{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T02:48:24Z","timestamp":1788230904452,"version":"build-2803163510"},"reference-count":83,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T00:00:00Z","timestamp":1732665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"P.A.L.\u2019s discretionary funds"},{"name":"Doctoral Dissertation Fellowship from the Graduate School Fellowship Office at the University of Minnesota"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Regarding Alzheimer\u2019s disease (AD), specific neuronal populations and brain regions exhibit selective vulnerability. Understanding the basis of this selective neuronal and regional vulnerability is essential to elucidate the molecular mechanisms underlying AD pathology. However, progress in this area is currently hindered by the incomplete understanding of the intricate functional and spatial diversity of neuronal subtypes in the human brain. Previous studies have demonstrated that neuronal subpopulations with high neuropeptide (NP) co-expression are disproportionately absent in the entorhinal cortex of AD brains at the single-cell level, and there is a significant decline in hippocampal NP expression in naturally aging human brains. Given the role of NPs in neuroprotection and the maintenance of microenvironments, we hypothesize that neurons expressing higher levels of NPs (HNP neurons) possess unique functional characteristics that predispose them to cellular abnormalities, which can manifest as degeneration in AD with aging. To test this hypothesis, multiscale and spatiotemporal transcriptome data from ~1900 human brain samples were analyzed using publicly available datasets. The results indicate that HNP neurons experienced greater metabolic burden and were more prone to protein misfolding. The observed decrease in neuronal abundance during stages associated with a higher risk of AD, coupled with the age-related decline in the expression of AD-associated neuropeptides (ADNPs), provides temporal evidence supporting the role of NPs in the progression of AD. Additionally, the localization of ADNP-producing HNP neurons in AD-associated brain regions provides neuroanatomical support for the concept that cellular\/neuronal composition is a key factor in regional AD vulnerability. This study offers novel insights into the molecular and cellular basis of selective neuronal and regional vulnerability to AD in human brains.<\/jats:p>","DOI":"10.3390\/biom14121518","type":"journal-article","created":{"date-parts":[[2024,11,27]],"date-time":"2024-11-27T08:17:42Z","timestamp":1732695462000},"page":"1518","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multifaceted Role of Specialized Neuropeptide-Intensive Neurons on the Selective Vulnerability to Alzheimer\u2019s Disease in the Human Brain"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3930-7117","authenticated-orcid":false,"given":"Manci","family":"Li","sequence":"first","affiliation":[{"name":"Department of Electrical and Computer Engineering, College of Science and Engineering, University of Minnesota, Minneapolis, MN 55455, USA"},{"name":"Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Flack","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA"},{"name":"Minnesota Center for Prion Research and Outreach, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3634-3625","authenticated-orcid":false,"given":"Peter A.","family":"Larsen","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA"},{"name":"Minnesota Center for Prion Research and Outreach, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,27]]},"reference":[{"key":"ref_1","first-page":"1598","article-title":"Alzheimer\u2019s disease facts and figures","volume":"19","author":"Better","year":"2023","journal-title":"Alzheimers Dement."},{"key":"ref_2","first-page":"a006189","article-title":"Neuropathological alterations in Alzheimer disease","volume":"1","author":"Frosch","year":"2011","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1002\/1097-0029(20001001)51:1<101::AID-JEMT11>3.0.CO;2-H","article-title":"Evaluating the function of hippocampal subregions with high-resolution MRI in Alzheimer\u2019s disease and aging","volume":"51","author":"Small","year":"2000","journal-title":"Microsc. Res. Tech."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1002\/ana.10086","article-title":"Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer\u2019s disease","volume":"51","author":"Mitchell","year":"2002","journal-title":"Ann. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"628","DOI":"10.2174\/156720512801322573","article-title":"Overview and findings from the religious orders study","volume":"9","author":"Bennett","year":"2012","journal-title":"Curr. Alzheimer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1016\/j.neuron.2012.03.004","article-title":"Predicting regional neurodegeneration from the healthy brain functional connectome","volume":"73","author":"Zhou","year":"2012","journal-title":"Neuron"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1038\/s41583-023-00731-8","article-title":"Connectome-based modelling of neurodegenerative diseases: Towards precision medicine and mechanistic insight","volume":"24","author":"Vogel","year":"2023","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1038\/s41593-018-0221-2","article-title":"Selective vulnerability in neurodegenerative diseases","volume":"21","author":"Fu","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.neuron.2011.06.031","article-title":"Selective neuronal vulnerability in neurodegenerative diseases: From stressor thresholds to degeneration","volume":"71","author":"Saxena","year":"2011","journal-title":"Neuron"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1016\/j.stemcr.2017.10.015","article-title":"Cell-type Dependent Alzheimer\u2019s Disease Phenotypes: Probing the Biology of Selective Neuronal Vulnerability","volume":"9","author":"Muratore","year":"2017","journal-title":"Stem Cell Rep."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Siletti, K., Hodge, R., Albiach, A.M., Lee, K.W., Ding, S.-L., Hu, L., L\u00f6nnerberg, P., Casper, T., Clark, M., and Dee, N. (2022). Transcriptomic diversity of cell types across the adult human brain. bioRxiv.","DOI":"10.1101\/2022.10.12.511898"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"R708","DOI":"10.1016\/S0960-9822(98)70454-3","article-title":"Neuronal diversity: Too many cell types for comfort?","volume":"8","author":"Stevens","year":"1998","journal-title":"Curr. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"R497","DOI":"10.1016\/j.cub.2004.06.035","article-title":"Neuronal cell types","volume":"14","author":"Masland","year":"2004","journal-title":"Curr. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1038\/nrn.2017.85","article-title":"Neuronal cell-type classification: Challenges, opportunities and the path forward","volume":"18","author":"Zeng","year":"2017","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.conb.2018.04.021","article-title":"Single cell transcriptomics in neuroscience: Cell classification and beyond","volume":"50","author":"Tasic","year":"2018","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e47889","DOI":"10.7554\/eLife.47889","article-title":"Single-cell transcriptomic evidence for dense intracortical neuropeptide networks","volume":"8","author":"Smith","year":"2019","journal-title":"eLife"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chen, X.Y., Du, Y.F., and Chen, L. (2018). Neuropeptides Exert Neuroprotective Effects in Alzheimer\u2019s Disease. Front. Mol. Neurosci., 11.","DOI":"10.3389\/fnmol.2018.00493"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3575","DOI":"10.1002\/alz.12979","article-title":"Single-cell sequencing of entorhinal cortex reveals widespread disruption of neuropeptide networks in Alzheimer\u2019s disease","volume":"19","author":"Li","year":"2023","journal-title":"Alzheimers Dement."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3942","DOI":"10.1038\/s41467-020-17405-z","article-title":"Multiscale causal networks identify VGF as a key regulator of Alzheimer\u2019s disease","volume":"11","author":"Beckmann","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4365","DOI":"10.1016\/j.cell.2023.08.039","article-title":"Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer\u2019s disease pathology","volume":"186","author":"Mathys","year":"2023","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/nrd.2017.178","article-title":"Trends in GPCR drug discovery: New agents, targets and indications","volume":"16","author":"Hauser","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1002\/biot.201200267","article-title":"Metabolic costs of amino acid and protein production in Escherichia coli","volume":"8","author":"Kaleta","year":"2013","journal-title":"Biotechnol. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"eabi9027","DOI":"10.1126\/sciadv.abi9027","article-title":"Synaptic vesicle pools are a major hidden resting metabolic burden of nerve terminals","volume":"7","author":"Pulido","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1038\/s41593-019-0539-4","article-title":"A single-cell atlas of entorhinal cortex from individuals with Alzheimer\u2019s disease reveals cell-type-specific gene expression regulation","volume":"22","author":"Grubman","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/s41593-020-00764-7","article-title":"Molecular characterization of selectively vulnerable neurons in Alzheimer\u2019s disease","volume":"24","author":"Leng","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref_27","unstructured":"Sage Bionetworks (2023, October 13). Synapse. Available online: https:\/\/www.synapse.org\/."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"GTEx Consortium (2020). The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science, 369, 1318\u20131330.","DOI":"10.1126\/science.aaz1776"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5803","DOI":"10.1038\/s41467-022-33509-0","article-title":"Tissue-specific impacts of aging and genetics on gene expression patterns in humans","volume":"13","author":"Yamamoto","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Guzzi, P.H., Lomoio, U., and Veltri, P. (2023). GTExVisualizer: A web platform for supporting ageing studies. Bioinformatics, 39.","DOI":"10.1093\/bioinformatics\/btad303"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"RP88623","DOI":"10.7554\/eLife.88623","article-title":"voyAGEr, a free web interface for the analysis of age-related gene expression alterations in human tissues","volume":"12","author":"Schneider","year":"2024","journal-title":"eLife"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nbt.4096","article-title":"Integrating single-cell transcriptomic data across different conditions, technologies, and species","volume":"36","author":"Butlet","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"CZI Single-Cell Biology Program, Abdulla, S., Aevermann, B., Assis, P., Badajoz, S., Bell, S.M., Bezzi, E., Cakir, B., Chaffer, J., and Chambers, S. (2023). CZ CELL \u00d7 GENE Discover: A single-cell data platform for scalable exploration, analysis and modeling of aggregated data. bioRxiv.","DOI":"10.1101\/2023.10.30.563174"},{"key":"ref_34","unstructured":"(2024, July 02). AD Knowledge Portal. Available online: https:\/\/adknowledgeportal.synapse.org\/Explore\/Studies\/DetailsPage\/StudyDetails?Study=syn52293417."},{"key":"ref_35","unstructured":"(2022, November 01). GTEx Portal. Available online: https:\/\/www.gtexportal.org."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1093\/bioinformatics\/btw726","article-title":"cerebroViz: An R package for anatomical visualization of spatiotemporal brain data","volume":"33","author":"Bahl","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1038\/s41467-021-21038-1","article-title":"A practical solution to pseudoreplication bias in single-cell studies","volume":"12","author":"Zimmerman","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING v11: Protein\u2013protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_39","unstructured":"Yu, G. (2024, November 20). enrichplot: Visualization of Functional Enrichment Result. R Package Version 1.26.2. Available online: https:\/\/yulab-smu.top\/biomedical-knowledge-mining-book\/."},{"key":"ref_40","unstructured":"Johnson, N.L., Kotz, S., and Kemp, A.W. (1992). Univariate Discrete Distributions, Wiley."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Tai, K.Y., Wong, K., Aghakhanian, F., Parhar, I.S., Dhaliwal, J., and Ayub, Q. (2020). Selected neuropeptide genes show genetic differentiation between Africans and non-Africans. BMC Genet., 21.","DOI":"10.1186\/s12863-020-0835-8"},{"key":"ref_42","first-page":"1","article-title":"Sexual and reproductive health of persons aged 10\u201324 years\u2014United States, 2002\u20132007","volume":"58","author":"Gavin","year":"2009","journal-title":"MMWR Surveill. Summ."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v094.i12","article-title":"PResiduals: An R Package for Residual Analysis Using Probability-Scale Residuals","volume":"94","author":"Liu","year":"2020","journal-title":"J. Stat. Softw."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Jorstad, N.L., Song, J.H.T., Exposito-Alonso, D., Suresh, H., Castro-Pacheco, N., Krienen, F.M., Yanny, A.M., Close, J., Gelfand, E., and Long, B. (2022). Comparative transcriptomics reveals human-specific cortical features. bioRxiv.","DOI":"10.1126\/science.ade9516"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1523\/ENEURO.0212-18.2018","article-title":"Systematic Analysis of Transmitter Coexpression Reveals Organizing Principles of Local Interneuron Heterogeneity","volume":"5","author":"Lizbinski","year":"2018","journal-title":"eNeuro"},{"key":"ref_47","unstructured":"(2024, June 20). ATP1B1 ATPase Na+\/K+ Transporting Subunit Beta 1 [Homo Sapiens (Human)]\u2014Gene\u2014NCBI, Available online: https:\/\/www.ncbi.nlm.nih.gov\/gene\/481."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2907","DOI":"10.1091\/mbc.12.10.2907","article-title":"Adaptins: The final recount","volume":"12","author":"Boehm","year":"2001","journal-title":"Mol. Biol. Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.neurobiolaging.2018.03.023","article-title":"High glucose forces a positive feedback loop connecting ErbB4 expression and mTOR\/S6K pathway to aggravate the formation of tau hyperphosphorylation in differentiated SH-SY5Y cells","volume":"67","author":"Nie","year":"2018","journal-title":"Neurobiol. Aging"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/s41398-023-02376-8","article-title":"HSV-1 cellular model reveals links between aggresome formation and early step of Alzheimer\u2019s disease","volume":"13","author":"Albaret","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1002\/cphg.105","article-title":"The AD Knowledge Portal: A Repository for Multi-Omic Data on Alzheimer\u2019s Disease and Aging","volume":"108","author":"Greenwood","year":"2020","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/BF02252964","article-title":"Volumes of hippocampus, amygdala and frontal lobes in the MRI-based diagnosis of early Alzheimer\u2019s disease: Correlation with memory functions","volume":"9","author":"Laakso","year":"1995","journal-title":"J. Neural Transm. Park. Dis. Dement. Sect."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Peters, A., and Morrison, J.H. (1999). Early Features of Alzheimer\u2019s Disease. Cerebral Cortex: Neurodegenerative and Age-Related Changes in Structure and Function of Cerebral Cortex, Springer.","DOI":"10.1007\/978-1-4615-4885-0"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1093\/cercor\/bhj105","article-title":"Differential regional atrophy of the cingulate gyrus in Alzheimer disease: A volumetric MRI study","volume":"16","author":"Jones","year":"2006","journal-title":"Cereb. Cortex"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1093\/brain\/awr020","article-title":"Unawareness of deficits in Alzheimer\u2019s disease: Role of the cingulate cortex","volume":"134","author":"Amanzio","year":"2011","journal-title":"Brain"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.cortex.2014.10.010","article-title":"Neuroanatomical correlates of awareness of illness in patients with amnestic mild cognitive impairment who will or will not convert to Alzheimer\u2019s disease","volume":"61","author":"Spalletta","year":"2014","journal-title":"Cortex"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.pscychresns.2011.06.014","article-title":"Alzheimer\u2019s Disease Neuroimaging Initiative. Amygdala atrophy is prominent in early Alzheimer\u2019s disease and relates to symptom severity","volume":"194","author":"Poulin","year":"2011","journal-title":"Psychiatry Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1860","DOI":"10.1523\/JNEUROSCI.5062-08.2009","article-title":"Cortical hubs revealed by intrinsic functional connectivity: Mapping, assessment of stability, and relation to Alzheimer\u2019s disease","volume":"29","author":"Buckner","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S0197-4580(03)00084-8","article-title":"Hippocampus and entorhinal cortex in mild cognitive impairment and early AD","volume":"25","author":"Pennanen","year":"2004","journal-title":"Neurobiol. Aging"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1093\/brain\/awaa012","article-title":"Basal forebrain volume reliably predicts the cortical spread of Alzheimer\u2019s degeneration","volume":"143","author":"Kronbichler","year":"2020","journal-title":"Brain"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.biopsych.2011.06.019","article-title":"Atrophy of the cholinergic Basal forebrain over the adult age range and in early stages of Alzheimer\u2019s disease","volume":"71","author":"Grothe","year":"2012","journal-title":"Biol. Psychiatry"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/0197-4580(95)00043-E","article-title":"VIP neurons in the human SCN in relation to sex, age, and Alzheimer\u2019s disease","volume":"16","author":"Zhou","year":"1995","journal-title":"Neurobiol. Aging"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.smrv.2016.02.002","article-title":"Candidate mechanisms underlying the association between sleep-wake disruptions and Alzheimer\u2019s disease","volume":"31","author":"Cedernaes","year":"2017","journal-title":"Sleep Med. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1038\/s41559-023-02186-7","article-title":"Comparative single-cell transcriptomic analysis of primate brains highlights human-specific regulatory evolution","volume":"7","author":"Suresh","year":"2023","journal-title":"Nat. Ecol. Evol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"332","DOI":"10.5115\/acb.2010.43.4.332","article-title":"Expression of ErbB4 in the apoptotic neurons of Alzheimer\u2019s disease brain","volume":"43","author":"Woo","year":"2010","journal-title":"Anat. Cell Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1002\/alz.12653","article-title":"Tau-induced deficits in nonsense-mediated mRNA decay contribute to neurodegeneration","volume":"19","author":"Zuniga","year":"2023","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"221","DOI":"10.3233\/JAD-2010-1220","article-title":"Neuropathologic alterations in mild cognitive impairment: A review","volume":"19","author":"Markesbery","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1212\/01.WNL.0000152982.47274.9E","article-title":"Mild cognitive impairment is related to Alzheimer disease pathology and cerebral infarctions","volume":"64","author":"Bennett","year":"2005","journal-title":"Neurology"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"eabq1019","DOI":"10.1126\/scitranslmed.abq1019","article-title":"Lateral mammillary body neurons in mouse brain are disproportionately vulnerable in Alzheimer\u2019s disease","volume":"15","author":"Huang","year":"2023","journal-title":"Sci. Transl. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1097\/00005072-199911000-00002","article-title":"Primary motor cortex involvement in Alzheimer disease","volume":"58","author":"Favre","year":"1999","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.neurobiolaging.2021.06.007","article-title":"Higher motor cortical excitability linked to greater cognitive dysfunction in Alzheimer\u2019s disease: Results from two independent cohorts","volume":"108","author":"Zadey","year":"2021","journal-title":"Neurobiol. Aging"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1002\/ana.10416","article-title":"Motor cortex excitability in Alzheimer\u2019s disease: A transcranial magnetic stimulation study","volume":"53","author":"Ferreri","year":"2003","journal-title":"Ann. Neurol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"671","DOI":"10.3233\/JAD-151052","article-title":"Tau Accumulation in Primary Motor Cortex of Variant Alzheimer\u2019s Disease with Spastic Paraparesis","volume":"51","author":"Lyoo","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"175","DOI":"10.21037\/atm.2018.04.23","article-title":"Tau in neurodegenerative disease","volume":"6","author":"Gao","year":"2018","journal-title":"Ann. Transl. Med."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/s41582-021-00529-1","article-title":"The human connectome in Alzheimer disease\u2014Relationship to biomarkers and genetics","volume":"17","author":"Yu","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1021\/jasms.2c00341","article-title":"Cerebrospinal Fluid and Brain Proteoforms of the Granin Neuropeptide Family in Alzheimer\u2019s Disease","volume":"34","author":"Quinn","year":"2023","journal-title":"J. Am. Soc. Mass Spectrom."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"155","DOI":"10.4137\/CIN.S11831","article-title":"Analysis of patterns of gene expression variation within and between ethnic populations in pediatric B-ALL","volume":"12","author":"Hicks","year":"2013","journal-title":"Cancer Inform."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1093\/humrep\/15.suppl_1.14","article-title":"Progesterone, progestagens and the central nervous system","volume":"15","author":"Genazzani","year":"2000","journal-title":"Hum. Reprod."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Yamashita, J., Nishiike, Y., Fleming, T., Kayo, D., and Okubo, K. (2021). Estrogen mediates sex differences in preoptic neuropeptide and pituitary hormone production in medaka. Commun. Biol., 4.","DOI":"10.1038\/s42003-021-02476-5"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1007\/s00221-020-05923-7","article-title":"Effects of estrogen and progesterone on the neurogenic inflammatory neuropeptides: Implications for gender differences in migraine","volume":"238","author":"Cetinkaya","year":"2020","journal-title":"Exp. Brain Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1001\/jamaneurol.2018.4693","article-title":"Sex Differences in the Association of Global Amyloid and Regional Tau Deposition Measured by Positron Emission Tomography in Clinically Normal Older Adults","volume":"76","author":"Buckley","year":"2019","journal-title":"JAMA Neurol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"eadf5357","DOI":"10.1126\/science.adf5357","article-title":"Single-cell DNA methylation and 3D genome architecture in the human brain","volume":"382","author":"Tian","year":"2023","journal-title":"Science"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"eadf7044","DOI":"10.1126\/science.adf7044","article-title":"A comparative atlas of single-cell chromatin accessibility in the human brain","volume":"382","author":"Li","year":"2023","journal-title":"Science"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/12\/1518\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:40:45Z","timestamp":1760114445000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/12\/1518"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,11,27]]},"references-count":83,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["biom14121518"],"URL":"https:\/\/doi.org\/10.3390\/biom14121518","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,11,27]]}}}