Integrating objective clinical testing with fluid biomarkers of Alzheimer’s disease (AD) has informed our understanding of the multiple etiologies of cognitive decline among older adults. Neuropathological correlates of dementia beyond AD pathology, such as vascular disease, may differ across subgroups of older adults with different risk factors including individuals from underrepresented racial/ethnic groups. We investigated vascular contributions to neurodegeneration (plasma neurofilament light, NfL) and memory loss beyond the effects of AD in cognitively impaired non-Hispanic/White (NHW) and Hispanic/White (HW) older adults.

We studied 170 participants from the 1Florida Alzheimer’s Disease Research Center with cognitive impairment (Clinical Dementia Rating scale global score > 0.5). Participants self-identified as either NHW (n=76; age= 73.01+7.82, education= 16.34+3.04, female=40.8%) or HW (n=94; age= 71.06+7.42, education= 14.63+3.24, female= 63.8%). All participants completed cognitive testing, brain imaging, and blood draw. AD pathology was quantified as cortical beta-amyloid burden (Aβ-PET Centiloids, CL) and plasma P-tau181. Vascular disease was defined by total white matter hyperintensity volume adjusted for head size (WMH) and Vascular Burden Score (VBS), a 1-7 scale representing the sum of 7 cardiovascular diagnoses or risk factors.  Main outcomes were objective memory scores (Hopkins Verbal Learning Test Delayed Recall; HVLT-DR) and neurodegeneration (plasma NfL). To evaluate the added contribution of vascular disease beyond AD, we constructed hierarchical linear regression models with demographics (Block 1: age, sex, education), AD pathology (Block 2: CLs, Ptau-181) and vascular disease (Block 3: WMH, VBS).  We ran separate models for NHW and HW participants and evaluated differences in explained variance at each step (R² change).

NHW and HW groups did not differ on AD pathology or vascular disease variables (p> .05 for all). For NHW and HW, AD pathology (Block 2) was associated with plasma NfL (NHW R² change = 0.18, p=<.001; HW R² change = 0.10, p=.003) and HVLT-DR (NHW R² change = 0.10, p = .02, HW R² change = 0.10, p = .003). The total unexplained variance in NfL and HVLT-DR after accounting for AD and demographics was greater in HW than NHW (NfL: HW = 69%, NHW = 61%; HVLT-DR: HW = 86%, NHW = 78%).  For NHW, worse vascular disease related to higher plasma NfL beyond the effects of AD (R² change = 0.10, p=.003; β(VBS)= .258, p= .006; β(WMH)= .198, p= .042) but did not explain additional variance in memory (R² change < .01, p=.91). Vascular contributions beyond AD were less apparent in HW participants (NfL model R² change = 0.01, p=.44; HVLT-DR model R² change = 0.04, p=.13). Examining individual variables, greater VBS was associated with worse memory in HW (β(VBS)= -.224, p= .044).

Among cognitively impaired older adults, a significant portion of neurodegeneration and memory decline is not accounted for by demographics and AD pathology. Vascular pathophysiology may differentially relate to brain-behavior relationships, with contributions to neurodegeneration being stronger in NHW than HW. Hypotheses about the role of vascular disease in later-life brain health among underrepresented groups may not be uniform across race/ethnicity.