Peripheral biomarkers associated with apathy and predicting response to methylphenidate: Secondary analysis of the Apathy in Dementia Methylphenidate Trial 2 (ADMET2) study

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BACKGROUND: In Apathy in Dementia Methylphenidate Trial 2 (ADMET2), apathy in Alzheimer's disease improved with methylphenidate (MPH) in a randomized, placebo-controlled trial, though response varied. Here we evaluated serum biomarkers for their association with apathy and with treatment response. METHODS: All ADMET2 participants with available blood samples were included. Markers of inflammation [interleukin (IL)-6, IL-10, Tumor Necrosis Factor (TNF)], oxidative stress [lipid hydroperoxide (LPH), 4-hydroxynonenal (4-HNE), 8-isoprostane (8-ISO)] and neuronal injury [neurofilament light (NfL), S100B] were assessed and values log-transformed. Neuropsychiatric Inventory-apathy (NPI-A) measured apathy. Least Absolute Shrinkage and Selection Operator (LASSO) regression was performed for feature selection of baseline markers predicting NPI-A at Month-6 (M6). Univariate analyses examined individual biomarker effects and multivariable models evaluated their combined effects. Treatment interactions, baseline and change in biomarker levels in treatment responders (≥4 change in NPI-A) and remitters (M6 NPI-A=0) were explored. RESULTS: In the ADMET2 biomarker subset (n = 44, MPH:21, age:75 years, MMSE:20.2), higher baseline TNF was associated with higher M6 NPI-A [B(SE)= 6.86 (1.71), p = .0003], and multivariable models found lower baseline TNF [B(SE)= 8.28(1.61), p < .001] and higher baseline S100B [B(SE)= -6.41(1.95), p = .002] were associated with lower M6 NPI-A. Exploratory analyses suggested that higher baseline NfL significantly interacted with treatment to predict lower M6 NPI-A [B(SE)= -8.36(4.21), p = .05], only when adjusting for cognition. MPH remitters had lower baseline TNF [B(SE)= -0.27(0.10), p = .02], higher baseline NfL [B(SE)= 0.33(0.14), p = .03], and a greater decrease in IL-6 [B(SE)= -0.44 (0.17), p = .02]. CONCLUSIONS: Inflammatory and neuronal injury biomarkers may have prognostic value and may potentially inform treatment response and remission outcomes in apathy. Apathy in Dementia Methylphenidate Trial 2 (ADMET2), NCT02346201, https://clinicaltrials.gov/study/NCT02346201.

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