Alzheimer's research & therapy · 2026
Steroid hormones in Alzheimer's disease: a molecular analysis of blood and cerebrospinal fluid.
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Muk Tik, Wretlind Asger, Hooshmand Kourosh, Clos-Garcia Marc, Liu Yue, Simonsen Anja Hviid, Winchester Laura M, Ahluwalia Tarunveer S, Proitsi Petroula, Marioni Riccardo E, Kümler Thomas, Hasselbalch Steen Gregers, Legido-Quigley Cristina, Alzheimer’s Disease Neuroimaging Initiative
Аннотация
BACKGROUND: Alzheimer's disease (AD) disproportionately affects women, yet existing studies have been limited to single biofluids, individual hormones, or single dementia subtypes, leaving sex-stratified profiles across the cognitive impairment spectrum poorly defined. Here we address this gap by simultaneously quantifying nine steroid hormones spanning glucocorticoid (cortisol, 11-deoxycortisol), mineralocorticoid (aldosterone), progestogen (progesterone, 17-hydroxyprogesterone), androgen (testosterone, dihydrotestosterone), and estrogen (estradiol, estrone) pathways in paired CSF and plasma across five cognitive categories: no cognitive impairment, mild cognitive impairment (MCI) with AD pathology, MCI without AD pathology, AD dementia, and vascular dementia.
METHODS: Steroid hormones were quantified by liquid chromatography-tandem mass spectrometry in paired cerebrospinal fluid (CSF) and plasma samples drawn from the same individuals from a cross-sectional study including 204 participants across five cognitive categories at the Danish Dementia Research Centre. Gender-stratified generalized linear models adjusted for age were applied. Cortisol findings were validated externally using the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (n = 426).
RESULTS: Female participants with AD exhibited elevated CSF cortisol (fold change [FC] = 1.13; P = .04) and CSF 11-deoxycortisol (FC = 1.01; P = .03), alongside reduced plasma progesterone (FC = 0.90; P = .04). Male participants with AD showed elevated plasma aldosterone (FC = 1.19; P = 2.81e-03; q = 0.02). CSF cortisol correlated with amyloid-β42 and phosphorylated tau in female participants. ADNI validation confirmed elevated plasma cortisol in AD, with a larger effect in female participants.
CONCLUSIONS: Gender-dependent steroid hormone dysregulation in dementia highlights cortisol and aldosterone as potentially modifiable targets warranting further investigation.
METHODS: Steroid hormones were quantified by liquid chromatography-tandem mass spectrometry in paired cerebrospinal fluid (CSF) and plasma samples drawn from the same individuals from a cross-sectional study including 204 participants across five cognitive categories at the Danish Dementia Research Centre. Gender-stratified generalized linear models adjusted for age were applied. Cortisol findings were validated externally using the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort (n = 426).
RESULTS: Female participants with AD exhibited elevated CSF cortisol (fold change [FC] = 1.13; P = .04) and CSF 11-deoxycortisol (FC = 1.01; P = .03), alongside reduced plasma progesterone (FC = 0.90; P = .04). Male participants with AD showed elevated plasma aldosterone (FC = 1.19; P = 2.81e-03; q = 0.02). CSF cortisol correlated with amyloid-β42 and phosphorylated tau in female participants. ADNI validation confirmed elevated plasma cortisol in AD, with a larger effect in female participants.
CONCLUSIONS: Gender-dependent steroid hormone dysregulation in dementia highlights cortisol and aldosterone as potentially modifiable targets warranting further investigation.