Role of FSH in Coupling Dementia and Fracture in the AGES-Reykjavik Cohort of Older Adults

PROJECT SUMMARY This project builds upon data from our current U19 AG060917 that (a) show a strong correlation between high serum FSH, low bone mineral density (BMD), and high fracture risk in older post-menopausal women in the AGES-Reykjavik cohort, and (b) provide compelling evidence for a direct effect of FSH in causing cognitive decline in mice [JCEM, 2021, PMID: 33326040; Nature, 2022, PMID: 28538730]1, 2. Dementia and fracture are both highly prevalent among older adults and have devastating consequences. Hip fracture risk is higher in older adults with dementia, and those who sustain a hip fracture have a nearly 6-fold higher six-month mortality if cognitively impaired3, 4. There is evolving evidence that dementia and osteoporosis do not simply coexist, but instead may be related causally––there may be “common causes” of cognitive decline and bone loss during aging. Declining estrogen is associated with both cognitive decline and bone loss, although the effect on cognition of replacing estrogen remains uncertain 5-9 . FSH is a compelling candidate for a “common cause” as rising FSH levels during the menopausal transition, when estrogen is unperturbed, track with a rapid rate of bone loss and spikes of cognitive decline10-12. AGES-Reykjavik presents a unique opportunity to understand brain- bone connectivity in aging, as its 5,764 Icelandic participants (66-90 years at baseline, 58% female) have undergone extensive phenotyping including cognitive testing, dementia ascertainment, brain MRI, and bone CT. Measurements were repeated after 5 years in 3,316 participants, and incident fractures and dementia were ascertained for years after. Given that FSH negatively affects both bone and brain2, 13 and the strong relationship between serum FSH, BMD and fracture risk in post-menopausal women in AGES-Reykjavik1, we hypothesize that FSH links deteriorating brain and bone health in older adults. We will use a two-pronged strategy to determine (a) relationships between bone and brain health, and (b) whether FSH is the common cause. In Specific Aim 1, we will examine, in a longitudinal study, whether cognitive function and MRI measures of brain health are associated with subsequent bone loss and fracture. We expect that older adults with poor cognition at baseline, or with global brain atrophy or infarct, will display greater bone loss. We further expect that deteriorating cognitive function or MRI features over 5 years will predict incident fracture. In Specific Aim 2, we will use a case-cohort design to test the hypothesis that higher serum FSH levels are associated with incident dementia and incident mild cognitive impairment (MCI), independent of sex steroids. During the current U19, we measured serum FSH, sex steroids, and sex hormone binding globulin (SHBG) on baseline samples from a random sub-cohort in AGES-Reykjavik, and we will now add serum levels on archived samples from cases with incident dementia and with incident MCI. The study should help shape evidence-based recommendations on prevention, screening and management of cognitive deficits and bone loss in older adults, and provide a firm foundation for testing FSH-blocking drugs to promote healthy aging.