{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T05:56:48Z","timestamp":1793426208501,"version":"4.5.0"},"posted":{"date-parts":[[2026,7,11]]},"group-title":"Neuroscience","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T00:00:00Z","timestamp":1783728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Frontotemporal lobar degeneration (FTLD) and Alzheimer\u2019s disease (AD) differ in their clinical features and genetic etiologies but share progressive cognitive decline. Emerging evidence implicates lipid dysregulation in neurodegeneration, but its extent across FTLD subtypes and how it compares to AD are unclear. Here, we performed integrated lipidomic and proteomic analyses of matched frontal (disease-vulnerable) and occipital (relatively spared) post-mortem cortices from individuals with genetic and sporadic FTLD-TDP, FTLD-tau (Pick\u2019s disease, PiD), AD, and controls. FTLD and AD exhibited convergent lipid alterations, including reduced levels of cardiolipins and phosphatidylethanolamines, alongside increased gangliosides, diacylglycerols, cholesterol esters, acylcarnitines, and coenzyme Q, with generally greater changes in FTLD frontal cortex. FTLD displayed additional alterations, including reductions in bis(monoacylglycerol)phosphate, ceramides, phosphatidylserines, phosphatidylinositols, and sulfatides. These lipid changes were accompanied by proteomic alterations involving lysosomal proteins, phospholipases, phospholipid remodeling enzymes, and fatty acid oxidation pathways. Although lipidomic and proteomic signatures were broadly shared across FTLD subtypes,\n                  <jats:italic>GRN<\/jats:italic>\n                  associated FTLD-TDP and PiD showed the most extensive alterations. Triglycerides were selectively reduced in PiD in association with decreased DGAT1 expression, whereas cholesterol esters were elevated across all subtypes except\n                  <jats:italic>C9orf72<\/jats:italic>\n                  associated FTLD-TDP. These findings identify shared disruptions in lipid homeostasis and lysosomal lipid metabolism across FTLD and AD, highlighting convergent metabolic pathways underlying neurodegeneration.\n                <\/jats:p>","DOI":"10.64898\/2026.07.11.737778","type":"posted-content","created":{"date-parts":[[2026,7,12]],"date-time":"2026-07-12T16:15:35Z","timestamp":1783872935000},"source":"Crossref","is-referenced-by-count":1,"title":["Shared lipidome and proteome signatures of frontotemporal lobar degeneration and Alzheimer\u2019s disease"],"prefix":"10.64898","author":[{"given":"Yohannes A.","family":"Ambaw","sequence":"first","affiliation":[{"name":"Cell Biology Program, Sloan Kettering Institute, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alissa L.","family":"Nana","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fein Memory and Aging Center, University of California San Francisco, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoning","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shubham","family":"Singh","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Sloan Kettering Institute, New York, New York, USA"},{"name":"Present address: Department of Pediatrics\/Neurology at Baylor College of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Monetti","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce L.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fein Memory and Aging Center, University of California San Francisco, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore E.","family":"Spina","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fein Memory and Aging Center, University of California San Francisco, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lea T.","family":"Grinberg","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William W.","family":"Seeley","sequence":"additional","affiliation":[{"name":"Department of Neurology, Fein Memory and Aging Center, University of California San Francisco, San Francisco, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias C.","family":"Walther","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Sloan Kettering Institute, New York, New York, USA"},{"name":"Howard Hughes Medical Institute, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Robert V.","family":"Farese","sequence":"additional","affiliation":[{"name":"Cell Biology Program, Sloan Kettering Institute, New York, New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026071505052852000_2026.07.11.737778v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30394-1"},{"key":"2026071505052852000_2026.07.11.737778v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)00461-4"},{"key":"2026071505052852000_2026.07.11.737778v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(21)00341-0"},{"key":"2026071505052852000_2026.07.11.737778v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nature05016"},{"key":"2026071505052852000_2026.07.11.737778v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.09.011"},{"key":"2026071505052852000_2026.07.11.737778v1.6","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-019-09363-4"},{"issue":"1","key":"2026071505052852000_2026.07.11.737778v1.7","doi-asserted-by":"crossref","first-page":"46263","DOI":"10.1038\/srep46263","article-title":"Distinct subtypes of Alzheimer\u2019s 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