{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T09:35:14Z","timestamp":1787996114013,"version":"build-2784847793"},"reference-count":29,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T00:00:00Z","timestamp":1710374400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["NIA 5P30AG072980-03"],"award-info":[{"award-number":["NIA 5P30AG072980-03"]}]},{"name":"National Institutes of Health","award":["NIGMS RL5GM118969"],"award-info":[{"award-number":["NIGMS RL5GM118969"]}]},{"name":"National Institutes of Health","award":["TL4GM118971"],"award-info":[{"award-number":["TL4GM118971"]}]},{"name":"National Institutes of Health","award":["UL1GM118970"],"award-info":[{"award-number":["UL1GM118970"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>This study investigates the sex-specific role of the Hypothalamic\u2013Pituitary\u2013Gonadal axis in Alzheimer\u2019s disease progression, utilizing ADNI1 data for 493 individuals, analyzing plasma levels of gonadotropic and sex hormones, and examining neurodegeneration-related brain structures. We assessed plasma levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P4), and testosterone (T), along with volumetric measures of the hippocampus, entorhinal cortex, and hypothalamic subunits, to explore their correlation with Alzheimer\u2019s disease markers across different cognitive statuses and sexes. Significant cognitive status effects were observed for all volumetric measures, with a distinct sex-by-cognitive status interaction for hypothalamic volume, indicating a decrease in males but not in females across cognitive impairment stages. Regression analyses showed specific hypothalamic subunit volume related to hormone levels, accounting for up to approximately 40% of the variance (p &lt; 0.05). The findings highlight sex differences in neurodegeneration and hormonal regulation, suggesting potential for personalized treatments and advancing the understanding of Alzheimer\u2019s disease etiology.<\/jats:p>","DOI":"10.3390\/brainsci14030276","type":"journal-article","created":{"date-parts":[[2024,3,14]],"date-time":"2024-03-14T05:43:08Z","timestamp":1710394988000},"page":"276","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The Association among Hypothalamic Subnits, Gonadotropic and Sex Hormone Plasmas Levels in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5440-1649","authenticated-orcid":false,"given":"Edward","family":"Ofori","sequence":"first","affiliation":[{"name":"College of Health Solutions, Arizona State University, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anamaria","family":"Solis","sequence":"additional","affiliation":[{"name":"Department of Social Work, University of Texas at El Paso, El Paso, TX 79968, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahid","family":"Punjani","sequence":"additional","affiliation":[{"name":"College of Medicine and Sciences, Mayo Clinic, Phoenix, AZ 85054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"on behalf of the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.yfrne.2005.10.003","article-title":"Pubertal hormones organize the adolescent brain and behavior","volume":"26","author":"Sisk","year":"2005","journal-title":"Front. Neuroendocr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.yhbeh.2012.04.006","article-title":"Gender, sex steroid hormones, and Alzheimer\u2019s disease","volume":"63","author":"Vest","year":"2013","journal-title":"Horm. Behav."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.yfrne.2014.01.002","article-title":"Sex differences in cognitive impairment and Alzheimer\u2019s disease","volume":"35","author":"Li","year":"2014","journal-title":"Front. Neuroendocr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"106106","DOI":"10.1016\/j.psyneuen.2023.106106","article-title":"Psychosocial health modifies associations between HPA-axis function and brain structure in older age","volume":"153","author":"Raina","year":"2023","journal-title":"Psychoneuroendocrinology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"189","DOI":"10.3390\/clockssleep3010012","article-title":"Circadian Rhythms of the Hypothalamus: From Function to Physiology","volume":"3","year":"2021","journal-title":"Clocks Sleep"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e042429","DOI":"10.1002\/alz.042429","article-title":"Energy intake and expenditure in patients with Alzheimer\u2019s disease and mild cognitive impairment: The NUDAD project","volume":"16","author":"Doorduijn","year":"2020","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"117287","DOI":"10.1016\/j.neuroimage.2020.117287","article-title":"Automated segmentation of the hypothalamus and associated subunits in brain MRI","volume":"223","author":"Billot","year":"2020","journal-title":"NeuroImage"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/B978-0-12-820107-7.00007-0","article-title":"The supraoptic and paraventricular nuclei in healthy aging and neurodegeneration","volume":"180","author":"Stewart","year":"2021","journal-title":"Handb. Clin. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/mp.2012.147","article-title":"Associations between gonadotropins, testosterone and \u03b2 amyloid in men at risk of Alzheimer\u2019s disease","volume":"19","author":"Verdile","year":"2014","journal-title":"Mol. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/bs.vh.2020.12.020","article-title":"Sex hormones and cognition in aging","volume":"115","author":"Gurvich","year":"2021","journal-title":"Vitam. Horm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"201","DOI":"10.3233\/JAD-2008-14208","article-title":"Luteinizing hormone levels are positively correlated with plasma amyloid-beta protein levels in elderly men","volume":"14","author":"Verdile","year":"2008","journal-title":"J. Alzheimer\u2019s Dis. JAD"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.jalz.2011.01.005","article-title":"Suitability of the Clinical Dementia Rating-Sum of Boxes as a single primary endpoint for Alzheimer\u2019s disease trials","volume":"7","author":"Coley","year":"2011","journal-title":"Alzheimer\u2019s Dement. J. Alzheimer\u2019s Assoc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.1212\/WNL.43.11.2412-a","article-title":"The Clinical Dementia Rating (CDR): Current version and scoring rules","volume":"43","author":"Morris","year":"1993","journal-title":"Neurology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0022-3956(75)90026-6","article-title":"\u201cMini-mental state\u201d. A practical method for grading the cognitive state of patients for the clinician","volume":"12","author":"Folstein","year":"1975","journal-title":"J. Psychiatr. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1002\/jmri.21049","article-title":"The Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI): MRI methods","volume":"27","author":"Jack","year":"2008","journal-title":"J. Magn. Reson. Imaging"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101985","DOI":"10.1016\/j.nicl.2019.101985","article-title":"Free-water imaging of the hippocampus is a sensitive marker of Alzheimer\u2019s disease","volume":"24","author":"Ofori","year":"2019","journal-title":"NeuroImage Clin."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kim, S., Swaminathan, S., Inlow, M., Risacher, S.L., Nho, K., Shen, L., Foroud, T.M., Petersen, R.C., Aisen, P.S., and Soares, H. (2013). Influence of genetic variation on plasma protein levels in older adults using a multi-analyte panel. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070269"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/1750-1326-6-85","article-title":"Adult hippocampal neurogenesis and its role in Alzheimer\u2019s disease","volume":"6","author":"Mu","year":"2011","journal-title":"Mol. Neurodegener."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e700","DOI":"10.1212\/WNL.0000000000013206","article-title":"Association of Cognitive Impairment With Free Water in the Nucleus Basalis of Meynert and Locus Coeruleus to Transentorhinal Cortex Tract","volume":"98","author":"Chu","year":"2022","journal-title":"Neurology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1080\/10253890.2017.1369523","article-title":"Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: Sex differences in regulation of stress responsivity","volume":"20","author":"Oyola","year":"2017","journal-title":"Stress"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1002\/jnr.23809","article-title":"Understanding the broad influence of sex hormones and sex differences in the brain","volume":"95","author":"McEwen","year":"2017","journal-title":"J. Neurosci. Res."},{"key":"ref_22","first-page":"1595","article-title":"Hormones as \u201cdifference makers\u201d in cognitive and socioemotional aging processes","volume":"5","author":"Ebner","year":"2014","journal-title":"Front. Psychol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.neurobiolaging.2014.10.031","article-title":"Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer\u2019s type","volume":"36","author":"Popp","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"100592","DOI":"10.1016\/j.bbih.2023.100592","article-title":"Longitudinal study of Alzheimer\u2019s disease biomarkers, allostatic load, and cognition among memory clinic patients","volume":"28","author":"Adedeji","year":"2023","journal-title":"Brain Behav. Immun. Health"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"471","DOI":"10.3389\/fncel.2018.00471","article-title":"Disorders of Body Weight, Sleep and Circadian Rhythm as Manifestations of Hypothalamic Dysfunction in Alzheimer\u2019s Disease","volume":"12","author":"Hiller","year":"2018","journal-title":"Front. Cell Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/7854_2016_50","article-title":"Orexin and Alzheimer\u2019s Disease","volume":"33","author":"Liguori","year":"2017","journal-title":"Curr. Top. Behav. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gegenhuber, B., and Tollkuhn, J. (2019). Sex Differences in the Epigenome: A Cause or Consequence of Sexual Differentiation of the Brain?. Genes, 10.","DOI":"10.3390\/genes10060432"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/978-3-319-40764-7_13","article-title":"Peripheral Inflammation and Demyelinating Diseases","volume":"949","author":"Murta","year":"2016","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"170963","DOI":"10.1016\/j.peptides.2023.170963","article-title":"Hypothalamic kisspeptin neurons as potential mediators of estradiol negative and positive feedback","volume":"163","author":"Starrett","year":"2023","journal-title":"Peptides"}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/14\/3\/276\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:13:19Z","timestamp":1760105599000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/14\/3\/276"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,14]]},"references-count":29,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["brainsci14030276"],"URL":"https:\/\/doi.org\/10.3390\/brainsci14030276","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,14]]}}}