Tau PET positivity predicts clinically relevant cognitive decline driven by Alzheimer's disease compared to comorbid cases; proof of concept in the ADNI study.

ABSTRACT

ß-amyloid (Aß) pathology is not always coupled with Alzheimer's disease (AD) relevant cognitive decline. We assessed the accuracy of tau PET to identify Aß(+) individuals who show prospective disease progression. 396 cognitively unimpaired and impaired individuals with baseline Aß and tau PET and a follow-up of ≥ 2 years were selected from the Alzheimer's Disease Neuroimaging Initiative dataset. The participants were dichotomously grouped based on either clinical conversion (i.e., change of diagnosis) or cognitive deterioration (fast (FDs) vs. slow decliners (SDs)) using data-driven clustering of the individual annual rates of cognitive decline. To assess cognitive decline in individuals with isolated Aß(+) or absence of both Aß and tau (T) pathologies, we investigated the prevalence of non-AD comorbidities and FDG PET hypometabolism patterns suggestive of AD. Baseline tau PET uptake was higher in Aß(+)FDs than in Aß(-)FD/SDs and Aß(+)SDs, independently of baseline cognitive status. Baseline tau PET uptake identified MCI Aß(+) Converters and Aß(+)FDs with an area under the curve of 0.85 and 0.87 (composite temporal region of interest) respectively, and was linearly related to the annual rate of cognitive decline in Aß(+) individuals. The T(+) individuals constituted largely a subgroup of those being Aß(+) and those clustered as FDs. The most common biomarker profiles in FDs (n = 70) were Aß(+)T(+) (n = 34, 49%) and Aß(+)T(-) (n = 19, 27%). Baseline Aß load was higher in Aß(+)T(+)FDs (M = 83.03 ± 31.42CL) than in Aß(+)T(-)FDs (M = 63.67 ± 26.75CL) (p-value = 0.038). Depression diagnosis was more prevalent in Aß(+)T(-)FDs compared to Aß(+)T(+)FDs (47% vs. 15%, p-value = 0.021), as were FDG PET hypometabolism pattern not suggestive of AD (86% vs. 50%, p-value = 0.039). Our findings suggest that high tau PET uptake is coupled with both Aß pathology and accelerated cognitive decline. In cases of isolated Aß(+), cognitive decline may be associated with changes within the AD spectrum in a multi-morbidity context, i.e., mixed AD.