Elevated plasma pTau181 in a specialty neuropsychiatric clinic is associated with opioid use and guides medication titration on a clinically relevant short-time scale

A combinatorial explosion of agents that delay neurodegeneration in animal models has created a crisis of abundance in human applications with too many combinations to try when time is short. Plasma biomarkers of premature neuronal aging, the amyloid-tau-neurodegeneration (ATN) profile, may provide a tool to rapidly optimize treatment in single-patient trials. We retrospectively analyzed plasma ATN profiles in patients with extensive neuropsychiatric polypharmacy and premature neuronal aging. ATN profiles were based on the biomarkers amyloid-β ratio, phosphorylated Tau 181 (pTau181), and neurofilament light chain (NfL). We investigated whether ATN profile biomarkers were associated with age, gender, metabolic syndrome markers, and medication use. Two case reports additionally provide examples of the application of ATN profiles in clinical settings. We found that in 80 patients with ATN profiles and complete clinical phenotypes, pTau181 was elevated in 31 (38.75%), amyloid-β ratio was below normal ranges in 11 (13.75%), and NfL was elevated in three (3.75%). The biomarkers correlated with age, as expected. Opioid use was significantly associated with pTau181 (p=0.004) and NfL (p=0.002), also after Bonferroni correction (both p <0.05), but not with amyloid-β ratio. No other medications were associated with the biomarkers. In conclusion, identifying the overlaps between complex behavioral phenotypes (pain and cognition), plasma endophenotypes (ATN profile), and medication-targeted components of age-related pathophysiology is now a technical problem rather than theoretical speculation. Rapid progress in single-patient trials for treatment optimization will require funding to promote using repurposed generic treatments, educate patients and providers regarding optimization principles, and continue developing sensitive biomarkers.