{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T19:44:40Z","timestamp":1785527080883,"version":"3.56.0"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":60,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"publisher","award":["PID2023-152593OB-I00 funded by MCIU\/AEI\/ 10.13039\/501100011033 \/ FEDER"],"award-info":[{"award-number":["PID2023-152593OB-I00 funded by MCIU\/AEI\/ 10.13039\/501100011033 \/ FEDER"]}],"id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017266","name":"Gobierno de Navarra","doi-asserted-by":"publisher","award":["0011-1411-2023-000028"],"award-info":[{"award-number":["0011-1411-2023-000028"]}],"id":[{"id":"10.13039\/501100017266","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Biol Sex Differ"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The amygdala is involved in the emotional expression, memory processing and managing stimulatory input. Although amygdala atrophy is early evidenced in Alzheimer\u2019s Disease (AD), the molecular mechanisms disrupted in initial neuropathological stages are still unknown. In the present study, we investigated the proteomic impairment of the amygdaloid region from AD-Braak stage I-II and III-IV subjects to better understand the neuropathological processes occurred early in this area and to identify potential targets that may face AD from the beginning of the disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Label-free quantitative proteomics was applied using an Orbitrap Exploris 480 mass-spectrometer in 24 postmortem amygdala specimens derived from non-demented (n\u2009=\u20093F\/5M), AD-Braak stage I-II (n\u2009=\u20094F\/4M) and AD-Braak stage III-IV (n\u2009=\u20094F\/4M). Data analysis was performed using MaxQuant and Perseus software (two-way Student T-test; p\u2009&lt;\u20090.05). Metascape and Ingenuity Pathway Analysis softwares were considered for biological interpretation. Connectivity map platform was used for drug repurposing analyses. Transcriptomic\/proteomic data of other brain regions were obtained from AlzData, Neuropro, and Agora repositories.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Amygdaloid proteome of AD-Braak stage I-II and III-IV subjects compared to controls revealed a progressive proteomic impairment with a minimal overlap across Braak stages. Some of the amygdaloid DEPs were known interactors of human A\u03b2 plaques, APP, or Tau proteins or were previously identified at transcriptional or translational level in other brain regions affected by AD. Interestingly, amygdaloid proteome was more severely affected in women than in men with a particular protein expression profile associated to each AD stage. Comparing our sex-dependent differential proteome datasets with transcriptomic data of different brain regions, we identified potential sex-specific proteins related to cognitive decline and neurodegeneration. Finally, data-driven drug repositioning using amygdaloid omics profiles unveiled that most of the small molecule candidates were neuropathological stage and\/or sex-specific.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Early and sex-specific amygdaloid proteome dysregulation in AD highlights the consideration of a deliberate stratification by sex in future research and clinical trials to develop effective therapeutic strategies in AD for both sexes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Plain english summary<\/jats:title>\n                    <jats:p>The amygdala is a brain region involved in the expression of emotions, memory processing and managing incoming stimulus. Atrophy of this area is evidenced at the first stages of Alzheimer\u2019s Disease (AD), pointing out a potential involvement of amygdala in the pathology of this disease. However, the molecular changes occurred early in this area are not fully understood. To this end, we interrogated the proteome of amygdala postmortem samples came from subjects of early AD stages. By applying data and functional analyses, we observed a stage-dependent and progressive proteomic impairment in this area. We detected proteins differentially expressed that were already known to interact with well-stablished neuropathological proteins or were altered in other brain areas. Importantly, data stratification by sex revealed that protein expression changes of amygdala were more abundant in women than men across AD progression. After comparing our results with published data in different brain regions affected by AD, we identified sex-specific proteins that could be used as biomarkers of cognitive decline and neurodegeneration. Finally, a drug repositioning-based approach proposed candidates with the potential to reverse amygdaloid malignant AD signature more effectively in one sex than in other or just in one sex. These observations highlight the consideration to include sex differences in future research to develop more precise and effective treatments in AD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13293-026-00930-9","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T02:56:43Z","timestamp":1780023403000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Early, sex-dependent and progressive proteomic imbalance in the amygdala during Alzheimer\u00b4s disease continuum"],"prefix":"10.1186","volume":"17","author":[{"given":"Silvia","family":"Romero-Murillo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"Lach\u00e9n-Montes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paz","family":"Cartas-Cejudo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Anaya-Cubero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"de Miguel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leire","family":"Extramiana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isidro","family":"Ferrer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaqu\u00edn","family":"Fern\u00e1ndez-Irigoyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"Santamar\u00eda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"930_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/brainsci10080502","author":"VN Nikolenko","year":"2020","unstructured":"Nikolenko VN, Oganesyan MV, Rizaeva NA, Kudryashova VA, Nikitina AT, Pavliv MP, et al. Neuroanatomical and morphophysiological features in terms of neurological and neurodegenerative diseases. Brain Sci. 2020. https:\/\/doi.org\/10.3390\/brainsci10080502.","journal-title":"Brain Sci"},{"key":"930_CR2","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1093\/jnen\/nlx099","volume":"77","author":"PT Nelson","year":"2018","unstructured":"Nelson PT, Abner EL, Patel E, Anderson S, Wilcock DM, Kryscio RJ, et al. The Amygdala as a locus of pathologic misfolding in neurodegenerative diseases. J Neuropathol Exp Neurol. 2018;77:2\u201320. https:\/\/doi.org\/10.1093\/jnen\/nlx099.","journal-title":"J Neuropathol Exp Neurol"},{"key":"930_CR3","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.pscychresns.2011.06.014","volume":"194","author":"SP Poulin","year":"2011","unstructured":"Poulin SP, Dautoff R, Morris JC, Barrett LF, Dickerson BC, Alzheimer\u2019s Disease Neuroimaging Initiative. Amygdala atrophy is prominent in early Alzheimer\u2019s disease and relates to symptom severity. Psychiatry Res. 2011;194:7\u201313. https:\/\/doi.org\/10.1016\/j.pscychresns.2011.06.014.","journal-title":"Psychiatry Res"},{"key":"930_CR4","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1016\/j.bbrc.2017.03.094","volume":"486","author":"C Guo","year":"2017","unstructured":"Guo C, Long B, Hu Y, Yuan J, Gong H, Li X. Early-stage reduction of the dendritic complexity in basolateral amygdala of a transgenic mouse model of Alzheimer\u2019s disease. Biochem Biophys Res Commun. 2017;486:679\u201385. https:\/\/doi.org\/10.1016\/j.bbrc.2017.03.094.","journal-title":"Biochem Biophys Res Commun"},{"key":"930_CR5","doi-asserted-by":"publisher","first-page":"951","DOI":"10.2174\/1567205012666151027124938","volume":"12","author":"T-W Lin","year":"2015","unstructured":"Lin T-W, Liu Y-F, Shih Y-H, Chen S-J, Huang T-Y, Chang C-Y, et al. Neurodegeneration in amygdala precedes hippocampus in the APPswe\/ PS1dE9 mouse model of Alzheimer\u2019s disease. Curr Alzheimer Res. 2015;12:951\u201363. https:\/\/doi.org\/10.2174\/1567205012666151027124938.","journal-title":"Curr Alzheimer Res"},{"key":"930_CR6","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-025-00874-5","volume":"20","author":"JM Yarbro","year":"2025","unstructured":"Yarbro JM, Shrestha HK, Wang Z, Zhang X, Zaman M, Chu M, et al. Proteomic landscape of Alzheimer\u2019s disease: emerging technologies, advances and insights (2021 - 2025). Mol Neurodegener. 2025;20:83. https:\/\/doi.org\/10.1186\/s13024-025-00874-5.","journal-title":"Mol Neurodegener"},{"key":"930_CR7","doi-asserted-by":"publisher","DOI":"10.1002\/pmic.202400298","author":"T Ryu","year":"2025","unstructured":"Ryu T, Kim K, Asiimwe N, Na CH. Proteomic insight into Alzheimer\u2019s disease pathogenesis pathways. Proteomics. 2025. https:\/\/doi.org\/10.1002\/pmic.202400298.","journal-title":"Proteomics"},{"key":"930_CR8","doi-asserted-by":"publisher","first-page":"6186","DOI":"10.1016\/j.cell.2025.08.038","volume":"188","author":"E Wang","year":"2025","unstructured":"Wang E, Yu K, Cao J, Wang M, Katsel P, Song W-M, et al. Multiscale proteomic modeling reveals protein networks driving Alzheimer\u2019s disease pathogenesis. Cell. 2025;188:6186-6204.e13. https:\/\/doi.org\/10.1016\/j.cell.2025.08.038.","journal-title":"Cell"},{"key":"930_CR9","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1002\/alz.13484","volume":"20","author":"JM Walker","year":"2024","unstructured":"Walker JM, Orr ME, Orr TC, Thorn EL, Christie TD, Yokoda RT, et al. Spatial proteomics of hippocampal subfield-specific pathology in Alzheimer\u2019s disease and primary age-related tauopathy. Alzheimers Dement. 2024;20:783\u201397. https:\/\/doi.org\/10.1002\/alz.13484.","journal-title":"Alzheimers Dement"},{"key":"930_CR10","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/s41593-021-00999-y","volume":"25","author":"ECB Johnson","year":"2022","unstructured":"Johnson ECB, Carter EK, Dammer EB, Duong DM, Gerasimov ES, Liu Y, et al. Large-scale deep multi-layer analysis of Alzheimer\u2019s disease brain reveals strong proteomic disease-related changes not observed at the RNA level. Nat Neurosci. 2022;25:213\u201325. https:\/\/doi.org\/10.1038\/s41593-021-00999-y.","journal-title":"Nat Neurosci"},{"key":"930_CR11","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s13293-023-00487-x","volume":"14","author":"P Cartas-Cejudo","year":"2023","unstructured":"Cartas-Cejudo P, Lach\u00e9n-Montes M, Ferrer I, Fern\u00e1ndez-Irigoyen J, Santamar\u00eda E. Sex-divergent effects on the NAD+-dependent deacetylase sirtuin signaling across the olfactory-entorhinal-amygdaloid axis in Alzheimer\u2019s and Parkinson\u2019s diseases. Biol Sex Differ. 2023;14:5. https:\/\/doi.org\/10.1186\/s13293-023-00487-x.","journal-title":"Biol Sex Differ"},{"key":"930_CR12","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.13252","volume":"34","author":"P Cartas-Cejudo","year":"2024","unstructured":"Cartas-Cejudo P, Cort\u00e9s A, Lach\u00e9n-Montes M, Anaya-Cubero E, Puerta E, Solas M, et al. Neuropathological stage-dependent proteome mapping of the olfactory tract in Alzheimer\u2019s disease: from early olfactory-related omics signatures to computational repurposing of drug candidates. Brain Pathol. 2024;34:e13252. https:\/\/doi.org\/10.1111\/bpa.13252.","journal-title":"Brain Pathol"},{"key":"930_CR13","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-09481-x","volume":"7","author":"M Lach\u00e9n-Montes","year":"2017","unstructured":"Lach\u00e9n-Montes M, Gonz\u00e1lez-Morales A, Zelaya MV, P\u00e9rez-Valderrama E, Aus\u00edn K, Ferrer I, et al. Olfactory bulb neuroproteomics reveals a chronological perturbation of survival routes and a disruption of prohibitin complex during Alzheimer\u2019s disease progression. Sci Rep. 2017;7:9115. https:\/\/doi.org\/10.1038\/s41598-017-09481-x.","journal-title":"Sci Rep"},{"key":"930_CR14","doi-asserted-by":"publisher","first-page":"80","DOI":"10.3389\/fncel.2014.00080","volume":"8","author":"J Fern\u00e1ndez-Irigoyen","year":"2014","unstructured":"Fern\u00e1ndez-Irigoyen J, Zelaya MV, Santamar\u00eda E. Applying mass spectrometry-based qualitative proteomics to human amygdaloid complex. Front Cell Neurosci. 2014;8:80. https:\/\/doi.org\/10.3389\/fncel.2014.00080.","journal-title":"Front Cell Neurosci"},{"key":"930_CR15","doi-asserted-by":"publisher","first-page":"1380","DOI":"10.1021\/acs.jproteome.9b00004","volume":"18","author":"J McKetney","year":"2019","unstructured":"McKetney J, Runde RM, Hebert AS, Salamat S, Roy S, Coon JJ. Proteomic atlas of the human brain in Alzheimer\u2019s disease. J Proteome Res. 2019;18:1380\u201391. https:\/\/doi.org\/10.1021\/acs.jproteome.9b00004.","journal-title":"J Proteome Res"},{"key":"930_CR16","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.13180","volume":"33","author":"M Gonzalez-Rodriguez","year":"2023","unstructured":"Gonzalez-Rodriguez M, Villar-Conde S, Astillero-Lopez V, Villanueva-Anguita P, Ubeda-Banon I, Flores-Cuadrado A, et al. Human amygdala involvement in Alzheimer\u2019s disease revealed by stereological and dia-PASEF analysis. Brain Pathol. 2023;33:e13180. https:\/\/doi.org\/10.1111\/bpa.13180.","journal-title":"Brain Pathol"},{"key":"930_CR17","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/nmeth.3901","volume":"13","author":"S Tyanova","year":"2016","unstructured":"Tyanova S, Temu T, Sinitcyn P, Carlson A, Hein MY, Geiger T, et al. The perseus computational platform for comprehensive analysis of (prote)omics data. Nat Methods. 2016;13:731\u201340. https:\/\/doi.org\/10.1038\/nmeth.3901.","journal-title":"Nat Methods"},{"key":"930_CR18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-019-09234-6","volume":"10","author":"Y Zhou","year":"2019","unstructured":"Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1\u201310. https:\/\/doi.org\/10.1038\/s41467-019-09234-6.","journal-title":"Nat Commun"},{"key":"930_CR19","doi-asserted-by":"publisher","first-page":"D672","DOI":"10.1093\/nar\/gkad1025","volume":"52","author":"M Milacic","year":"2024","unstructured":"Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. The Reactome pathway knowledgebase 2024. Nucleic Acids Res. 2024;52:D672\u20138. https:\/\/doi.org\/10.1093\/nar\/gkad1025.","journal-title":"Nucleic Acids Res"},{"key":"930_CR20","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1016\/j.cell.2017.10.049","volume":"171","author":"A Subramanian","year":"2017","unstructured":"Subramanian A, Narayan R, Corsello SM, Peck DD, Natoli TE, Lu X, et al. A next generation connectivity map: L1000 platform and the first 1,000,000 profiles. Cell. 2017;171:1437-1452.e17. https:\/\/doi.org\/10.1016\/j.cell.2017.10.049.","journal-title":"Cell"},{"key":"930_CR21","doi-asserted-by":"publisher","first-page":"1997","DOI":"10.4103\/NRR.NRR-D-24-00334","volume":"20","author":"P Cartas-Cejudo","year":"2025","unstructured":"Cartas-Cejudo P, Cort\u00e9s A, Lach\u00e9n-Montes M, Anaya-Cubero E, Fern\u00e1ndez-Irigoyen J, Santamar\u00eda E. Data-driven drug repositioning using olfactory omics profiles: challenges and perspectives in neurodegeneration. Neural Regen Res. 2025;20:1997\u20138. https:\/\/doi.org\/10.4103\/NRR.NRR-D-24-00334.","journal-title":"Neural Regen Res"},{"key":"930_CR22","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1093\/nsr\/nwy127","volume":"6","author":"D-F Zhang","year":"2019","unstructured":"Zhang D-F, Fan Y, Xu M, Wang G, Wang D, Li J, et al. Complement C7 is a novel risk gene for Alzheimer\u2019s disease in han chinese. Natl Sci Rev. 2019;6:257\u201374. https:\/\/doi.org\/10.1093\/nsr\/nwy127.","journal-title":"Natl Sci Rev"},{"key":"930_CR23","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.jalz.2017.08.012","volume":"14","author":"M Xu","year":"2018","unstructured":"Xu M, Zhang D, Luo R, Wu Y, Zhou H, Kong L, et al. A systematic integrated analysis of brain expression profiles reveals YAP1 and other prioritized hub genes as important upstream regulators in Alzheimer\u2019s disease. Alzheimer\u2019s & Dementia. 2018;14:215\u201329. https:\/\/doi.org\/10.1016\/j.jalz.2017.08.012.","journal-title":"Alzheimer\u2019s & Dementia"},{"key":"930_CR24","doi-asserted-by":"publisher","unstructured":"Askenazi M, Kavanagh T, Pires G, Ueberheide B, Wisniewski T, Drummond E. Compilation of all known protein changes in the human Alzheimer\u2019s disease brain 2023. https:\/\/doi.org\/10.1101\/2023.04.13.","DOI":"10.1101\/2023.04.13"},{"key":"930_CR25","doi-asserted-by":"publisher","DOI":"10.1002\/alz.089824","author":"JS Britton","year":"2024","unstructured":"Britton JS, Wiley JC, Beck J, Leal K, Yi L, Macdonald B, et al. Agora: an openly available web resource to enable exploration of nascent therapeutic targets for Alzheimer\u2019s disease. Alzheimers Dement. 2024. https:\/\/doi.org\/10.1002\/alz.089824.","journal-title":"Alzheimers Dement"},{"key":"930_CR26","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1007\/s00401-017-1691-0","volume":"133","author":"E Drummond","year":"2017","unstructured":"Drummond E, Nayak S, Faustin A, Pires G, Hickman RA, Askenazi M, et al. Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer\u2019s disease. Acta Neuropathol. 2017;133:933\u201354. https:\/\/doi.org\/10.1007\/s00401-017-1691-0.","journal-title":"Acta Neuropathol"},{"key":"930_CR27","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1002\/pro.3978","volume":"30","author":"R Oughtred","year":"2021","unstructured":"Oughtred R, Rust J, Chang C, Breitkreutz B, Stark C, Willems A, et al. The BioGRID database: a comprehensive biomedical resource of curated protein, genetic, and chemical interactions. Protein Sci. 2021;30:187\u2013200. https:\/\/doi.org\/10.1002\/pro.3978.","journal-title":"Protein Sci"},{"key":"930_CR28","doi-asserted-by":"publisher","first-page":"2583","DOI":"10.1111\/j.1582-4934.","volume":"16","author":"Y Chen","year":"2012","unstructured":"Chen Y, Neve RL, Liu H. Neddylation dysfunction in Alzheimer\u2019s disease. J Cell Mol Med. 2012;16:2583\u201391. https:\/\/doi.org\/10.1111\/j.1582-4934.","journal-title":"J Cell Mol Med"},{"key":"930_CR29","doi-asserted-by":"publisher","DOI":"10.1186\/s40035-021-00277-8","volume":"11","author":"AD Confettura","year":"2022","unstructured":"Confettura AD, Cuboni E, Ammar MR, Jia S, Gomes GM, Yuanxiang P, et al. Neddylation-dependent protein degradation is a nexus between synaptic insulin resistance, neuroinflammation and Alzheimer\u2019s disease. Transl Neurodegener. 2022;11:2. https:\/\/doi.org\/10.1186\/s40035-021-00277-8.","journal-title":"Transl Neurodegener"},{"key":"930_CR30","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1016\/j.stem.2024.06.001","volume":"31","author":"N Saurat","year":"2024","unstructured":"Saurat N, Minotti AP, Rahman MT, Sikder T, Zhang C, Cornacchia D, et al. Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration. Cell Stem Cell. 2024;31:1162-1174.e8. https:\/\/doi.org\/10.1016\/j.stem.2024.06.001.","journal-title":"Cell Stem Cell"},{"key":"930_CR31","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23126747","author":"B Tu-Sekine","year":"2022","unstructured":"Tu-Sekine B, Kim SF. The inositol phosphate system-a coordinator of metabolic adaptability. Int J Mol Sci. 2022. https:\/\/doi.org\/10.3390\/ijms23126747.","journal-title":"Int J Mol Sci"},{"key":"930_CR32","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1038\/s41593-024-01664-w","volume":"27","author":"Y Huang","year":"2024","unstructured":"Huang Y, Wang M, Ni H, Zhang J, Li A, Hu B, et al. Regulation of cell distancing in peri-plaque glial nets by Plexin-B1 affects glial activation and amyloid compaction in Alzheimer\u2019s disease. Nat Neurosci. 2024;27:1489\u2013504. https:\/\/doi.org\/10.1038\/s41593-024-01664-w.","journal-title":"Nat Neurosci"},{"key":"930_CR33","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1111\/febs.14712","volume":"286","author":"P S\u00e1nchez-Mart\u00edn","year":"2019","unstructured":"S\u00e1nchez-Mart\u00edn P, Saito T, Komatsu M. p62\/SQSTM1: \u201cJack of all trades\u201d in health and cancer. FEBS J. 2019;286:8\u201323. https:\/\/doi.org\/10.1111\/febs.14712.","journal-title":"FEBS J"},{"key":"930_CR34","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000210152","author":"JD Grill","year":"2025","unstructured":"Grill JD, Tam S, Thai G, Vides B, Pierce AL, Green K, et al. Phase 2A proof-of-concept double-blind, randomized, placebo-controlled trial of nicotinamide in early Alzheimer disease. Neurology. 2025. https:\/\/doi.org\/10.1212\/WNL.0000000000210152.","journal-title":"Neurology"},{"key":"930_CR35","doi-asserted-by":"publisher","first-page":"19331","DOI":"10.1074\/jbc.M110.197707","volume":"286","author":"S Thompson","year":"2011","unstructured":"Thompson S, Pearson AN, Ashley MD, Jessick V, Murphy BM, Gafken P, et al. Identification of a novel Bcl-2-interacting mediator of cell death (Bim) E3 ligase, tripartite motif-containing protein 2 (TRIM2), and its role in rapid ischemic tolerance-induced neuroprotection. J Biol Chem. 2011;286:19331\u20139. https:\/\/doi.org\/10.1074\/jbc.M110.197707.","journal-title":"J Biol Chem"},{"key":"930_CR36","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2019.104509","volume":"130","author":"CF Mendon\u00e7a","year":"2019","unstructured":"Mendon\u00e7a CF, Kuras M, Nogueira FCS, Pl\u00e1 I, Hortob\u00e1gyi T, Csiba L, et al. Proteomic signatures of brain regions affected by tau pathology in early and late stages of Alzheimer\u2019s disease. Neurobiol Dis. 2019;130:104509. https:\/\/doi.org\/10.1016\/j.nbd.2019.104509.","journal-title":"Neurobiol Dis"},{"key":"930_CR37","doi-asserted-by":"publisher","first-page":"1966","DOI":"10.1002\/alz.12362","volume":"17","author":"KB Rajan","year":"2021","unstructured":"Rajan KB, Weuve J, Barnes LL, McAninch EA, Wilson RS, Evans DA. Population estimate of people with clinical Alzheimer\u2019s disease and mild cognitive impairment in the United States (2020-2060). Alzheimers Dement. 2021;17:1966\u201375. https:\/\/doi.org\/10.1002\/alz.12362.","journal-title":"Alzheimers Dement"},{"key":"930_CR38","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1016\/j.neuron.2024.01.024","volume":"112","author":"C Lopez-Lee","year":"2024","unstructured":"Lopez-Lee C, Torres ERS, Carling G, Gan L. Mechanisms of sex differences in Alzheimer\u2019s disease. Neuron. 2024;112:1208\u201321. https:\/\/doi.org\/10.1016\/j.neuron.2024.01.024.","journal-title":"Neuron"},{"key":"930_CR39","doi-asserted-by":"publisher","first-page":"37","DOI":"10.2147\/CLEP.S37929","volume":"6","author":"MM Mielke","year":"2014","unstructured":"Mielke MM, Vemuri P, Rocca WA. Clinical epidemiology of Alzheimer\u2019s disease: assessing sex and gender differences. Clin Epidemiol. 2014;6:37\u201348. https:\/\/doi.org\/10.2147\/CLEP.S37929.","journal-title":"Clin Epidemiol"},{"key":"930_CR40","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1007\/s00401-018-1920-1","volume":"136","author":"S Oveisgharan","year":"2018","unstructured":"Oveisgharan S, Arvanitakis Z, Yu L, Farfel J, Schneider JA, Bennett DA. Sex differences in Alzheimer\u2019s disease and common neuropathologies of aging. Acta Neuropathol. 2018;136:887\u2013900. https:\/\/doi.org\/10.1007\/s00401-018-1920-1.","journal-title":"Acta Neuropathol"},{"key":"930_CR41","doi-asserted-by":"publisher","DOI":"10.1186\/s13293-020-00310-x","author":"EE Sundermann","year":"2020","unstructured":"Sundermann EE, Panizzon MS, Chen X, Andrews M, Galasko D, Banks SJ. Alzheimer\u2019s Disease Neuroimaging Initiative. Sex differences in Alzheimer\u2019s-related Tau biomarkers and a mediating effect of testosterone Biol Sex Differ. 2020. https:\/\/doi.org\/10.1186\/s13293-020-00310-x.","journal-title":"Sex differences in Alzheimer\u2019s-related Tau biomarkers and a mediating effect of testosterone. Biol Sex Differ"},{"key":"930_CR42","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1038\/s41586-022-04463-0","volume":"603","author":"J Xiong","year":"2022","unstructured":"Xiong J, Kang SS, Wang Z, Liu X, Kuo T-C, Korkmaz F, et al. FSH blockade improves cognition in mice with Alzheimer\u2019s disease. Nature. 2022;603:470\u20136. https:\/\/doi.org\/10.1038\/s41586-022-04463-0.","journal-title":"Nature"},{"key":"930_CR43","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaz5677","author":"EJ Davis","year":"2020","unstructured":"Davis EJ, Broestl L, Abdulai-Saiku S, Worden K, Bonham LW, Mi\u00f1ones-Moyano E, et al. A second X chromosome contributes to resilience in a mouse model of Alzheimer\u2019s disease. Sci Transl Med. 2020. https:\/\/doi.org\/10.1126\/scitranslmed.aaz5677.","journal-title":"Sci Transl Med"},{"key":"930_CR44","doi-asserted-by":"publisher","first-page":"3913","DOI":"10.1016\/j.cell.2022.09.002","volume":"185","author":"Y Yan","year":"2022","unstructured":"Yan Y, Wang X, Chaput D, Shin M-K, Koh Y, Gan L, et al. X-linked ubiquitin-specific peptidase 11 increases tauopathy vulnerability in women. Cell. 2022;185:3913-3930.e19. https:\/\/doi.org\/10.1016\/j.cell.2022.09.002.","journal-title":"Cell"},{"key":"930_CR45","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s13195-023-01162-4","volume":"15","author":"A Strefeler","year":"2023","unstructured":"Strefeler A, Jan M, Quadroni M, Teav T, Rosenberg N, Chatton J-Y, et al. Molecular insights into sex-specific metabolic alterations in Alzheimer\u2019s mouse brain using multi-omics approach. Alzheimers Res Ther. 2023;15:8. https:\/\/doi.org\/10.1186\/s13195-023-01162-4.","journal-title":"Alzheimers Res Ther"},{"key":"930_CR46","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s13293-024-00588-1","volume":"15","author":"J Llera-Oyola","year":"2024","unstructured":"Llera-Oyola J, Carceller H, Andreu Z, Hidalgo MR, Soler-S\u00e1ez I, Gordillo F, et al. The role of microRNAs in understanding sex-based differences in Alzheimer\u2019s disease. Biol Sex Differ. 2024;15:13. https:\/\/doi.org\/10.1186\/s13293-024-00588-1.","journal-title":"Biol Sex Differ"},{"key":"930_CR47","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.13318","volume":"35","author":"H Wen","year":"2025","unstructured":"Wen H, He Y, Tang Y, Zhu L, Tao Q, Jin B, et al. Altered immune response is associated with sex difference in vulnerability to Alzheimer\u2019s disease in human prefrontal cortex. Brain Pathol. 2025;35:e13318. https:\/\/doi.org\/10.1111\/bpa.13318.","journal-title":"Brain Pathol"},{"key":"930_CR48","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s13024-023-00624-5","volume":"18","author":"L Guo","year":"2023","unstructured":"Guo L, Cao J, Hou J, Li Y, Huang M, Zhu L, et al. Sex specific molecular networks and key drivers of Alzheimer\u2019s disease. Mol Neurodegener. 2023;18:39. https:\/\/doi.org\/10.1186\/s13024-023-00624-5.","journal-title":"Mol Neurodegener"},{"key":"930_CR49","doi-asserted-by":"publisher","first-page":"5621","DOI":"10.1038\/s41467-025-60746-w","volume":"16","author":"Y Su","year":"2025","unstructured":"Su Y, Li H, Zhang W, Tao S, Wang Q, Zhang X, et al. Connexin43 hemichannel blockade turns microglia neuroprotective and mitigates cognitive deficits in a mouse model of amyloidosis. Nat Commun. 2025;16:5621. https:\/\/doi.org\/10.1038\/s41467-025-60746-w.","journal-title":"Nat Commun"},{"key":"930_CR50","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.neuint.2013.10.013","volume":"64","author":"MGK Tan","year":"2014","unstructured":"Tan MGK, Lee C, Lee JH, Francis PT, Williams RJ, Ram\u00edrez MJ, et al. Decreased rabphilin 3A immunoreactivity in Alzheimer\u2019s disease is associated with A\u03b2 burden. Neurochem Int. 2014;64:29\u201336. https:\/\/doi.org\/10.1016\/j.neuint.2013.10.013.","journal-title":"Neurochem Int"},{"key":"930_CR51","doi-asserted-by":"publisher","first-page":"5516","DOI":"10.1016\/j.cell.2025.06.035","volume":"188","author":"Y Li","year":"2025","unstructured":"Li Y, Pereda Serras C, Blumenfeld J, Xie M, Hao Y, Deng E, et al. Cell-type-directed network-correcting combination therapy for Alzheimer\u2019s disease. Cell. 2025;188:5516-5534.e18. https:\/\/doi.org\/10.1016\/j.cell.2025.06.035.","journal-title":"Cell"},{"key":"930_CR52","doi-asserted-by":"publisher","DOI":"10.1002\/trc2.70098","author":"JL Cummings","year":"2025","unstructured":"Cummings JL, Zhou Y, Lee G, Zhong K, Fonseca J, Leisgang\u2010Osse AM, et al. Alzheimer\u2019s disease drug development pipeline: 2025. Alzheimers Dement Transl Res Clin Interv. 2025. https:\/\/doi.org\/10.1002\/trc2.70098.","journal-title":"Alzheimers Dement Transl Res Clin Interv"},{"key":"930_CR53","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1038\/s41573-025-01164-x","volume":"24","author":"Z Tanoli","year":"2025","unstructured":"Tanoli Z, Fern\u00e1ndez-Torras A, \u00d6zcan UO, Kushnir A, Nader KM, Gadiya Y, et al. Computational drug repurposing: approaches, evaluation of in silico resources and case studies. Nat Rev Drug Discov. 2025;24:521\u201342. https:\/\/doi.org\/10.1038\/s41573-025-01164-x.","journal-title":"Nat Rev Drug Discov"},{"key":"930_CR54","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.canlet.2008.12.026","volume":"280","author":"S Thomas","year":"2009","unstructured":"Thomas S, Munster PN. Histone deacetylase inhibitor induced modulation of anti-estrogen therapy. Cancer Lett. 2009;280:184\u201391. https:\/\/doi.org\/10.1016\/j.canlet.2008.12.026.","journal-title":"Cancer Lett"},{"key":"930_CR55","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1056\/NEJMoa2212948","volume":"388","author":"CH van Dyck","year":"2023","unstructured":"van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in early Alzheimer\u2019s disease. N Engl J Med. 2023;388:9\u201321. https:\/\/doi.org\/10.1056\/NEJMoa2212948.","journal-title":"N Engl J Med"},{"key":"930_CR56","doi-asserted-by":"publisher","DOI":"10.1038\/s44222-025-00355-w","author":"L Castro-Aldrete","year":"2025","unstructured":"Castro-Aldrete L, Einsiedler M, Cun\u00ed-L\u00f3pez C, Vanhaelen Q, Silvestri A, Ferretti MT, et al. Modelling sex differences of neurological disorders in vitro. Nat Rev Bioeng. 2025. https:\/\/doi.org\/10.1038\/s44222-025-00355-w.","journal-title":"Nat Rev Bioeng"},{"key":"930_CR57","doi-asserted-by":"publisher","first-page":"D543","DOI":"10.1093\/nar\/gkae1011","volume":"53","author":"Y Perez-Riverol","year":"2025","unstructured":"Perez-Riverol Y, Bandla C, Kundu DJ, Kamatchinathan S, Bai J, Hewapathirana S, et al. The PRIDE database at 20 years: 2025 update. Nucleic Acids Res. 2025;53:D543\u201353. https:\/\/doi.org\/10.1093\/nar\/gkae1011.","journal-title":"Nucleic Acids Res"},{"key":"930_CR58","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/s41592-021-01168-6","volume":"18","author":"KM Bond","year":"2021","unstructured":"Bond KM, McCarthy MM, Rubin JB, Swanson KR. Molecular omics resources should require sex annotation: a call for action. Nat Methods. 2021;18:585\u20138. https:\/\/doi.org\/10.1038\/s41592-021-01168-6.","journal-title":"Nat Methods"},{"key":"930_CR59","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12859-015-0611-3","volume":"16","author":"H Heberle","year":"2015","unstructured":"Heberle H, Meirelles VG, da Silva FR, Telles GP, Minghim R. InteractiVenn: a web-based tool for the analysis of sets through venn diagrams. BMC Bioinformatics. 2015;16:1\u20137. https:\/\/doi.org\/10.1186\/s12859-015-0611-3.","journal-title":"BMC Bioinformatics"}],"container-title":["Biology of Sex Differences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13293-026-00930-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13293-026-00930-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13293-026-00930-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T18:08:35Z","timestamp":1785521315000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13293-026-00930-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,29]]},"references-count":59,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["930"],"URL":"https:\/\/doi.org\/10.1186\/s13293-026-00930-9","relation":{},"ISSN":["2042-6410"],"issn-type":[{"value":"2042-6410","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,29]]},"assertion":[{"value":"9 December 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 May 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"According to the Declaration of Helsinki, all assessments, postmortem evaluations, and experimental procedures were previously approved by the Clinical Ethics Committee of Navarra Health Service (study code: PI_2024\/3). According to the Spanish Law 14\/2007 of Biomedical Research, informed written consent from relatives of subjects included in this study.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All authors gave final approval of the manuscript and are accountable for all aspects of the work.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"139"}}