Abstract Body: Cerebral small vessel disease, particularly characterized by white matter hyperintensities (WMHs), is a prominent contributor to cognitive impairment. The concurrent role of Alzheimer's disease (AD) pathology, as measured by hyperphosphorylated tau species (pTau), in vascular cognitive impairment remains unclear. While plasma pTau217 is an established biomarker for AD, its relevance in vascular disease-enriched populations has not been extensively studied. This study investigates plasma pTau217 as a biomarker for distinguishing cognitive impairment and dementia in a cohort de-enriched for AD but enriched for vascular disease, focusing on its relationship with cognitive status and Fazekas scores. A cohort of 72 participants (mean age: 70.4, SD 7.9, 58% female) from the MarkVCID Consortium study were selected with 75% having a Fazekas score ≥ 2. pTau217 levels were quantified using the Meso Scale Discovery S Plex assay. Individuals were classified based on their cognitive status into cognitively normal, mild cognitive impairment (MCI), or dementia. Receiver operating characteristic (ROC) curve analysis was performed to assess the ability of pTau217 to distinguish between these groups. Linear regression models were used to examine the association between pTau217 levels and Clinical Dementia Rating (CDR) global scores. Plasma pTau217 levels were found to be elevated in individuals with MCI and dementia. The ROC curve analysis showed pTau217 could distinguish between patients with MCI (AUC: 0.74) and dementia (AUC: 0.72), suggesting moderate diagnostic accuracy in this vascular disease-enriched cohort. No significant relationship was observed between pTau217 levels and Fazekas scores. Regression analysis revealed plasma pTau217 levels were significantly associated with CDR global scores (β=0.337; p=0.0007), a correlation that remained significant after adjusting for sex, age, and education, underscoring pTau217 as an independent predictor of cognitive decline. Additionally, 75% of participants with an AD diagnosis (6/8) had pTau217 levels >10 pg/mL (consistent with prior studies) ranging from 12.2 to 35.3 pg/mL. In conclusion, for this cohort enriched for vascular disease and de-enriched for AD, plasma pTau217 exhibited accuracy in distinguishing patients with MCI and dementia, independent of Fazekas scores. These findings support the utility of plasma pTau217 as a biomarker for cognitive impairment, even in populations with a significant vascular pathology.