages of NFT progression. The main group of dysregulated phosphoproteins was made up of components of the membranes, cytoskeleton, synapses, proteins linked to membrane transport and ion channels, and kinases. The present results show abnormal phosphorylation of proteins at the first stages of NFT pathology in the elderly (in individuals clinically considered representative of normal aging) and sporadic Alzheimer's disease (sAD). Dysregulated protein phosphorylation in the FC precedes the formation of NFTs and SPs. The most active period of dysregulated phosphorylation is at stages III\u2013IV when a subpopulation of individuals might be clinically categorized as suffering from mild cognitive impairment which is a preceding determinant stage in the progression to dementia. Altered phosphorylation of selected proteins, carried out by activation of several kinases, may alter membrane and cytoskeletal functions, among them synaptic transmission and membrane\/cytoskeleton signaling. Besides their implications in sAD, the present observations suggest a molecular substrate for \u201cbenign\u201d cognitive deterioration in \u201cnormal\u201d brain aging.<\/jats:p>","DOI":"10.1111\/bpa.12996","type":"journal-article","created":{"date-parts":[[2021,7,4]],"date-time":"2021-07-04T08:51:56Z","timestamp":1625388716000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Dysregulated protein phosphorylation: A determining condition in the continuum of brain aging and Alzheimer's disease"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9888-8754","authenticated-orcid":false,"given":"Isidro","family":"Ferrer","sequence":"first","affiliation":[{"name":"Department of Pathology and Experimental Therapeutics University of Barcelona Hospitalet de Llobregat Spain"},{"name":"CIBERNED (Network Centre of Biomedical Research of Neurodegenerative Diseases) Institute of Health Carlos 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