Combined Therapies May Improve Outcomes in Alzheimer Disease

Therapeutic approaches that combine pharmacologic and nonpharmacologic interventions are associated with the best outcomes for patients with Alzheimer disease (AD), according to findings published in the Journal of Alzheimer’s Disease.

Researchers systematically reviewed randomized controlled trials published between March 2021 and December 2022 in Medline and Scopus to compare the efficacy of pharmacologic, nonpharmacologic, and combined treatments for adults aged 60 years and older with mild to moderate AD. Eligible trials assessed the efficacy of interventions and reported outcomes related to cognition, behavior, or daily function.

A total of 153 trials were included in the final analysis. Most studies were single-center, study duration ranged from 1 week to 2 years, mean participant age ranged from 64.0 to 86.5 years, and the percentage of women ranged widely (9%-100%).

[O]ur [network meta-analysis] emphasizes the clinical advantages of combining pharmacotherapies and non-pharmacotherapies for AD patients.

Pharmacological interventions included acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine), N-methyl-D-aspartate receptor antagonists (memantine), and herbal preparations (huperzine A, Ginkgo biloba extract). Nonpharmacologic approaches included cognitive therapy, cognitive stimulation, cognitive rehabilitation, exercise, and noninvasive brain stimulation.

Across 110 cognitive trials (n=12,326), combination strategies such as rivastigmine plus cognitive rehabilitation and donepezil plus cognitive therapy yielded the greatest improvements in Mini-Mental State Examination scores, approaching or exceeding the study’s threshold for clinically meaningful change (3.5-3.95 points), and ranked highest in surface under the cumulative ranking analysis (SUCRA; 92.8% and 90.3%, respectively). Nonpharmacologic interventions such as exercise (mean difference [MD], 2.02), cognitive training (MD, 1.67), and brain stimulation (MD, 2.41) also improved cognition compared with placebo.

For behavioral symptoms measured by the Neuropsychiatric Inventory (62 trials; n=10,336), the greatest reductions in symptom burden occurred with brain stimulation plus exercise (MD, -12.0; SUCRA, 93.1%) and rivastigmine plus cognitive stimulation (MD, -11.7; SUCRA, 93.0%), both surpassing the 8-point minimal clinically important difference.

Functional outcomes assessed in 43 trials (n=6945) improved most with rivastigmine plus cognitive stimulation (standardized MD [SMD], 0.92; SUCRA, 94.1%), followed by structured exercise programs (SMD, 0.41; SUCRA, 78.8%).

Limitations include variability in outcome measures and study quality across trials, modest heterogeneity in intervention protocols, and potential publication bias favoring smaller studies with positive findings.

“[O]ur [network meta-analysis] emphasizes the clinical advantages of combining pharmacotherapies and non-pharmacotherapies for AD patients,” the study authors concluded.

Disclosures: This research was supported by Health Systems Research Institute, Thailand. Please see the original reference for a full list of disclosures.