AS746 - Menopause and related midlife risk factors and their impact on later-life Alzheimer’s disease pathology and cognition – WHIMSY-AD study

Investigator Names and Contact Information

Rachel Buckley (rfbuckley@mgh.harvard.edu)

Suzanne Baker (slbaker@lbl.gov)

Introduction/Intent

Women are more likely to live and die with Alzheimer’s disease (AD) dementia than men1. Even at the earliest stages of AD, findings consistently show that they exhibit higher levels of tau pathology2-4. This is particularly true in women who carry the APOEe4 allele, who show faster rates of cognitive decline5, higher levels of tau pathology in cerebrospinal fluid4, and higher AD dementia incidence rates than men between the ages of 65-75 years6. Given the 20-year latency period from the onset of abnormal pathological burden to the point of a dementia diagnosis7, then encroaching pathological burden initiates proximal to the age at menopause onset. The menopause transition is defined by a permanent cessation of menses for 12 months, with a median age of onset of 51 years in the United States8. Age of onset, which is marked by a significant decline in estrogen and progesterone levels, may play a role in elevating risk for dementia in women9-11. Surgically induced onset appears to be particularly potent for dementia risk12. Post-menopausal women may also exhibit elevated cross-sectional biomarkers of AD, specifically b-amyloid13, 14, tau15 and neurodegeneration14 relative to pre-menopausal women and age-matched men. What remains unclear are the potential pathways connecting mid-life hormonal cessation events, such as menopause, and the downstream genesis of AD clinicopathology. A milieu of risk factors drastically change around the time of menopause in women, such as increased risk of glucose intolerance, metabolic syndrome, and high blood pressure16. Although there exist large cohort samples of women who have been deeply phenotyped proximal to their menopause transition, none have followed these cohorts decades later with comprehensive AD neuroimaging and biofluid measures. Despite earlier suggestions that menopausal hormone therapy might protect against dementia, the Women’s Health Initiative Memory Study (WHIMS), an ancillary study of women aged 65 and older in the WHI, found a nearly 2-fold higher dementia risk in women in the conjugated equine estrogens + progestin trial and greater verbal memory decline17, 18. By contrast, a follow-up study of women aged 50-55 year at time of WHI enrolment, an age proximal to their menopause transition, showed neither cognitive harm nor benefit of hormone therapy when tested longitudinally from ~63 years19, 20. Our focus is on these ~1100 women who were enrolled in the WHI Memory Study-Young (WHIMSY) ancillary study (Resnick: NIA/HHSN-271-2011-00004C), and who are now 74-82 years old. This is a unique cohort that was randomized to treatment during their critical window of menopausal onset and are now experiencing another critical window for dementia risk. These women have a vast array of longitudinal biofluid, survey and cognitive data available, and underwent annual cognitive assessments from 2008-201519, 20. We propose a highly innovative project to recontact WHIMSY women with the overall objective to identify the impact of menopause and related midlife risk factors (including retrospective data on peripheral inflammation, cardiovascular risk, sleep) on AD risk (biomarkers [plasma and neuroimaging] and cognitive change) captured almost 25 years later. We will re-establish WHIMSY remote cognitive assessments using a virtual Zoom platform and introduce state-of-the-art digital testing. We will analyze banked baseline plasma for AD biomarkers (Ab40, Ab42). For contemporaneous bloods we will extend this panel to include p-taus (p-tau181, p-tau217, p-tau231), microtubule binding region [MTBR]243, neurofilament light [NfL] and glial fibrillary acidic protein [GFAP]). On a smaller subset (n=200), we propose an additional objective to investigate influences on regional amyloid and tau deposition (PET), cortical thickness, functional connectivity, white matter integrity and glymphatic clearance (MRI) using a comprehensive neuroimaging protocol. We put forward an interdisciplinary team of neuroimagers, cognitive neuroscientists, neurologists, clinical trialists and endocrinologists to establish the WHIMSY-AD study.

Aim 1: Elucidate the impact of midlife menopausal and midlife risk factors on regional AD biomarkers of amyloid, tau, and atrophy via neuroimaging (n=200) gathered 25 years later. This unique dataset will allow us to investigate the degree to which multiple menopausal and related risk factors impact downstream regional biomarkers of amyloid, tau and neurodegeneration. We hypothesize that menopause (age-at-menopause plus elevated midlife inflammatory and cardiovascular markers) is associated with later-life AD risk.

Aim 2: Examine menopause and midlife risk factors to influence decades-long change in AD plasma markers (n=700). In addition to collecting contemporaneous plasma, banked plasma samples exist up approximately 25 years prior to enrolment for the current study, giving us the opportunity to test novel hypotheses that decades-long increases in plasma levels of AD biomarkers are significantly impacted by mid-life menopause, and are related to changes in inflammation, and cardiovascular risk.

Aim 3: Determine the influence of menopause and midlife risk factors, as well as midlife and late life AD biomarkers, on cognitive decline (n=700). Given the rich nature of legacy cognitive data available, and the proposed comprehensive neuropsychological battery to be gathered now, we are in a singular position to examine how menopause, inflammation, and cardiovascular factors, in conjunction with current AD and inflammatory biomarkers, influence cognitive decline.