Longitudinal cognitive changes in SCD participants in relation to plasma amyloid status and the potential additive effect of plasma ptau181 levels: A CLoCODE study

Abstract Background Subjective cognitive decline (SCD), in the absence of objective cognitive impairment, may be the first symptomatic manifestation of Alzheimer's disease (AD). Previous studies have suggested that its combination with amyloid‐positivity (Aβ+) may represent stage 2 AD, and is associated with a higher risk of future cognitive decline. Here, we aim to (1) confirm this using the plasma Aβ42/40 ratio, and (2) test whether the addition of plasma phospho‐tau181 (ptau 181 , a marker of Aβ and tau pathology) could help refine the prediction of future cognitive decline in SCD patients. Method We included 290 cognitively unimpaired older adults with SCD from two cohorts included in the ongoing Sino‐German CLoCODE collaborative project (49.3% female, 70.80±6.18y): 31 from SILCODE, and 259 from DELCODE. All participants had available baseline plasma biomarkers (Aβ42/40 ratio and ptau 181 using the SIMOA method), and serial assessment of global cognition using a z‐transformed standard composite score over up to 6 years. Linear mixed‐effects models were conducted to confirm the predictive value of plasma Aβ+ for longitudinal cognitive decline in participants with SCD (model 1), and to determine the additive value of plasma ptau 181 levels by examining their interaction (model 2), but also its effect in samples stratified by Aβ+/‐ (models 3). Result In the combined CLoCODE sample, we found a significant interaction between time and Aβ confirming that Aβ+ SCD (42.1% of CLoCODE SCD patients) had a faster cognitive decline than Aβ‐ SCD patients, who showed test‐repetition improvement (p<0.001). This association remained significant when ptau 181 was added to the model (p=0.002). A triple interaction between time, Aβ, and ptau 181 was also found (p<0.001), showing that those with a faster cognitive decline were Aβ+ SCD patients with higher baseline ptau 181 levels (Figure A). This was also confirmed in stratified analyses, where there was a significant interaction between time and ptau 181 levels only in Aβ+ participants (p<0.001; Aβ‐, p=0.72; Figure B). Similar results were obtained in stratified cohort analyses. Conclusion Our findings suggest that plasma biomarkers of AD pathology may help to identify SCD patients who will experience future cognitive decline due to AD, and thus require closer follow‐up.