Neuromodulatory interventions for Alzheimer's disease

Alzheimer's disease (AD) and mild cognitive impairment (MCI) represent an escalating global public health challenge with major socioeconomic consequences. Although anti-amyloid monoclonal antibodies have introduced disease-modifying treatment options for early symptomatic AD, their benefits remain modest and must be balanced against cost, monitoring burden, and safety risks. Neuromodulatory interventions have therefore emerged as promising investigational strategies that may complement existing therapeutic approaches. This narrative review evaluates current clinical and neurophysiological evidence for seven major neuromodulation approaches: 40 Hz gamma rhythm sensory stimulation, also known as gamma entrainment using sensory stimulation (GENUS), transcranial alternating current stimulation (tACS), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), focused ultrasound (FUS), deep brain stimulation (DBS), and transcranial photobiomodulation (tPBM). Integrating clinical findings with mechanistic evidence, we examine synaptic plasticity, neuroinflammation, glymphatic clearance, oscillatory entrainment, and cholinergic signaling as candidate therapeutic mechanisms. A comparative matrix summarizes target specificity, invasiveness, stimulation parameters, and translational status. Finally, we discuss key barriers, including biological heterogeneity, protocol standardization, durability of benefit, caregiver burden, and the uncertain implications of continuous network stimulation for future personalized and closed-loop interventions.