Improvements in Alzheimer Apathy From Methylphenidate Not Driven by Cognitive Changes, ADMET 2 Data Show

Author(s):

Over a 6-month treatment period, changes in apathy for methylphenidate-treated patients were not associated with performance on the remaining cognitive tests.

Krista Lanctôt, PhD

Additional data from the previously completed ADMET 2 trial (NCT0234601) showed that changes in apathy among patients with Alzheimer disease (AD) treated with methylphenidate were not driven by cognitive changes. These data contrast previous natural history studies that link changes with apathy to improvements in cognition within this patient population.¹

Presented at the 2024 Alzheimer’s Association International Conference (AAIC), held July 28-August 1 in Philadelphia, Pennsylvania, the analysis featured 199 participants from the original study who received 20 mg of methylphenidate or placebo for 6 months. In the multicenter study, apathy was measured using the Neuropsychiatric Inventory apathy (NPI-A) subscale, while cognition was assessed through a litany of tests, including the Mini-Mental State Exam (MMSE), Hopkins Verbal Learning-immediate (HVLT-I) and delayed (HVLT-D), Digit Span forward (DF) and backward (DB), Trail Making (TMT A and B), Action Verbal Fluency (AV), Category Fluency (CF), and Boston Naming Test (BNT).

Led by senior author Krista Lanctôt, PhD, a clinical pharmacologist at the University of Toronto, worsening apathy was associated with worsening MMSE (B = –0.10 [SE, 0.03]; P = .003), CF (B = –0.13 [SE, 0.04]; P = .0009) and HVL-I (B = –0.13 [SE, 0.05]; P = .005) across the entire cohort. Among those taking methylphenidate (n = 98) worsening apathy was only associated with worsening CF (B = –0.21 [SE, 0.06]; P = .0008).

Methylphenidate has been one of the most studied catecholaminergic compounds in older adults and has a good safety profile, with 2 trials, including ADMET 2, that have shown preliminary efficacy in apathy in AD. In the analysis, those who received placebo showed that worsening apathy was associated with worsening MMSE (B = –0.13 [SE, 0.05]; P = .006), HLVT-I (B = –0.30 [SE, 0.06]; P = .000002), and HVLT-D (B = –0.06 [SE, 0.02]; P = .002). Overall, changes in apathy among methylphenidate-treated participants were not associated with performance on the remaining cognitive tests.

ADMET 2, a randomized placebo-controlled trial conducted from 2016 to 2020, had data originally published in JAMA Neurology. The study’s original coprimary outcomes included changes from baseline to 6 months in the NPI-A subscale or improved rating on the Alzheimer’s Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC). After 6 months of treatment, results showed a larger decrease in NPI-A in those who received methylphenidate compared with placebo (mean difference, –1.25; 95% CI, –2.03 to –0.47; P = .002).²

Additional data from the original study showed that the largest decrease in NPI-A score was observed in the first 100 days of treatment, with a significant hazard ratio for the proportion of patients with no apathy symptoms receiving methylphenidate vs placebo (2.16; 95% CI, 1.19-3.91; P = .01). At 6 months, the odds ratio for having an improved rating on the ADCS-CGIC for methylphenidate compared with placebo was 1.90 (95% CI, 0.95-3.84; P = .07). Between the 2 groups, there were no significant differences in cognitive measures and quality of life.

A secondary, exploratory analysis published in 2023 revealed that methylphenidate has no meaningful impact on other neuropsychiatric symptoms of AD. Although these data should be cautioned, considering the multiple limitations involved, no clinically meaningful improvement was observed in any NPI domain, excluding apathy, in treated participants compared with placebo after 6 months. A statistical difference between groups was appreciated in the domains of elation/euphoria (P = .044) and appetite/eating disorders (P = .014); however, these findings were not considered significant.³

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REFERENCES
1. Sankhe K, Tumani S, Perin J, et al. Correlation between changes in apathy and cognition in Alzheimer’s disease associated apathy: analysis of the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2). Presented at: AAIC; July 28-August 1, 2024; Philadelphia, PA. ABSTRACT 91793
2. Mintzer J, Lanctôt KL, Scherer RW, et al. Effect of methylphenidate on apathy in patients with Alzheimer disease: the ADMET 2 randomized clinical trial. JAMA Neurol. 2021;78(11):1324-1332. doi:10.1001/jamaneurol.2021.3356
3. Clark ED, Perin J, Herrmann N, et al. Effects of methylphenidate on neuropsychiatric symptoms in Alzheimer’s disease: evidence from the ADMET 2 study. Alzheim Assoc. 2023;9(3):e12403. doi:10.1002/trc2.12403