P1-352: white matter hyperintensities, amyloid-β, and risk of cognitive decline in healthy older people

Cerebral white-matter hyperintensities (WMH), generally presumed to be of vascular origin, are associated with an increased risk of cognitive decline and dementia. The influence of preclinical Alzheimer's disease (AD) on this association is not well understood. We aimed to investigate the significance of WMH in cognitively normal adults ≥60 years old and how this is modulated by amyloid-β burden. Participants from the Australian Imaging, Biomarker, and Lifestyle Study who were cognitively normal and had high-resolution FLAIR-MRI were included. WMH volume was expressed as percentage of total intracranial volume. Participants with WMH above the upper quartile for decade of life were classified as having high WMH burden (WMH+). Amyloid-β load was assessed using PET (Aβ+ defined as SUVR/BeCKeT≥1.4). In participants with ≥3 assessment timepoints, linear mixed models were used to compare slopes of change in executive function by Aβ and WMH status, adjusting for age, sex, and education. Cox proportional hazards analysis was used to investigate the association between WMH/Aβ status and risk of progression to MCI/dementia over 8 years, adjusting for demographic and clinical risk factors. A total of 483 participants with baseline WMH volumes were included to derive thresholds of WMH+ by decade of life. Of these, 375 had ≥3 neuropsychological assessments (mean age 69 years [SD 6.3], 56.1% female, 23.5% ApoE4 carriers, 35.9% Aβ+). There were no differences between WMH+ and WMH- participants in age, sex, education, ApoE4, Aβ burden (dichotomised or continuous) or baseline cognitive performance. Aβ+ (B=−0.02, SE=0.009, p<0.05) and WMH+ (B=−0.04, SE=0.01, p<0.001) status were both independently and in combination (B=−0.07, SE=0.02, p<0.001) associated with greater executive function decline. Aβ+/WMH+ participants had 7.4x greater risk of transition to MCI/dementia compared to Aβ-/WMH-; Aβ+ or WMH+ in isolation were not associated with a significantly increased risk of transition to MCI/dementia. High WMH and Aβ burden were independently and jointly associated with decline in executive function, but only the combination was associated with increased risk of transition to MCI/Dementia over 8 years. These results highlight the impact of comorbidity of AD and cerebrovascular disease on clinical outcomes.