Abstract There is a sex-based difference in the etiology of Alzheimer’s disease (AD) and Vascular contribution to cognitive impairment and dementia (VCID), the two most common forms of dementia. Females have a higher incidence of Alzheimer’s disease and related dementias (ADRD), as well as sex-based differences in cardiovascular risk factors for dementia. In a subgroup of participants from the risk reduction for Alzheimer’s disease (rrAD; NCT02913664) clinical trial at baseline, we found a sex difference in plasma AD biomarkers. Females had higher levels of total tau and total tau/Ab42 while pTau181 was higher in males, with no difference found in the Ab42/40 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/Ab42, and bFGF associated with Tau/Ab42. 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 pro-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 a sex-mediated amelioration in alteration in peripheral immune cells 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.