Biomarkers.

Background: Combining plasma phosphorylated Tau 217 (pTau217), with cognitive assessments allows for predicting incident dementia in mild cognitive impairment (MCI). However, the performance of this approach in primary care as well as the added value of other blood-based biomarkers (BBM) in this setting is unclear.

Methods: We examined 833 older primary care patients from the AgeCoDe/AgeQualiDe study (median age=83). Plasma ALZpath pTau217 and other blood-based biomarkers (BBM; pTau181, GFAP, NfL, Abeta-42/40) were measured using single-molecule arrays. Subjective cognitive decline (SCD) and the Mini-Mental State Examination (MMSE) were assessed at baseline. We evaluated the performance of BBM, MMSE, and SCD reports for predicting the development of any cognitive impairment (MCI or dementia) or conversion to dementia at 3.5 and 7 years of follow-up using time-dependent ROC analysis with death as competing risk.

Results: Plasma pTau217 improved the prognosis of developing any cognitive impairment at follow-up beyond age, sex, and renal function (base model; Figure 1) and showed a high prognostic value at 7 years of follow-up (p<0.001, AUC=0.809; 3.5 years prognosis: p<0.001; AUC=0.767). Adding SCD and MMSE to the model provided only a small improvement in short-term prediction (3.5 years prognosis: p=0.002; AUC=0.785) while no significant improvements were observed by considering other BBM. For predicting incident dementia, pTau217 also increased the prognostic value beyond the base model (3.5 years: p=0.044, AUC=0.689; 7 years: p=0.002; AUC=0.697). However, this increase was smaller as compared to the prognosis of any cognitive impairment since individuals developing MCI but not dementia showed similar pTau217 levels at baseline. Furthermore, considering MMSE and SCD reports resulted in a considerable increase in prognostic value beyond pTau217 (3.5 years: p<0.001, AUC=0.791; 7 years: p=0.002; AUC=0.749). Plasma pTau217 in turn improved the long-term prediction beyond SCD reports and MMSE (p<0.001, AUC=0.749 vs 0.724). Again, other BBM did not increase the prognostic value.

Conclusions: In our sample, pTau217 showed a high ability to discriminate between older primary care patients who will stay cognitively stable over seven years from patients developing any cognitive impairment, in contrast to other BBM. Assessments of SCD and cognition can further improve the identification of patients at increased short-term risk for dementia.