Short-Term Cognitive and Behavioral Changes After Low-Intensity Transcranial Ultrasound Stimulation in Early Alzheimer’s Disease: An IPTW-Adjusted Retrospective Exploratory Comparative Study

Background: Low-intensity ultrasound (LIUS) has been proposed as a non-invasive approach to modulate cerebrospinal fluid movement, glymphatic–lymphatic clearance, and amyloid-beta (Aβ) handling in Alzheimer’s disease (AD). However, clinical comparisons in amyloid biomarker-confirmed patients receiving standard pharmacotherapy remain limited, and the short-term cognitive domains most likely to change after LIUS remain uncertain. Objective: The objective of this study was to compare 4-week changes in cognitive function, executive function, quality of life, and neuropsychiatric symptoms between amyloid PET-positive patients receiving add-on LIUS with donepezil-based standard treatment and those receiving donepezil-based standard treatment alone. Methods: This retrospective exploratory comparative cohort study included amyloid PET-positive patients with mild cognitive impairment or early AD who received donepezil-based standard treatment. The treatment cohort received 4 weeks of add-on LIUS at Dongtan or Bundang centers, whereas the comparator cohort received donepezil-based standard treatment alone at Soonchunhyang. Outcomes were changes from baseline to 4 weeks in Trail Making Test A (TMT-A), Trail Making Test B (TMT-B), Mini-Mental State Examination, Second Edition (MMSE-II), Quality of Life in Alzheimer’s Disease (QoL-AD), and Neuropsychiatric Inventory (NPI). Group differences were examined using unadjusted change-score comparisons and stabilized inverse probability of treatment weighting (IPTW). Results: The full analysis set included 51 amyloid PET-positive participants receiving donepezil-based standard treatment: 20 who additionally received LIUS and 31 who received standard treatment alone. Compared with controls, the add-on LIUS group showed greater improvement in TMT-A completion time in unadjusted analysis (−20.0 ± 31.3 s vs. −0.1 ± 5.6 s; p = 0.011), and this association remained significant after IPTW adjustment. TMT-B showed a favorable but less robust pattern, with borderline findings in the primary Fail-excluded analyses and a significant result in the Fail = 300 sensitivity analysis. MMSE-II change did not differ between groups. NPI improved more in the add-on LIUS group in unadjusted analysis, although this finding was exploratory. Conclusions: In amyloid PET-positive patients receiving donepezil-based standard treatment, 4 weeks of add-on LIUS was associated with short-term improvement in TMT-A performance compared with standard treatment alone, while MMSE-II remained unchanged. The findings suggest a preliminary signal for processing-speed or visual-search improvement and support prospective randomized sham-controlled studies with harmonized cognitive testing and biomarker endpoints.