Whitney L. Wharton, Ph.D. - US grants

DESCRIPTION (provided by applicant): Neuroimaging and postmortem histopathological studies report that up to one-third of AD patients have some degree of vascular pathology. Midlife vascular risk factors, particularly hypertension, have been associated with an increased risk of AD in later life. Similarly, reductions in BP are associated with protection against AD. Ths indicates that long-standing uncontrolled BP and other vascular factors may contribute to AD pathology, possibly through decreased cerebral blood flow (CBF) and accumulation of ?-amyloid (A?) a key pathological feature of preclinical AD. While studies show that vascular risk factors contribute to AD risk and progression, there are currently no effective interventions to prevent or slow AD progression that target these modifiable vascular factors. Although vascular risk factors have been linked to AD, the mechanism has yet to be clarified and it is unknown to what extent these measures interact with ApoE and familial history. Two mechanisms by which vascular risk factors may contribute to AD are reduced CBF and A? neuropathology. To better understand the mechanisms by which increased vascular risk and subsequent arterial dysfunction may modify CBF, A? levels and cognition, we propose a longitudinal study enrolling 80 asymptomatic, middle-aged (45-65 yrs) adults at risk for AD, due to a parental history of AD. We will make use of the University of Wisconsin Alzheimer's Disease Research Center's (ADRC) NIH-funded cohort, comprised of middle-aged participants 'at risk' for AD based on family history and created to facilitate AD prevention studies. This cohort is at high risk for AD and would likely benefit the most from an early intervention. CBF will be quantitatively ascertained via a state-of-the art neuroimaging modality developed at the UW Madison, called 3D phase contrast, vastly undersampled, isotropic voxel radial projection imaging (PC VIPR). This novel technique provides a thorough evaluation of cerebral arterial function, including flow volume, velocity, pressure gradient and shear wall stress, measures closely related to the peripheral arterial indices that we will collect in the proposed project (i.e. pulse-wave velocity and flow mediated vasodilation). CBF will be assessed in the middle and posterior cerebral arteries, bilaterally. These arteries are responsible for blood flow to the hippocampus and frontal lobes, regions impaired in AD. A? levels will be collected in CSF and cognitive tasks of particular interest will include executive function and working memory domains. The objective of the proposed study is to determine the extent to which arterial function, as ascertained by cardiac index, flow-mediated vasodilation (FMD), pulse wave velocity (PWV) and nocturnal blood pressure patterns predict: 1) cerebral blood flow (CBF) in medium and large cerebral arteries and cerebral perfusion via ASL, 2) A? levels in cerebrospinal fluid (CSF) and 3) cognition over 2 years, in participants at-risk for AD based on family history. Outcomes will then be combined to test our model described in the application and determine the primary mechanism by which arterial function may influence cognition (i.e. CBF) over time.

Women are more likely than men to develop Alzheimer's disease (AD), and available research suggests this is not only because they have a longer life expectancy than men. This increased risk is likely due, in part, to fluctuating sex hormones across the lifespan. Sex hormones likely have direct actions on AD brain biomarkers (A? and tau levels), as well as indirect actions via inflammation, sleep disruptions, and reduced brain blood flow and volume, all of which are independent risk factors for AD. African Americans ?men and women? are also at increased risk for AD vs. Caucasians. As such, mechanistic studies and interventions need to be thoroughly examined and tested in both African American and Caucasian participants. The purpose of the proposed project is to determine the relationship between brain and systemic sex hormones on known AD biomarkers in individuals most at risk for AD. 150 middle age, African American (n=75) and Caucasian (n=75) women will be enrolled in this observational, two year study. The main objectives are to test whether brain and serum sex hormones (estradiol, estrone, progesterone, testosterone) differentially influence AD risk factors (inflammation, sleep and cerebral blood flow,), and if sex hormone levels moderate the relationship between these risk factors and AD biomarkers (cognition, CSF, neuro-imaging). We will leverage existing NIH funded, well characterized cohorts (n=291; followed by MPIs Wharton & Hu), including middle- age women at high risk for AD (through family history or APOE e4 allele) who already have baseline and longitudinal blood, CSF, and MRI analysis for at least 2 years. We will also test our hypotheses in a unique cohort enriched for African Americans based on our extensive track record in recruiting and analyzing aging and AD biomarkers in a diverse cohort. Participants will complete 3 study visits annually. At each year, we will collect medical and medication history, subjective sleep, cognitive testing and questionnaires (stress, sleep, exercise, nutrition) Participants also undergo blood draw for sex hormone and inflammatory markers. At Baseline and Year 2, participants will undergo the aforementioned protocol, AND take part in: lumbar puncture for spinal fluid collection, neuroimaging and will take home a non-invasive monitor for collection of objective sleep data to wear for 1 night. We have assembled a multidisciplinary team with complementary expertise in sex hormones and aging, AD biomarkers, inflammation, neuroimaging, sleep, and biostatistics. Data inform larger NIH funded studies and, to our knowledge, provide the largest and most comprehensive, biomarker driven, characterization of brain and sex hormone levels in a racially diverse sample of middle-age women.

Abstract By 2030, there will be nearly six million sexual and gender minority (SGM) older adults aged 50 and older in the U.S. who identify as lesbian, gay, bisexual, transgender, and/or queer. This number will more than double by 2050. Approximately 350,000 SGM older adults in the U.S. currently are living with Alzheimer's disease and related dementias (ADRD), with projections nearing one million by 2030. SGM older adults experience greater health disparities than their heterosexual counterparts. Several recent studies have shown a higher prevalence of risk factors for ADRD, including higher rates of cardiovascular disease, hypertension, diabetes, depression or frequent mental distress, and subjective cognitive decline. In addition, SGM older adults are less likely to have informal caregiving support and for those with caregivers, their caregivers often lack access to inclusive services and resources. Research participation from SGM older adults is extremely limited and the sparse research suggests that SGM older adults are interested in being engaged in research, but concerns regarding the lack of inclusive services and mistrust need to be addressed to improve participation in ADRD research, including clinical trials and intervention research studies. To overcome these barriers to participation in ADRD- related research, this study will implement culturally appropriate and inclusive recruitment strategies aimed at engaging, recruiting, and retaining SGM older adults with ADRD and SGM caregivers in research. This will be accomplished through (1) the development of a national network of existing SGM organizations, programs, and academic institutions to engage SGM people with ADRD and SGM ADRD caregivers in clinical research; 2) establishing a sustainable research registry of SGM people with ADRD and SGM caregivers by developing, implementing, and evaluating tailored recruitment and engagement programs, for use by ADRDc and clinical research institutions; and 3) the development of a replicable model for recruitment and retention of SGM people with ADRD and SGM caregivers in ADRD and aging-related research. Our collaborative team will address the National Institute of Aging's Strategic Directions for Research on Aging ?F-3: Develop and implement strategies to increase inclusion of diverse populations in research.?