PROJECT SUMMARY / ABSTRACT In the United States, approximately 6.2 million people live with a clinical diagnosis of Alzheimer disease (AD). Postmenopausal women account for up to 70% of them. The overall goal of this proposed research is to elucidate the progressive pathophysiological mechanisms by which menopausal hormone therapy (HT) influences the risk of AD dementia in women. The applicant’s prior work showed that the timing of HT use relative to menopause onset influences females’ susceptibility to the deposition AD pathology in later life. It is critical that longitudinal cohort studies and randomized controlled trials are conducted to substantiate these findings. During the K99 phase, the applicant will combine three observational studies (n=772) with longitudinal biomarkers of AD, as measured with positron emission tomography (PET), to determine to influence of HT and its timing on neocortical Aβ accumulation (over 6.5 years; Aim 1), region-specific tau accumulation (over 4.2 years; Aim 1) and cognitive decline (over 7.4 years; Aim 2). To achieve these aims, the applicant will leverage their existing strengths in neuroimaging, genetic-risk, cognitive neuroscience and big data and gain expertise in following five areas of training: (1) PET-neuroimaging (2) Biofluids (3) Statistics (4) Hormones and (5) Clinical trials (analytical approaches). With these skills, the applicant will be well positioned in the R00 phase to conduct the final aim: to determine how early and late HT randomization impacts the pathological progression of AD, relative to respective placebo groups, as measured with multiple plasma AD biomarkers (Ab42/Ab40, p-tau181, p-tau217, p-tau231; Aim 3). In the R00, the applicant will utilize existing samples from the Women Health Initiative; a landmark randomized controlled trial on HT (n=3,472). Further, non-AD specific plasma biomarkers will be integrated to determine how HT randomization impacts markers of astrogliosis (Glial fibrillary acidic protein; GFAP) and axonal damage (Neurofilament light chain; NfL) and in addition, how GFAP and NfL may moderate the effect of HT on the pathological progression of AD. A highly innovative component of this project is the use of cutting- edge multi-modal measures of AD, wherein PET biomarkers and novel plasma biomarkers are integrated across observations studies and a randomized controlled trial. Successful outcomes will alleviate uncertainty regarding the downstream impact of HT on the brain and inform how exogenous hormones alter the underlying neurobiology of AD. The project will highlight hormones as sex-specific risk factors underlying sex differences in the prevalence of AD. These outcomes will have direct implications for AD prevention and treatment strategies. For the applicant, this program will enhance a rapid transition to independence using a short period of intensive training and mentorship from researchers at Massachusetts General Hospital/Harvard Medical School, which wil...