LAUSR

BACKGROUND The underlying cause of cognitive decline in individuals who are positive for biomarkers of neurodegeneration (N) but negative for biomarkers of amyloid-beta (A), designated as Suspected Non-Alzheimer's Pathophysiology (SNAP), remains unclear. We evaluate whether cerebrovascular disease (CeVD) is more prevalent in those with SNAP compared to A-N- and A+N+ individuals and whether CeVD is associated with cognitive decline over time in SNAP patients. METHODS A total of 216 individuals from a prospective memory clinic cohort [mean (SD) age, 72.7(7.3) years, 100 women (56.5%)] were included and were diagnosed as no cognitive impairment (NCI), cognitive impairment no dementia (CIND), Alzheimer's dementia (AD) or Vascular dementia (VaD). All individuals underwent clinical evaluation and neuropsychological assessment annually for up to 5 years. [11 C]-PiB or [18 F]-Flutafuranol-PET imaging was performed to ascertain amyloid-beta status. MRI was performed to assess neurodegeneration as measured by medial temporal atrophy≥2, as well as significant CeVD (sCeVD) burden, defined by cortical infarct count≥1, Fazekas-score≥2, lacune count≥2 or cerebral microbleed count≥2. RESULTS Of the 216 individuals, 50(23.1%) A-N+ were (SNAP), 93(43.1%) A-N-, 36(16.7%) A+N- and 37(17.1%) A+N+. A+N+ individuals were significantly older, while A+N+ and SNAP individuals were more likely to have dementia. The SNAP group had a higher prevalence of sCeVD (90.0%) compared to A-N-. Moreover, SNAP individuals with sCeVD had significantly steeper decline in global cognition compared to A-N- over 5 years (P=0.042). CONCLUSIONS These findings suggest that CeVD is a contributing factor to cognitive decline in SNAP. Therefore, SNAP-individuals should be carefully assessed and treated for CeVD.