JAMA 2014 Jan 01;311(1)33-44, MW Dysken, M Sano, S Asthana, JE Vertrees, M Pallaki, M Llorente, S Love, GD Schellenberg, JR McCarten, J Malphurs, S Prieto, P Chen, DJ Loreck, G Trapp, RS Bakshi, JE Mintzer, JL Heidebrink, A Vidal-Cardona, LM Arroyo, AR Cruz, S Zachariah, NW Kowall, MP Chopra, S Craft, S Thielke, CL Turvey, C Woodman, KA Monnell, K Gordon, J Tomaska, Y Segal, PN Peduzzi, PD Guarino Research

January 08, 2014

TAKE-HOME MESSAGE

• Evidence has shown a benefit for vitamin E (alpha tocopherol) and memantine to slow progression of moderate to severe Alzheimer’s disease. In this randomized, placebo-controlled study of more than 600 veterans, alpha tocopherol given at 2000 IU/d was shown to also slow progression of mild to moderate disease in patients taking an acetylcholinesterase inhibitor.
• The results are highly significant, showing an annual delay for disease progression of 19% (~ 6.2 months) with vitamin E during the average follow-up period of 2.27 years and reduction of 13% in the hazard rate for mortality. No delay in progression was seen in patients taking memantine or memantine plus alpha tocopherol.

Commentary By:   David Rakel MD, FAAFP

In individuals with early Alzheimer’s disease, vitamin E reduced functional decline (by 19% compared with placebo) with no change with the acetylcholinesterase inhibitor memantine or a combination of vitamin E and memantine. Vitamin E was also associated with a 2-hour reduction in caretaking time per day, which can have a significant effect on caregiver fatigue and medical costs.

Dl-alpha tocopherol, used in the study, is just one of four tocopherols. The dl-alpha is the synthetic form. The natural form, d-tocopherol (without the “l”), is better absorbed, with stronger tissue penetration. Although alpha tocopherol is the most bioactive tocopherol, beta, gamma, and delta tocopherols are also beneficial and work synergistically. This is why you may see many vitamin E products with “mixed tocopherols” on the label.

The vitamin E used in this study: 1000 IU twice daily of dl-alpha tocopherol showed benefit for a challenging disease that we have few treatments for.

What may be even better? Taking vitamin E at the same total dose (1000 IU twice daily) but using the natural form of vitamin E (d-alpha tocopherol) along with beta, gamma, and delta tocopherols in a formulation that has “mixed tocopherols” on the label.

What may be best? There has been a concern with using high doses of alpha tocopherol. The study that turned the tide for vitamin E use was a meta-analysis of 19 studies showing that doses > 400 IU were associated with an increase in all-cause mortality.1 The RDA is 22 IU daily. So do we run the risk of increasing mortality for slowing the progression of AD? We recently learned in a study published in The New England Journal of Medicine that about a handful of nuts (rich in mixed tocopherols) was associated with a 20% reduction in all-cause mortality.2 And, earlier in 2013, we learned that those with Alzheimer’s disease with a high homocysteine level had less brain atrophy when treated with a B-vitamin supplement.3 So, the best of both worlds may be to return to our common mantra of eating a whole-food diet with a handful of nuts with an assortment of vegetables and high-fiber grains, all rich in vitamins E and B.

References

Miller ER, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Int Med. 2005;142(1):37-46.
Bao Y, Han J, Hu FB, et al. Association of nut consumption with total and cause-specific mortality. N Engl J Med. 2013;369(21):2001-2011.
Douaud G, Refsum H, de Jager CA, et al. Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci U S A. 2013;110(23):9523-9528.

ABSTRACT

IMPORTANCE

Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD.

OBJECTIVE

To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor.

DESIGN, SETTING, AND PARTICIPANTS

Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers.

INTERVENTIONS

Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152).

MAIN OUTCOMES AND MEASURES

Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures.

RESULTS

Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, -0.24 to 4.20; adjusted P = .40) than the placebo group’s decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of “infections or infestations,” with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants).

CONCLUSIONS AND RELEVANCE

Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden.

JAMA : The Journal of the American Medical Association
Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease: The TEAM-AD VA Cooperative Randomized Trial

JAMA 2014 Jan 01;311(1)33-44, MW Dysken, M Sano, S Asthana, JE Vertrees, M Pallaki, M Llorente, S Love, GD Schellenberg, JR McCarten, J Malphurs, S Prieto, P Chen, DJ Loreck, G Trapp, RS Bakshi, JE Mintzer, JL Heidebrink, A Vidal-Cardona, LM Arroyo, AR Cruz, S Zachariah, NW Kowall, MP Chopra, S Craft, S Thielke, CL Turvey, C Woodman, KA Monnell, K Gordon, J Tomaska, Y Segal, PN Peduzzi, PD Guarino

Full Story:  http://www.practiceupdate.com/journalscan/7490
Journal Reference:  http://jama.jamanetwork.com/article.aspx?articleid=1810379