# Elevated Levels of Plasma Phosphorylated Tau 181 (pTau181) Associated With Opioid Use to Guide Medication Titration Over a Clinically Relevant Short Timescale

## TL;DR

This study shows that plasma pTau181 levels are linked to opioid use and could help guide medication adjustments in patients with premature neuronal aging.

## Contribution

The study demonstrates a novel association between opioid use and pTau181 levels for rapid medication titration in clinical settings.

## Key findings

- pTau181 was elevated in 38.75% of patients with neuropsychiatric polypharmacy.
- Opioid use was significantly associated with elevated pTau181 and NfL levels.
- Biomarkers correlated with age but not with other medication use.

## Abstract

Background: The identification of many medications that delay neurodegeneration in animal models has created too many combinations to try in patients when time is short. We hypothesized that biomarkers of premature neuronal aging that are part of the amyloid-tau-neurodegeneration (ATN) profile, namely amyloid-β ratio, phosphorylated tau 181 (pTau181), and neurofilament light chain (NfL), could provide tools to optimize treatment in single-patient trials rapidly.

Methods: We retrospectively analyzed these biomarkers in patients with extensive neuropsychiatric polypharmacy and premature neuronal aging. We investigated whether ATN profile biomarkers were associated with age, gender, metabolic syndrome markers, and medication use. Additionally, two case reports provided examples of ATN biomarker application in clinical settings.

Results: We identified 113 patients with plasma ATN profiles. Of 80 of those patients, clinical phenotypic data were available. Among these 80 patients, 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. The biomarkers were not associated with other medication use.

Conclusion: It is now possible to identify the overlaps between complex behavioral phenotypes (pain and cognition), plasma endophenotypes (ATN profile), and medication-targeted components of age-related pathophysiology. The current study provides a proof of concept; future research should focus on single-patient trials in patients with premature neuronal aging, where medication and dosage choices are based on individual ATN profiles. To facilitate such single-patient trials, funding is needed to promote the use of repurposed generic treatments, educate patients and providers regarding optimization principles, and continue developing sensitive biomarkers. Together, these can ensure the rapid progress of single-patient trials for treatment optimization.