Efficacy of acetylcholinesterase inhibitors on reducing hippocampal atrophy rate: a systematic review and meta-analysis
Authors: Ismail Youssef A. , Haitham Youssef , Walid Mohammad , Mohamed Hazim , El-Satar Youssef M. Abd 
Published: February 2025

Abstract

Background
Neurodegenerative diseases (NDs) are conditions characterized by irreversible progressive degeneration to the nervous tissue and are usually associated with cognitive decline and functional deficits, especially in elderly. Acetylcholinesterase inhibitors (AChEIs) like donepezil, rivastigmine, and galantamine are commonly prescribed to alleviate cognitive symptoms associated with NDs. However, their long-term impact on slowing structural brain degeneration, particularly hippocampal atrophy, remains unclear.

Objective
This systematic review and meta-analysis assess the efficacy of AChEIs in reducing hippocampal atrophy in patients with NDs or clinical syndromes that lead to cognitive decline.

Methods
A systematic search of PubMed, Scopus, Web of Science, and Cochrane databases, since inception till 20th August 2024, identified randomized controlled trials (RCTs) and comparative studies that measured hippocampal volume changes in elderly patients with NDs and other clinical syndromes. Random effect model was employed to estimate the pooled atrophy rates. Subgroup analysis was conducted by disease, dosage, and side of the measurement.

Results
From 5,943 initially screened studies, nine were included in the review, and six were analyzed in the meta-analysis, encompassing a total of 2,179 participants. The meta-analysis showed that donepezil at a 10 mg dose significantly reduced hippocampal atrophy compared to placebo (SMD = 0.44, 95% CI [0.08 to 0.81], p = 0.01), whereas the 5 mg dose showed no significant effect on hippocampal volume. Overall, pooled results favored donepezil in reducing hippocampal atrophy (SMD = 0.33, p = 0.04), indicating that higher doses are more effective. Among patients with mild cognitive impairment (MCI), both donepezil and vitamin E were associated with a significant reduction in hippocampal atrophy compared to placebo (SMD = 0.27, p = 0.01). In contrast, galantamine did not significantly reduce hippocampal atrophy in the overall analysis, but it was associated with reduced whole brain atrophy in APOE ε4 carriers. Further analysis revealed no significant difference in the reduction of right or left hippocampal atrophy in donepezil-treated patients. These findings suggest that donepezil, particularly at higher doses, may have a protective effect against hippocampal atrophy in patients with AD and MCI, while galantamine’s effect may be more limited, especially in certain genetic subgroups.

Conclusion
Higher doses of donepezil (10 mg) significantly reduce hippocampal atrophy in Alzheimer’s disease and mild cognitive impairment, suggesting potential neuroprotective effects. In contrast, lower doses (5 mg) and galantamine showed no significant impact on hippocampal volume, though galantamine reduced whole brain atrophy in APOE ε4 carriers. Dosage and genetic factors are crucial in determining the efficacy of acetylcholinesterase inhibitors in slowing neurodegeneration.