QUANTIFYING PRECLINICAL STAGES OF AUTOSOMAL DOMINANT ALZHEIMER DISEASE (ADAD) AND THE ASSOCIATED OVERALL BIOMARKER SIGNATURE ACROSS MODALITIES USING THE DOMINANTLY INHERITED ALZHEIMER NETWORK (DIAN)

Abstract

The preclinical stages of ADAD and the associated overall preclinical biomarker signature(PBS) across established biomarkers: CSF Aβ42and Tau, PET amyloid plaques via Pittsburgh Compound B positron emission tomography[PIB PET], MRI cortical thickness and hippocampal volume, and PET FDG cortical uptake, remain to be accurately quantified. Dichotomizing the expected year to onset(EYO) of symptoms by each plausible cutoff on asymptomatic DIAN mutation carriers(MC), we estimated the correlation matrix for each EYO sub-interval between the sets of biomarkers and clinical/cognitive outcomes including EYO itself and a global cognitive composite from 22 tests, and compared the matrix from the two EYO sub-intervals. If the correlation matrices were different, we repeated the procedure to each EYO sub-interval until no further dichotomization led to different correlation matrices. A canonical correlation analysis was subsequently performed to MCs in each EYO sub-interval to derive the optimum correlation between the two sets of markers and the optimum weighted canonical variates of biomarkers. Similar analyses were repeated to Non-MCs. The correlation structure from 101 asymptomatic MCs between the sets of biomarkers and clinical/cognitive outcomes was significantly different with EYO dichotomized at -7 years (p<0.0001). Further dichotomization led to a statistical trend, suggesting another possible cutoff of EYO=-19yr. For MCs at least 19 years prior to symptom onset (EY)<=-19yr), the canonical variate of biomarkers had large weights on CSF Aβ42 and PET PIB cortical uptake but almost 0 weights on CSF tau, MRI cortical thickness(precuneus), and PET FDG mean cortical uptake. In contrast, the canonical variate of biomarkers within 7 years of symptom onset(EYO>-7yr) had large weights on MRI cortical thickness, hippocampal volume, and PET FDG uptake. Finally, the canonical variate of biomarkers with EYO from -19 to -7 years weighed largely on CSF Tau and Aβ42. Interestingly, the weight on MRI hippocampal volume was large even in the earliest preclinical stage(EYO<=-19yr). Analyses on 95 asymptomatic Non-MCs revealed no significant difference on correlation structures between biomarkers and clinical/cognitive outcomes as a function of EYO. Results support the hypothesized biomarker orderings and NIA-AA preclinical stages of AD, but the role of hippocampal volume mandates further investigation.