Evidence map›Paper›PMID 42178577›Full record

Trial reportAlzheimer's research & therapy2026

Uncovering lipid biomarkers linked to methylphenidate efficacy in treating apathy in Alzheimer's disease: insights from the ADMET 2 trial.

Myuri Ruthirakuhan, Maya Mills, Paul Rosenberg, Norman Haughey, Jacobo Mintzer, Olga Brawman-Mintzer, Suzanne Craft, Nathan Herrmann, Alan J Lerner, Allan I Levey and 5 more

Abstract readRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Alzheimer's research & therapy, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0cells of the map it votes in
0citing papers in PubMed
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1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors.

Myuri RuthirakuhanSunnybrook Research Institute, University of Toronto, 2075 Bayview Avenue, EG04, Toronto, ON, M2N 3M5, Canada.
Maya MillsSunnybrook Research Institute, University of Toronto, 2075 Bayview Avenue, EG04, Toronto, ON, M2N 3M5, Canada.
Paul RosenbergJohns Hopkins University School of Medicine, Baltimore, MD, USA.
Norman HaugheyTulane University School of Medicine, New Orleans, LA, USA.
Jacobo MintzerRalph H. Johnson VA Health Care System, Medical University of South Carolina, Charleston, USA.
Olga Brawman-MintzerRalph H. Johnson VA Health Care System, Medical University of South Carolina, Charleston, USA.
Suzanne CraftWake Forest University, Winston-Salem, NC, USA.
Nathan HerrmannSunnybrook Research Institute, University of Toronto, 2075 Bayview Avenue, EG04, Toronto, ON, M2N 3M5, Canada.
Alan J LernerUniversity Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
Allan I LeveyEmory Goizueta Alzheimer's Disease Research Center, Atlanta, GA, USA.
Prasad R PadalaCentral Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, USA.
Anton PorsteinssonUniversity of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
Christopher H van DyckYale School of Medicine, New Haven, CT, USA.
David ShadeJohns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Krista L LanctôtSunnybrook Research Institute, Toronto, ON, Canada. krista.lanctot@sunnybrook.ca.

Funding

Apathy in Alzheimer's Disease Methyphenidate Trial II (ADMET II)R01AG046543 · NIA · MEDICAL UNIVERSITY OF SOUTH CAROLINA · PI HERRMANN, NATHAN, LANCTOT, KRISTA L. · 2014 to 2018
$8.1M
NIA NIH HHS R01 AG046543
6 · The paper itself

Abstract

backgroundApathy is a prevalent neuropsychiatric symptom (NPS) in Alzheimer's disease (AD), linked to functional impairment and reduced quality of life. The Apathy in Dementia Methylphenidate Trial 2 (ADMET-2) found methylphenidate (MPH) had modest efficacy for treating apathy, but treatment responses varied. MPH blocks dopamine and noradrenaline transporters, inhibiting dopamine and noradrenaline reuptake. Lipids are closely tied to monamine transporter function through their structural and signaling roles in neurotransmission, neuroinflammation, and synaptic plasticity. This study aimed to identify lipid species associated with MPH response and explore lipid pathway disruptions in responders versus non-responders.

methodsParticipants from ADMET-2 with baseline lipidomic data were included. Responders were defined by a ≥4-point improvement on the Neuropsychiatric Inventory Apathy subscale (NPI-A), or moderate-to-marked improvement on the ADCS-Clinicians Global Impression-Change (ADCS-CGIC). Baseline plasma samples underwent lipidomic profiling. Sparse Partial Least Squares Discriminant Analysis (sPLS-DA) in the MPH group was used to identify lipid species distinguishing responders from non-responders. Model performance was evaluated by area under the curve (AUC). Identified lipid species were analyzed in MetaboAnalyst for pathway enrichment. A secondary analysis in the placebo group assessed specificity of findings to MPH.

resultsOf the 43 MPH-treated participants, 28 were NPI-apathy responders, and 10 were ADCS-CGIC responders. The PLS-DA model achieved robust discrimination between responders and non-responders (NPI-apathy: AUC = 0.82 +/- 0.05; ADCS-CGIC: AUC=0.84 +/- 0.07). Pathway analysis revealed disruptions in ceramide, phosphosphingolipid, and glycosphingolipid metabolism for NPI-apathy responders, and ceramide and glycosphingolipid metabolism for ADCS-CGIC responders. In 55 placebo-treated participants (30 NPI-apathy responders), an AUC of 0.79 +/- 0.05 was achieved, with pathway analysis indicating disruption in glycosphingolipid metabolism only.

conclusionsThis study demonstrates the utility of lipidomic profiling in identifying biomarkers of response to MPH in AD patients with apathy. The identified lipidomic species are broadly related to monoamine transporter function, reflecting their role in neurotransmission and synaptic plasticity. While glycosphingolipid metabolism appears broadly linked to changes in apathy, disruptions in ceramide and phospholipid metabolism may be specific to MPH treatment. Further study of these pathways may offer insights into the molecular mechanisms underlying apathy and treatment response, and could inform future biomarker-guided interventions.

Indexed as

Alzheimer DiseaseApathyCentral Nervous System StimulantsLipidsMethylphenidateAgedBiomarkersFemaleHumansLipidomicsMaleTreatment OutcomeBiomarkersCentral Nervous System StimulantsLipidsMethylphenidateAlzheimer’s diseaseApathyLipidomicsMethylphenidate

Identifiers

PMID42178577
PMCPMC13540924

What Socratic holds

Textmetadata
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.