Steroid hormones in Alzheimer's disease: a molecular analysis of blood and cerebrospinal fluid.

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.