{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T16:59:43Z","timestamp":1790009983532,"version":"4.0.1"},"reference-count":111,"publisher":"SAGE Publications","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAD"],"published-print":{"date-parts":[[2024,4,16]]},"abstract":"<jats:p>Background: Although sporadic Alzheimer\u2019s disease (AD) is a neurodegenerative disorder of unknown etiology, familial AD is associated with specific gene mutations. A commonality between these forms of AD is that both display multiple pathogenic events including cholinergic and lipid dysregulation. Objective: We aimed to identify the relevant lipids and the activity of their related receptors in the frontal cortex and correlating them with cognition during the progression of AD. Methods: MALDI-mass spectrometry imaging (MSI) and functional autoradiography was used to evaluate the distribution of phospholipids\/sphingolipids and the activity of cannabinoid 1 (CB1), sphingosine 1-phosphate 1 (S1P1), and muscarinic M2\/M4 receptors in the frontal cortex (FC) of people that come to autopsy with premortem clinical diagnosis of AD, mild cognitive impairment (MCI), and no cognitive impairment (NCI). Results: MALDI-MSI revealed an increase in myelin-related lipids, such as diacylglycerol (DG) 36:1, DG 38:5, and phosphatidic acid (PA) 40:6 in the white matter (WM) in MCI compared to NCI, and a downregulation of WM phosphatidylinositol (PI) 38:4 and PI 38:5 levels in AD compared to NCI. Elevated levels of phosphatidylcholine (PC) 32:1, PC 34:0, and sphingomyelin 38:1 were observed in discrete lipid accumulations in the FC supragranular layers during disease progression. Muscarinic M2\/M4 receptor activation in layers V-VI decreased in AD compared to MCI. CB1 receptor activity was upregulated in layers V-VI, while S1P1 was downregulated within WM in AD relative to NCI. Conclusions: FC WM lipidomic alterations are associated with myelin dyshomeostasis in prodromal AD, suggesting WM lipid maintenance as a potential therapeutic target for dementia.<\/jats:p>","DOI":"10.3233\/jad-231485","type":"journal-article","created":{"date-parts":[[2024,4,2]],"date-time":"2024-04-02T14:02:49Z","timestamp":1712066569000},"page":"1515-1532","source":"Crossref","is-referenced-by-count":20,"title":["Frontal Cortex Lipid Alterations During the Onset of Alzheimer\u2019s Disease"],"prefix":"10.1177","volume":"98","author":[{"given":"Marta","family":"Moreno-Rodriguez","sequence":"first","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvia E.","family":"Perez","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonatan","family":"Martinez-Gardeazabal","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country, Leioa, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Manuel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine and Nursing, University of the Basque Country, Leioa, Spain"},{"name":"Neurodegenerative Diseases, BioBizkaia Health Research Institute, Barakaldo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Malek-Ahmadi","sequence":"additional","affiliation":[{"name":"Banner Alzheimer\u2019s Institute, Phoenix, AZ, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Rodriguez-Puertas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine 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