Association of vascular risk and alzheimer’s disease pathology with neurodegeneration and cognitive decline

Background: It is not fully understood how vascular risk factors (VRFs) are associated with Alzheimer’s disease (AD) pathology to promote neurodegeneration and cognitive decline. Objective: Investigate whether VRF burden synergistically interacts with AD pathology to accelerate neurodegeneration and cognitive decline in cognitively unimpaired (CU) individuals. Methods: We assessed 503 CU participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Individuals were dichotomized as having an elevated VRF burden if ≥ 2 VRFs (V+) and as presenting biological AD if CSF p-tau181 ≥ 24 pg/mL and CSF Aβ1-42 ≤ 976.6 pg/mL [(AT)+]. Neurodegeneration was assessed with plasma neurofilament light (NfL) and cognition with the modified version of the Preclinical Alzheimer’s Cognitive Composite. Results: Linear mixed-effects models demonstrated that an elevated VRF burden interacted with AD pathology to promote higher rates of neurodegeneration (β=5.68, p=.005) and cognitive decline (β=- 0.43, p=.019). Survival analysis demonstrated that only (AT)+V+ individuals had a significantly greater risk of clinical progression to cognitive impairment (adjusted Hazard Ratio=3.5, p <.001). Conclusion: Our results suggest that VRF burden and AD pathology synergistically lead to neurodegeneration and cognitive decline, favoring the onset of cognitive impairment. These findings support that the clinical evaluation of VRF burden might improve the clinical assessment especially of subjects at higher risk for developing cognitive impairment.