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Objective: The only approved pharmacological approach for the symptomatic treatment of Alzheimer's disease in Japan is the use of a cholinesterase inhibitor, donepezil hydrochloride. Recent in vivo and in vitro studies raise the possibility that cholinesterase inhibitors can slow the progression of Alzheimer's disease. The purpose of the present study was to determine whether donepezil has a neuroprotective effect in Alzheimer's disease by using the rate of hippocampal atrophy as a surrogate marker of disease progression. Method: In a prospective cohort study, 54 patients with Alzheimer's disease who received donepezil treatment and 93 control patients with Alzheimer's disease who never received anti-Alzheimer drugs underwent magnetic resonance imaging (MRI) twice at a 1-year interval. The annual rate of hippocampal atrophy of each subject was determined by using an MRI-based volumetric technique. Background characteristics, age, sex, disease duration, education, MRI interval, apolipoprotein E (APOE) genotype, and baseline Alzheimer's Disease Assessment Scale score were comparable between the treated and control groups. Results: The mean annual rate of hippocampal volume loss among the treated patients (mean=3.82%, SD-2.84%) was significantly smaller than that among the control patients (mean=5.04%, SD=2.54%). Upon analysis of covariance, where those confounding variables (age, sex, disease duration, education, MRI interval, APOE genotype, and baseline Alzheimer's Disease Assessment Scale score) were entered into the model as covariates, the effect of donepezil treatment on hippocampal atrophy remained significant. Conclusions: Donepezil treatment slows the progression of hippocampal atrophy, suggesting a neuroprotective effect of donepezil in Alzheimer's disease.

Objective: Diffuse brain atrophy is one of the gross pathological features of Alzheimer's disease and is a result of degenerative changes. The [Epsilon]4 allele of apolipoprotein E (APOE) is a risk factor or susceptibility gene in late-onset sporadic Alzheimer's disease and may influence the pathological changes associated with the disease. The aim of this study was to examine the relationship between the APOE [Epsilon]4 allele and whole brain atrophy. Method: Whole brain volume was quantified by using high-resolution magnetic resonance imaging and the computerized brain segmentation technique in 178 patients with late-onset sporadic Alzheimer's disease who carried no APOE [Epsilon]4 alleles (N = 62), one [Epsilon]4 allele (N = 93), or two (N = 23) and had comparable clinical severity of dementia. Results: An apparent positive correlation was found between normalized whole brain volume (relative to total intracranial volume) and number of APOE [Epsilon]4 alleles; i.e., patients carrying two APOE [Epsilon]4 alleles had the least brain atrophy. This association between the APOE [Epsilon]4 allele and brain volume was similar in women and men and was independent of age, level of education, duration of illness since symptom onset, and severity of dementia. Conclusions: The results indicate that cognitive dysfunction progresses before severe brain atrophy develops in patients carrying the APOE [Epsilon]4 allele and suggest that an APOE [Epsilon]4-allele-related mechanism that affects neuronal function before a decrement in brain matter is involved in the development of dementia.