International psychogeriatrics · 2026
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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Sankhe Krushnaa, Ruthirakuhan Myuri, Andreazza Ana C, Brawman-Mintzer Olga, Craft Suzanne, Herrmann Nathan, Ismail Zahinoor, Lerner Alan J, Levey Allan I, Mintzer Jacobo, Padala Prasad R, Perin Jamie, Porsteinsson Anton P, Rosenberg Paul B, Shade David, Tumati Shankar, van Dyck Christopher H, Lanctôt Krista L
Аннотация
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.
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.