Meh: In Cognitive Dysfunction, Vitamin E May Help, or...It May Do Nothing, or...It May Harm

Vitamin E and other antioxidants are included in the branded, nutritional drink Souvenaid, which is being developed as a treatment for Alzheimer disease. However, well-controlled clinical data to justify their use in AD or mild cognitive impairment (MCI) are scarce, and positive trial data require qualification.

The most prominent (and confounding) trial in which vitamin E was assessed in AD was the Alzheimer Disease Cooperative Study, published in 1997 in the NEJM. In this multicenter US study, 341 patients with moderately severe AD received randomized selegiline (10 mg/d), vitamin E (2000 IU/d), both, or placebo in a double-blind fashion.

In the unadjusted analysis, there were no significant differences among the 4 treatment arms with respect to the combined primary outcome of death, institutionalization, loss of the ability to perform basic ADLs, or severe dementia at 2 years. However, the trial results had to be statistically accommodated, because the mean baseline MMSE score of placebo-treated patients, despite randomization, was significantly higher than those of other enrollees. "[A]nd this variable," the authors predictably concluded, "was highly predictive of the primary outcome."

And so an adjusted analysis was performed, in which the investigators observed significant delays in the combined primary outcome with all 3 randomized treatments—selegiline, vitamin E, and both—when compared with placebo.

But these data are at odds with results from a 3-part Italian study of vitamin E and donepezil (Aricept; Eisai/Pfizer), published sequentially in 2001, 2002, and 2003. Among 40 patients with moderately severe AD who received randomized vitamin E (2000 IU/d), latencies of P300 recordings (a very rough, electrophysiologic indicator of cognition*), and cognitive scores declined significantly at 26 weeks (when compared with donepezil treatment [5-10 mg/d]).

These findings are supported by follow-up results, in which P300 latencies and cognitive test scores deteriorated with vitamin E supplementation at 3 months in patients with mild AD (n = 30). Cognition also significantly declined in subjects with moderate-to-severe AD (n = 30) who received vitamin E. Other electrophysiologic indicators of cognition worsened in a smaller and much briefer (ie, 30-day) study of vitamin E and donepezil in patients with "mild dementia."

To assess the potential benefit of vitamin E supplementation to prevent AD, investigators at the Mayo Clinic conducted a randomized, double-blind, placebo-controlled study of 769 patients with amnestic MCI. The results, published in a 2005 issue of the NEJM, showed no significant delay in the development of AD at 3 years with vitamin E (2000 IU/d) or donepezil (10 mg/d).** The annual rate of progression from MCI to AD was 16%, a rate that has been subsequently confirmed. 

The most recent trial assessing vitamin E in AD was published last year. In this small Spanish study, 57 patients with AD were assigned to placebo or vitamin E (800 IU/d) for 6 months. Among the 33 study completers, investigators correlated a controversial measure of oxidative stress (reduced glutathione) with maintained cognition in vitamin E-treated subjects. The authors concluded that "supplementation of AD patients with vitamin E cannot be recommended without determination of its antioxidant effect in each patient."

The American Psychiatric Association, as of 2007, no longer recommends vitamin E for the treatment of dementia because of limited efficacy data and potential safety concerns. The latter relate to reports of increased cardiovascular and cerebrovascular mortality. However, these risks may not be relevant in AD patients, according to a recent, longitudinal survival study.

So these clinical data for vitamin E in AD or MCI leave us firmly nowhere.

But there are other potential antioxidants in Souvenaid: namely, selenium and vitamin C. What are the clinical data to support their use in dementing disorders?

There is one semi-controlled Polish study (1999) in which selenium (100 µg every other day) was compared with placebo and some proline-rich substance isolated from sheep colostrum [yeesh] in patients with mild or moderate AD (N = 46). Psychiatrists blinded to treatment determined that cognition stabilized in 13 of 15 selenium-treated patients at 1 year, vs 8 of 16 placebo-treated patients. (The sheep colostrum product reportedly improved or stabilized cognition in all 15 treated patients.)

Controlled assessments of vitamin C, aka ascorbic acid, in AD are virtually absent, at least by my search. An Italian AD study, published in 1995, used ascorbic acid as a reference standard. In a later Czech study, 50 mg of ascorbic acid was given daily to all AD enrollees. 

* Increased latencies suggest delays in neuronal transmission.

** However, the rate of progression to AD at 12 months was reduced with donepezil treatment, and the AChEI prevented full-blown dementia at all time points in carriers of 1 or more APOE e4 alleles--a known genetic risk factor for late-onset AD. More recent, controlled studies of donepezil in patients with amnestic MCI suggest that the drug delays the progression to AD among depressed individuals but has only a modest effect on cognition in a more inclusive population with MCI.

AChEI = acetylcholinesterase inhibitor; ADLs = activities of daily living; MMSE = Mini-Mental State Examination; APOE = apolipoprotein E.