Therapeutics

Neither vitamin E nor donepezil delays progression from amnestic mild cognitive impairment to Alzheimer’s disease in the long term

Petersen RC, Thomas RG, Grundman M, et al. Vitamin E and donepezil for the treatment of mild cognitive impairment. N Engl J Med 2005;352:2379–88.[Abstract/Free Full Text]

Q Do vitamin E or donepezil delay the clinical diagnosis of Alzheimer’s disease in people with the amnestic form of mild cognitive impairment?

Key Words: vitamin E • donepezil • Alzheimer’s disease • mild cognitive impairment

Design: Randomised controlled trial.

Allocation: Unclear.

Blinding: Double blind.

Follow up period: Three years.

Setting: Sixty nine sites in the United States and Canada; March 1999 to January 2004.

Patients: 790 people aged 55–90 years, with amnestic mild cognitive impairment of a degenerative nature. Other inclusion criteria: Clinical Dementia Rating of 0.5; Mini-Mental State Examination score 24 to 30; impaired memory; and Logical Memory delayed recall score about 1.5 to 2 standard deviations below education adjusted norm.

Intervention: Donepezil (10 mg daily) plus placebo vitamin E; vitamin E (2000 IU daily) plus placebo donepezil; or placebo vitamin E plus placebo donepezil for three years. All participants received a daily multivitamin tablet that contained 15 IU of vitamin E.

Outcomes: Possible or probable Alzheimer’s disease (National Institute of Neurological and Communicative Diseases and Stroke, and the Alzheimer’s Disease and Related Disorders Association clinical criteria); adverse events.

Patient follow up: 68% completed the study, 97% included in analyses.

Compared with placebo, neither vitamin E nor donepezil altered the probability of progression to Alzheimer’s disease after three years (vitamin E v placebo: HR for progression 1.02, 95% CI 0.74 to 1.41; donepezil v placebo: HR for progression 0.80, 95% CI 0.57 to 1.13). However, there was some indication that donepezil slowed progression to Alzheimer’s disease over the first two years compared with placebo (p = 0.03). Donepezil increased adverse events compared with placebo (diarrhoea, muscle cramps, insomnia, nausea, abnormal dreams: p<0.01; loose stools, vomiting, arthritis: p<0.05).

Neither vitamin E nor donepezil were associated with a lower rate of progression to Alzheimer’s disease after three years for people with mild cognitive impairment, although donepezil may lower rate of progression in the shorter term.

For correspondence: Dr Ronald C Petersen, Alzheimer’s Disease Research Center, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA; peter8{at}mayo.edu

Sources of funding: National Institute on Aging, Pfizer, and Eisai.

---

 

Commentary

Deborah Blacker, MD, ScD

Department of Psychiatry, Mass General Hospital/Harvard Medical School, Boston, MA, USA

The paper by Petersen et al presents the results of a large, carefully conducted, three year clinical trial to examine whether vitamin E or standard Alzheimer’s therapy (the cholinesterase inhibitor donepezil) delays the progression from mild cognitive impairment (MCI)^1,2 to Alzheimer’s disease (AD). Because MCI likely represents the prodromal phase of AD, when significant neuropathology is already present,³ this trial is probably best viewed as a secondary prevention trial. Extensive in vitro evidence supported a potential role for vitamin E in AD prevention,⁴ a wide variety of epidemiological studies suggested that it was protective against AD,⁵ and a single clinical trial in established AD suggested that it delayed progression.⁶

Alas, the results of the present trial were disappointing. Vitamin E showed no benefit whatsoever, one in a string of negative results for the antioxidant vitamin in the past year.^7,9 Donepezil showed modest benefits at one year, but the difference between the treatment and placebo groups was gone by the three year end point. The results were somewhat more promising in a post hoc analysis of a subset defined by the AD risk factor gene APOE-4,¹⁰ but this likely represents a difference in statistical power (because more such individuals developed AD) than a true pharmacogenomic difference. Overall, the modest and time limited benefits of donepezil are consistent with AD treatment studies¹¹—not surprisingly, because many investigators believe that MCI represents the early stage of AD.¹²

Taken together with other recent negative findings about vitamin E,^7,9 the present results are likely to discourage the use of vitamin E for prevention of progression in MCI, but do not speak to the larger question of whether vitamin E taken earlier, before the onset of neuropathological changes, might be helpful in the primary prevention of AD. For donepezil, the results are less clear, and there is no consensus as to whether it makes sense to continue to offer the drug to individuals with mild cognitive symptoms.

1. Petersen RC, Smith GE, Waring SC. et al. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999;56:303–8.[Abstract/Free Full Text]
2. Petersen RC, Morris JC. Mild cognitive impairment as a clinical entity and treatment target. Arch Neurol 2005;62:1160–3.[Free Full Text]
3. Kordower JH, Chu Y, Stebbins GT. et al. Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment. Ann Neurol 2001;49:202–13.[CrossRef][Medline]
4. Luchsinger JA, Mayeux R. Dietary factors and Alzheimer’s disease. Lancet Neurology 2004;3:579–87.
5. Behl C, Moosmann B. Oxidative nerve cell death in Alzheimer’s disease and stroke: antioxidants as neuroprotective compounds. Biol Chem 2002;383:521–36.[CrossRef][Medline]
6. Sano M, Ernesto C, Thomas R. et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease: The Alzheimer’s Disease Cooperative Study. New Engl J Medicine 1997;336:1216–22.[Abstract/Free Full Text]
7. Miller ER 3rd, Pastor-Barriuso R, Dalal D. et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Int Medicine 2005;142:37-46.
8. The HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: A randomized controlled trial. JAMA 2005;293:1338–47.[Abstract/Free Full Text]
9. Lee IM, Cook NR. Gaziano JM. et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA 2005;294:56–65.[Abstract/Free Full Text]
10. Saunders AM, Strittmatter WJ, Schmechel D. et al. Association of apolipoprotein E allele 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 1993;43:1467–72.[Abstract/Free Full Text]
11. Courtney C, Farrell D, Gray R. el al. Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet 2004;363:2105–15.[CrossRef][Medline]
12. Petersen RC, Bennett D. Mild cognitive impairment: is it Alzheimer’s disease or not? J Alzheimers Dis 2005;7:241–5.[Medline]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?