Diversity Supplement for Jenny Lutshumba

Abstract There is a sex-based difference in the etiology of AD and VCID. Women have a higher incidence of ADRD, as well as sex-based differences in cardiovascular risk factors for dementia. In a subgroup from the rrAD clinical trial at baseline, we found a sex difference in plasma AD biomarkers (Fig. 1). Females had higher levels of total tau and total tau/Aβ42 while pTau181 was higher in males, with no difference found in the Aβ42/40 ratio. VCID biomarkers also show no sex-based differences. There was however a sex-based difference in the association between AD and VCID biomarkers. In females, VEGF-D associated with total Tau, while in males VEGF-D associated with pTau181 and pTau181/Aβ42, and bFGF associated with Tau/Aβ42. These preliminary findings support a sex-based difference of biomarkers in the pathogenesis of VCID and AD in cognitively healthy older adults. However, there is still a reluctance in human studies to stratify cohorts by sex. Moreover, there is great appreciation for the importance of the crosstalk between the systemic immune system and the brain pathologies in ADRDs. However, the role of systemic inflammation in the pathogenesis of ADRDs remains under-explored. The purpose of the proposed supplement is to investigate the sex effects of independent and combined effects of Intensive pharmacological Reduction of Vascular Risk factors (IRVR) i.e. hypertension and dyslipidemia and aerobic Exercise (Ex) on inflammation and cognitive function. Here, we will test the hypothesis that females in IRVR+Ex will ameliorate AD/VCID-associated biomarkers and inflammatory cytokines and associate with better cognitive function by testing the following aims: Aim1: To determine whether there is a sex difference in inflammatory cytokines and injury markers in the plasma between IRVR+Ex and IRVR or Ex and their association with AD/VCID biomarkers. Aim2: To determine whether there is amelioration in alteration in immune cells in both sexes in IRVR+Ex compared to IRVR or Ex. The long-term goal of this project is to identify inflammatory biomarkers that will be predictive of ADRD in males and females.