Research Paper Volume 12, Issue 20 pp 20350—20365

Blood-based biomarkers in hypothalamic-pituitary axes for the risk of dementia or cognitive decline: a systematic review and meta-analysis

Yi-Jun Ge1, *, , Wei Xu1, *,&, , Chen-Chen Tan1, , Lan Tan1, &, ,

  • 1 Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
* Equal contribution

Received: March 3, 2020       Accepted: July 20, 2020       Published: October 26, 2020
How to Cite

Copyright: © 2020 Ge et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Blood-based biomarkers are ideal candidates for dementia prediction. This systematic review and meta-analysis aimed to evaluate longitudinal relationships of blood hormones and hormone-binding proteins in hypothalamic-pituitary (HP) axes with dementia or cognitive decline. PubMed, MEDLINE, EMBASE, PsycINFO, and BIOSIS were systematically searched from 1919 to June 2020. Fifteen types of hormones and four types of hormone-binding proteins were measured in 48 prospective studies. Increased risk of dementia or cognitive decline could be predicted by elevated blood concentrations of free-thyroxine (free-T4, RR = 1.06, p = 0.001) and sex hormone-binding globulin (SHBG, RR = 1.10, p = 0.025). Lower thyroid-stimulating hormone (TSH) levels within (RR = 1.28, p < 0.001) and below (RR = 1.27, p = 0.004) the normal range were both risky. Current evidence suggests the alterations of multiple blood molecules in HP axes, especially TSH, free-T4, and SHBG precede the incidence of dementia or cognitive decline. The underpinning etiology remains to be elucidated in the future.


AD: Alzheimer’s disease; bio: bioavailable; CI: confidence interval; DHEAS: dehydroepiandrosterone sulfate; E2: estradiol; HP: hypothalamic-pituitary; HPA: hypothalamic-pituitary-adrenal; HPG: hypothalamic-pituitary-gonadal; HPT: hypothalamic-pituitary-thyroid; HPS: hypothalamic-pituitary-somatic; IGF: insulin-like growth factor; IGFBP: insulin-like growth factor-binding protein; RCT: randomized controlled trial; RR: relative risk; SHBG: sex hormone-binding globulin; T4: thyroxine; TSH: thyroid-stimulating hormone.