Biomarkers.

Background: Plasma tau phosphorylated at threonine 231 (p-tau231) is a promising novel biomarker of emerging Alzheimer's disease (AD) pathology. We aimed to characterize cross-sectional and longitudinal plasma p-tau231 measurements and estimated ages of biomarker onset in an exceptionally large number of presenilin (PSEN1) E280A (Glu280Ala) mutation carriers and age-matched non-carriers from the Colombian autosomal dominant Alzheimer's disease kindred.

Method: We included a cohort of 722 PSEN1 E280A mutation carriers (mean age 36.36± 12.43 years; 399 females) and 640 non-carriers (mean age=37.29±13.29 years; 350 females) with baseline assessments from the Alzheimer's Prevention Initiative Registry at the University of Antioquia (Medellín, Colombia); of these participants, longitudinal measures were available for 164 mutation carriers and 132 non-carriers (with a mean follow-up of 4.8±3.1 and 5.6±3.2 years respectively). We used an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p-tau231 developed at the University of Gothenburg. Using log-transformed data, we examined the relationship between plasma p-tau231 levels and age to establish the earliest age at which p-tau231 concentrations begin to diverge between mutation carriers and non-carriers. Rates of change in p-tau231 levels were also compared between the two groups. Data were modeled using Linear Mixed Effects Models, a restricted cubic spline, & Hamiltonian Markov chain Monte Carlo analyses.

Result: Carriers had higher levels of plasma p-tau231, compared to non-carriers (9.05±7.44 vs. 5.21±3.37, p<0.001). Plasma p-tau231 measurements were significantly correlated with age in both groups (r=0.63 in carriers vs. r=0.19 in non-carriers, p<0.001) and began to differentiate carriers from non-carriers at age 23 (21 years before the estimated median age at mild cognitive impairment [MCI] onset for this kindred). In population with longitudinal data, PSEN1 E280A mutation carriers had a higher rate of change in p-tau231 levels compared to non-carriers (0.03±0.02 vs. 0.01±0.01, p<0.001) and began to differ from non-carriers at age 19, 25 years before the carriers' estimated median age of MCI onset.

Conclusion: Our findings support the promise of plasma p-tau231 as a biomarker for the detection and tracking of AD pathology, the identification of potential candidates for clinical trials and the evaluation of disease-modifying therapies.