Efficacy and safety of neuromodulation for apathy in patients with Alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials

Background: Non-pharmacological interventions, including noninvasive neuromodulation, may alleviate apathy in individuals with Alzheimer's disease. This systematic review and meta-analysis investigated the efficacy and safety of neuromodulation for apathy in elderly patients with Alzheimer's disease (AD) or mild cognitive impairment (MCI).

Methods: The Cochrane Central Register of Controlled Trials, EMBASE, and PubMed databases were searched for randomized controlled trials (RCTs) of neuromodulation for apathy in AD or MCI. The primary outcome was change in apathy based on the Apathy Evaluation Scale. Secondary outcomes were change in global cognition and trial discontinuation.

Results: The meta-analysis included four RCTs involving 89 patients (aged 65.6-80.5 years) with apathy in AD or MCI. Findings showed no significant improvement in apathy (SMD = 0.57, 95% CI = -0.22-1.36; P = 0.16) or global cognition (SMD = 0.83, 95% CI = -0.11-1.78; P = 0.08) with neuromodulation compared to sham. Subgroup analyses showed significant improvement in apathy with high-frequency rTMS at 120% RMT compared to sham (SMD = 1.36, [95% CI = 0.61-2.12]; P = 0.0004), but not with rTMS at 80% RMT. For global cognition, high-frequency rTMS resulted in significant enhancement (SMD = 1.34 [95% CI = 0.59-2.10]; P = 0.0005), but no notable difference was observed with tDCS compared to sham. There was no significant difference in trial discontinuation in patients with AD or MCI treated with neuromodulation compared to sham.

Conclusion: High-frequency rTMS at 120% RMT for four weeks may be efficacious and safe for the treatment of apathy in elderly patients with AD or MCI. High-frequency rTMS may also improve global cognition in these patients. This implies rTMS has potential as an intervention for apathy in AD and MCI. Large well conducted RCTs are warranted to explore this effect further.