Neurology · Medical Literature
Comparative efficacy and safety of photobiomodulation, transcranial direct current stimulation, and repetitive transcranial magnetic stimulation in Alzheimer's disease: a network meta-analysis of randomized controlled trials.
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which current pharmacological therapies provide only modest and transient benefits, underscoring the need for effective non-pharmacological interventions. Non-invasive brain stimulation (NIBS), including photobiomodulation (PBM), transcranial direct current stimulation (tDCS), and repetitive transcranial magnetic stimulation (rTMS), is a promising approach. This study compared the efficacy, feasibility, and safety of PBM, tDCS, and rTMS in AD. We conducted a Bayesian network meta-analysis (NMA) of randomized controlled trials (RCTs), prospectively registered in PROSPERO (CRD420251006868) and reported according to PRISMA-NMA. The primary outcome was global cognitive performance, assessed by the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were feasibility and safety, evaluated by dropout rates and adverse events, respectively. A total of 34 studies, comprising 35 RCTs (n = 1,559), were included, with one study contributing two independent randomized controlled trials. All three interventions improved global cognitive performance compared with control. PBM showed the highest estimated effects on both MMSE (MD = 3.14, 95% CrI: 1.71 to 4.60) and ADAS-Cog (MD = - 8.01, 95% CrI: -12.82 to - 3.13). In indirect comparisons, PBM was superior to rTMS for ADAS-Cog (MD = - 5.24, 95% CrI: -10.23 to - 0.12), while the MMSE comparison narrowly missed statistical significance (MD = 1.57, 95% CrI: -0.02 to 3.18). These findings were generally consistent across subgroups stratified by baseline cognition and intervention duration. PBM tended to rank highest for cognitive improvement with feasibility and safety comparable to tDCS and rTMS in AD. These findings support the therapeutic potential of PBM, and large-scale RCTs are needed to guide individualized treatment strategies, with implications for clinical decision-making in geriatric care.
Clinical relevance
Among adults with Alzheimer's disease, which non-invasive brain stimulation modality—photobiomodulation (PBM), transcranial direct current stimulation (tDCS), or repetitive transcranial magnetic stimulation (rTMS)—produces the greatest improvement in global cognitive performance, and how do the three compare in feasibility and safety? __SNAPSHOT__ {"studyDesign":"Bayesian network meta-analysis (NMA) of randomized controlled trials; prospectively registered (PROSPERO CRD420251006868); reported per PRISMA-NMA guidelines","setting":"Multinational; comprised trials from multiple institutions and countries (specific settings of included trials not individually reported in the abstract)","sampleSize":"n = 1,559 participants across 35 RCTs drawn from 34 publications (one publication contributed two independent RCTs)","population":"Adults with a diagnosis of Alzheimer's disease; subgroups stratified by baseline cognition severity and intervention duration in sensitivity analyses; specific inclusion/exclusion criteria of the NMA not detailed in the abstract","intervention":"Photobiomodulation (PBM), transcranial direct current stimulation (tDCS), or repetitive transcranial magnetic stimulation (rTMS); specific device parameters, dosing protocols, and stimulation targets not reported in the abstract","comparator":"Sham/control conditions for each respective modality; indirect comparisons between active modalities conducted via network meta-analytic methods","primaryOutcome":"Global cognitive performance assessed by the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog)","followUp":"Not reported in the abstract; subgroup analyses stratified by intervention duration were conducted","fundingSource":"Not reported"}
Key findings
All three active interventions (PBM, tDCS, and rTMS) demonstrated improvement in global cognitive performance relative to control. In the network meta-analysis, PBM showed the highest estimated treatment effect on both primary cognitive scales: MMSE mean difference (MD) = +3.14 points (95% credible interval [CrI]: 1.71 to 4.60) and ADAS-Cog MD = −8.01 points (95% CrI: −12.82 to −3.13), with negative ADAS-Cog values indicating cognitive improvement. In indirect head-to-head comparisons, PBM was statistically superior to rTMS for ADAS-Cog (MD = −5.24, 95% CrI: −10.23 to −0.12). The MMSE comparison of PBM versus rTMS narrowly missed statistical significance (MD = +1.57, 95% CrI: −0.02 to 3.18). Quantitative effect estimates for tDCS versus rTMS direct or indirect comparisons are not reported in the abstract. PBM ranked highest for cognitive improvement across the network. Findings were generally consistent across subgroups stratified by baseline cognition and intervention duration. Effect sizes for tDCS on individual cognitive scales and specific p-values for individual comparisons are not reported in the abstract. NNT is not calculable from the available data. No specific adverse event rates or dropout proportions are reported in the abstract, though dropout rates were used as a feasibility proxy and adverse events as a safety measure; PBM safety and feasibility were described as comparable to tDCS and rTMS.
Practice implications
This NMA establishes that all three NIBS modalities—PBM, tDCS, and rTMS—produce statistically significant improvements in global cognition relative to sham in patients with Alzheimer's disease, with PBM demonstrating the largest estimated effect sizes on both MMSE and ADAS-Cog. The finding that PBM was statistically superior to rTMS for ADAS-Cog in indirect comparison is notable, although the MMSE comparison only narrowly missed significance and credible intervals were wide, signaling uncertainty. Critically, the clinical significance of the MMSE and ADAS-Cog effect sizes remains uncertain: an MMSE improvement of ~3 points and ADAS-Cog improvement of ~8 points may be clinically meaningful, but whether they reflect durable functional benefit, generalize beyond the trial window, or translate to patient-important outcomes (e.g., activities of daily living, caregiver burden, institutionalization) cannot be determined from this data. The PBM evidence base was notably smaller than that for rTMS at the time of this analysis, and indirect comparisons in a network meta-analysis carry additional uncertainty compared to head-to-head RCT data. Patients with very severe AD, significant comorbidities, or who were not enrolled in the constituent trials are not adequately represented. Additionally, the abstract does not specify stimulation parameters, session frequency, or duration of effect, which are critical for real-world implementation. Only an abstract was available for review; full-text data on heterogeneity, risk-of-bias assessments, publication bias analyses, and granular safety outcomes were not accessible. Practice should not change based on this NMA alone; results support prioritizing PBM in future large-scale, well-powered, adequately blinded head-to-head RCTs with clinically meaningful and durable endpoints before adoption into routine clinical care. __LIMITATIONS__ Only an abstract was available for full appraisal; heterogeneity statistics (I², τ²), SUCRA values, risk-of-bias assessments, and complete safety/dropout data were not accessible.,Small total sample size (n = 1,559 across 35 RCTs) with likely unequal distribution across modalities, limiting statistical precision especially for PBM, which has a smaller evidence base than rTMS.,Network meta-analysis relies on indirect comparisons; the transitivity assumption (that trials of different modalities are sufficiently similar to permit indirect inference) cannot be verified from the abstract and may be violated by differences in patient populations, disease severity, stimulation protocols, or sham procedures across modalities.,PBM effect size estimates carry the widest credible intervals, suggesting high uncertainty and potentially fewer contributing trials; the PBM versus tDCS indirect comparison is not reported.,Stimulation parameters (frequency, intensity, site, session number, duration) vary substantially across included trials, contributing to clinical heterogeneity that may inflate or deflate apparent efficacy differences.,Global cognitive scales (MMSE, ADAS-Cog) are surrogate endpoints; translation to patient-important outcomes (functional independence, quality of life, caregiver burden) was not assessed.,Duration of follow-up and durability of cognitive improvements post-intervention are not reported, limiting understanding of whether benefits are sustained.,Potential publication bias favoring positive results in all three NIBS literatures; Egger or Begg test results are not reported in the abstract.,Funding source is not reported, precluding assessment of potential conflicts of interest.,Generalizability is uncertain: AD severity, ethnicity, concomitant pharmacotherapy (e.g., cholinesterase inhibitors, anti-amyloid agents), and setting (inpatient vs. outpatient) of constituent trials are not described. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ This Bayesian network meta-analysis of 35 RCTs (n = 1,559) found that PBM, tDCS, and rTMS all improved global cognition in Alzheimer's disease versus sham, with PBM producing the largest estimated effects (MMSE MD +3.14, ADAS-Cog MD −8.01) and demonstrating statistical superiority over rTMS on ADAS-Cog in indirect comparison. However, the evidence base for PBM is smaller than that for rTMS, indirect comparisons carry inherent uncertainty, and the clinical durability and functional significance of these gains remain unestablished. Large-scale, head-to-head RCTs with patient-important outcomes and long-term follow-up are required before PBM or any NIBS modality can be recommended as standard adjunctive therapy for Alzheimer's disease.