Introduction: Methylphenidate has been shown to improve apathy in patients with Alzheimer's disease (AD). The authors evaluated the impact of methylphenidate on neuropsychiatric symptoms (NPS) of AD, excluding apathy, using data from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) study., Methods: A secondary analysis was conducted on data from the ADMET 2 study to determine the effect of methylphenidate on Neuropsychiatric Inventory (NPI) scores outside of apathy. Caregiver scores were compared from baseline to month 6 in 199 participants receiving methylphenidate (20 mg/day) or placebo regarding the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and individual domain scores., Results: No clinically meaningful improvement was observed in any NPI domain, excluding apathy, in participants treated with methylphenidate compared to placebo after 6 months. A statistical difference between groups was appreciated in the domains of elation/euphoria ( P = 0.044) and appetite/eating disorders ( P = 0.014); however, these findings were not considered significant., Discussion: Methylphenidate is a selective agent for symptoms of apathy in patients with AD with no meaningful impact on other NPS. Findings from this secondary analysis are considered exploratory and multiple limitations should be considered when interpreting these results, including small sample size and use of a single questionnaire. HIGHLIGHTS: Methylphenidate was not associated with significant improvement on the Neuropsychiatric Inventory in domains outside of apathy.Methylphenidate did not show a statistically significant emergence of new neuropsychiatric symptoms (NPS) throughout the 6-month treatment period compared to placebo.Methylphenidate appears to be a highly selective agent for apathy in Alzheimer's disease, potentially supporting catecholaminergic dysfunction as the driving force behind this presentation of symptoms., Competing Interests: Dr. Brawman‐Mintzer receives grant funding from the National Institute on Aging, Merck, Alzheimer's Trials Research Institute and Alzheimer's Cooperative Trials Consortium, and the Department of Defense. Dr. Brawman‐Mintzer has served as a steering committee member for the Alzheimer's Disease Cooperative Study and as an associate steering committee member with the Alzheimer's Clinical Trials Consortium. Dr. Brawman‐Mintzer has received payment or honoraria from Medscape. Dr. Clark reports grants to her institution for clinical trials from Alzheon and Biogen. Dr. Lanctôt reports grants from Alzheimer's Association (PTC‐18‐543823, PTCG‐20‐ 700751), Alzheimer Society of Canada, Alzheimer's Drug Discovery Foundation (Grant No: 2016354), Canadian Institutes Health Research (PJ2‐179752, PJT‐183584), National Institute on Aging (R01AG046543), and Weston Brain Institute; consulting fees from BioXcel Therapeutics, Bright Minds, Cerevel Therapeutics, Eisai Co. Ltd, Exciva, ICG Pharma, Jazz Pharmaceuticals, Kondor Pharma, H Lundbeck A/S, Merck, Novo Nordisk, Praxis Therapeutics, Sumitomo Pharma Co. Ltd; stock options from Highmark Interactive outside the submitted work. Krista Lanctôt is the Bernick Chair in Geriatric Psychopharmacology of Sunnybrook Health Sciences Centre and University of Toronto's Temerty Faculty of Medicine. Dr. Lerner receives research grant support from the National Institutes of Health and National Institute on Aging (P30AG072959), Alzheimer's Clinical Trials Consortium, the Elisabeth S. Prentiss Foundation. He receives honoraria for consulting from Premier Inc (PINC AI Applied Sciences). He has received book royalties from Elsevier. He is a steering committee member of the Alzheimer's Clinical Trials Consortium. Dr. Jacobo Mintzer is a consultant and Governance Committee Member for AARP's Global Council on Brain Health and a consultant and Scientific Advisor for AARP's Staying Sharp Scientific Advisory Committee. He is a consultant for ACADIA, AiOmed, Corium, Exciva, Genentech (affiliate of F. Hoffmann‐La Roche Ltd), Ironshore Pharmaceuticals, Lundbeck, Praxis Bioresearch, and Sygnature Discovery. Dr. Mintzer is a Steering Committee Member for the Alzheimer's Clinical Trials Consortium, Alzheimer's Disease Cooperative Study, and the Elder Court. He is a Board Member for the Alzheimer's Association, SC Chapter and the Technology Accelerator Company as well as an Association Member of the International Psychogeriatric Association. He is a Scientific Advisory Board Member for Exciva and Advisory Board Member for ACADIA. Dr. Mintzer is a stockholder and the VP for Clinical Affairs for NeuroQuest, a majority owner of Biopharma Connex, and a majority partner for Recruitment Partners. Dr. Mintzer has received payment or honoraria from ACADIA. He is receiving support for specific clinical trials from Cerevel Therapeutics, LLC, Eisai Inc., Eli Lilly and Company, the Alzheimer's Association, the Alzheimer's Drug Discovery Foundation, the National Institute on Aging, the National Institutes of Health, and the National Endowment for the Arts. Dr. Mintzer has received support for attending meetings and/or travel from AARP Global Council on Brain Health (GCBH), AiOmed, and Alzheimer's Clinical Trials Consortium. Finally, he has served as a DSMB member for NAB‐It: Nabilone for Agitation Blinded Intervention Trial. Dr. Padala receives support for his time from the Department of Veterans Affairs and the National Institutes of Health. Dr. Perin received grant support for the present manuscript from the National Institutes of Health (Grant R01AG046543). Dr. Rosenberg has received research grants from the National Institute on Aging, Alzheimer's Association, Alzheimer's Clinical Trials Consortium, Alzheimer's Trials Research Institute and Alzheimer's Cooperative Trials Consortium, Richman Family Precision Medicine Center of Excellence on Alzheimer's Disease, Eisai, Functional Neuromodulation, and Lilly; honoraria from consulting for GLG, Leerink, Cerevel, Cerevance, Bioxcel, Sunovion, Acadia, Medalink, Novo Nordisk, Noble Insights, TwoLabs, Otsuka, Lundbeck, Biogen, MedaCorp, ExpertConnect, and HMP Global. He participates on an advisory board for Synaptogenix. He has received honoraria for presentations from Medscape and Neurology Week, and has received support for travel for a consultation meeting from Lundbeck. Dr. David Shade received grant support for the present manuscript from the National Institutes of Health. Dr. van Dyck serves as a scientific advisor for Eisai, Roche, Ono, and Cerevel and reports grant support for clinical trials from Biogen, Biohaven, Cerevel, Eisai, Eli Lilly, Genentech, Janssen, Roche, and UCB. He also participates as a member of the Medical and Scientific Advisory Group for the Alzheimer's Association. Dr. Porsteinsson reports DSMB membership fees from Acadia, Cadent, Cognitive Research Corp, Functional Neuromodulation, Neurim, Novartis, and Tetra Discovery Partners; consulting fees from Athira, Avanir, Biogen, BioXcel, Eisai, Grifols, IQVIA, Lundbeck, Maplight Therapeutics, Merck, ONO Pharmaceuticals, Pfizer, and Toyama; grants for clinical trials from the National Institute on Aging, National Institute on Mental Health, the Department of Defense, Alector, AstraZeneca, Athira, Avanir, Biogen, Biohaven, Cassava, Eisai, Eli Lilly, Genentech/Roche, Janssen, Merck, Novartis, Toyama, and Vaccinex outside the submitted work. Dr. Herrmann declares no conflicts of interest. Susie Sami declares no conflicts of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not‐for‐profit sectors. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)