Donepezil May Slow Hippocampal Atrophy in Prodromal AD

Laird Harrison

February 04, 2015

Donepezil (Aricept, Esai) slows atrophy of the hippocampus in patients with prodromal Alzheimer's disease, a new randomized study shows.

"After 1 year we were surprised to see a 42% reduction of hippocampal atrophy in prodromal Alzheimer's patients," lead researcher Bruno Dubois, MD, told Medscape Medical News. "This is a very strong result."

Dr Dubois, a neurology professor at Hôpital La Salpêtrière, Paris, France, and his colleagues at 15 French institutions published their findings online January 14 in Alzheimer's & Dementia.

However, the study did not show any effects on cognition, disappointing researchers who had hoped to identify a subgroup of patients who might especially benefit from the medication.

Early Intervention

Researchers have been working to identify patients with prodromal Alzheimer's disease: mild cognitive impairment that foreshadows progression to full-blown disease. They hope that by intervening early enough they might prevent the disease from progressing.

Earlier studies showed that the hippocampus shrinks rapidly in patients with mild cognitive impairment as that condition progresses to Alzheimer's disease. Donepezil slows atrophy of the hippocampus in patients with mild to moderate Alzheimer's disease, as well as slowing the patients' cognitive decline, but few researchers have looked at donepezil in patients with mild cognitive impairment.

To fill that gap, Dr Dubois and colleagues used a memory test, the Free and Cued Selective Reminding Test (FCSRT), to identify patients most likely to have prodromal Alzheimer's disease. The test has been correlated with hippocampal volume and changes in cerebrospinal fluid characteristic of Alzheimer's disease.

They recruited 216 people over age 50 who had no dementia but scored low on the FCSRT. They randomly assigned 103 to take a placebo and 113 to take donepezil, 10 mg/day.

They used brain MRI to measure the volume of the patients' hippocampus at baseline, 6 months, and 1 year.

Adverse reactions occurred more frequently in the donepezil group and included muscle spasms, nightmares, diarrhea, headache, nausea, sleep disorder, abdominal pain, and vertigo.

Partly because of the adverse reactions, several patients dropped out. After a year, 81 remained in the placebo group and 75 remained in the donepezil group.

In these remaining patients, the donepezil group lost 1.89% of hippocampal volume over the year, while the placebo group lost 3.47%. The difference was statistically significant (P < .001).

Although apolipoprotein has been linked to the decline in hippocampal volume in people with Alzheimer's disease, hippocampal volume did not differ between APOE4 carriers in the 2 groups.

The researchers gave their patients a battery of neuropsychological tests but didn't find any significant differences between the two groups.

This last finding means this study has no implications for current clinical practice, Dr Dubois said.

Direction for Future Research

Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer's Association, agreed.

"At this point it's more about giving direction to additional research," said Dr Fargo, who was not associated with this study. "The literature in this area has been somewhat mixed, and this paper answers a question. But all research has to be followed up on."

One possibility for future researchers is to look further for neuropsychological benefits from donepezil in this category of patients.

"If you follow people longer, if you had more people in the study, would you see benefits to cognition, would you see benefits to daily living, for example?" Dr Fargo asked.

Dr Dubois said he and his colleagues are planning to continue analyzing their current data, looking further at the effect of donepezil on other brain structures.

This study was funded by Eisai, the company that markets donepezil as Aricept. The authors and commenter have disclosed no relevant financial relationships.

Alzheimers Dement. Published online January 14, 2015. Abstract


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