Contingency of Plasma Dementia Biomarkers on Cognitive Profiles for Prognosis of Incident Dementia

BACKGROUND AND OBJECTIVES: Plasma biomarkers such as phospho-tau species are increasingly used in clinical practice for the diagnosis of Alzheimer disease (AD). Phosphorylated-tau at threonine 181 (p-tau181) values also provide prognostic information about incident dementia. Cognitive status similarly conveys prognostic information, but the relationship between plasma biomarkers for AD and cognitive status requires clarification. METHODS: Participants from the Atherosclerosis Risk in Communities (ARIC) study who were adjudicated as free of dementia in 2011-2013 had plasma samples analyzed for p-tau181 and other biomarkers. Participants were surveilled for incident dementia through December 31, 2022. Cumulative incidence curves, Cox models, and Fine-Gray models were used to evaluate the independent and combined discriminatory accuracy of cognitive status and plasma biomarkers for incident dementia. RESULTS: The sample comprised 1,577 ARIC participants (age 76.5 years, 60% women, 73% White, 27% Black). The risk of incident dementia was higher in persons with a baseline status of mild cognitive impairment (covariate-adjusted hazard ratio [HR] 2.94, 95% CI 2.61-3.33) compared with those who were cognitively unimpaired independent of biomarker status. The risk of dementia was also higher in persons with more abnormal concentrations of p-tau181 and other biomarkers independent of cognitive status. When age, cognitive status, and p-tau181 were included in the same models, the risk was attenuated relative to models where only cognitive status or plasma biomarkers were included. For continuous p-tau181 concentrations, the covariate-adjusted HR without cognitive status was 1.45 (95% CI 1.36-1.54), but when cognitive status was included, the HR decreased to 1.37 (95% CI 1.29-1.46). Models showed that when combined with age, p-tau181 alone, cognitive status alone, or the combination of p-tau181 and cognitive status had similar discriminatory accuracy. DISCUSSION: Cognitive status and plasma biomarker concentrations convey independent but overlapping information about the risk of incident dementia. Although cognitive status and plasma p-tau181 have similar discriminatory accuracies, the far lower incidence rate of dementia in persons who are initially cognitively unimpaired highlights the importance of an accurate clinical diagnosis.