Supplements for Preventing Alzheimer’s

Today, we look at new research about the efficacy of supplements in preventing Alzheimer’s disease.

Oxidative stress from free radicals is the one of the pathways implicated in the development and deterioration of Alzheimer’s brains, given the evidence of excess of oxidative DNA damage on autopsy. So, what about trying an antioxidant? Vitamin E levels tend to be lower in the bloodstreams of those with cognitive impairment or dementia, but which came first? Maybe Alzheimer’s disease led to poor eating, rather than poor eating leading to Alzheimer’s disease. Greater vitamin E intake from foods is clearly associated with lower risk of developing Alzheimer’s, but greater vitamin E intake from supplements is not. But that didn’t stop researchers from including a vitamin E arm in the largest primary prevention study of Alzheimer’s disease to date.

The Prevention of Alzheimer’s Disease by Vitamin E and Selenium trial randomized more than 7,500 older men to take vitamin E, selenium, both, or neither—just placebos—for five years. To quote from the conclusion: “Neither supplement prevented dementia.” A separate long-term vitamin E supplementation trial of older women similarly found no protection against cognitive decline. Neither did vitamin E appear to benefit those with mild cognitive impairment. But the trials on Alzheimer’s patients themselves started to get more interesting.

The first trial, published in the New England Journal of Medicine, randomized more than 150 Alzheimer’s patients to vitamin E or placebo to see if vitamin E could slow the progression of the disease. The primary outcome was the number of days until of one of any of the following happened: death, institutionalization, loss of the ability to perform basic activities of daily living, or sliding into severe dementia, where you suffer a complete loss of sense of time or place. On first analysis, vitamin E flopped: no significant slowing of progression. Digging deeper, the researchers realized that despite the random allotment, the placebo group just by chance ended up with patients with milder disease. After taking that into account, the difference in outcomes between the vitamin E and placebo groups widened substantially. Now, this kind of unplanned post-hoc analysis is heavily frowned upon, but the effect seemed so sizable they went ahead and published it. In the placebo group, the adjusted time to death or loss of independence was 440 days. But in the vitamin E group, after the baseline cognition was normalized, it was 670 days––more than seven months later. However, given the unorthodox analysis, the scientific world waited for the study to be replicated.

And here we go: more than 600 patients with mild to moderate Alzheimer’s disease were subsequently randomized to vitamin E supplements, the drug memantine, both, or neither (just placebos) for two years. Although there was no slowing of cognitive decline after adjusting for multiple comparisons, there was a slowing of functional decline, in terms of managing daily activities like bathing or dressing. The vitamin E group appeared to only suffer about 1.5 years of functional deterioration in the two years’ time, resulting in approximately two hours less caregiver time required each day compared to the drug group.

If those were the only two clinical vitamin E trials, I would give vitamin E serious consideration for those with Alzheimer’s disease. But, there’s a third, a six-month trial that suggested vitamin E may be detrimental to cognition in some Alzheimer’s patients. Obviously, more research needs to be done.

I’ll cover other antioxidants that have been put to the test, including vitamin C, beta carotene, Centrum multivitamin, and the minerals zinc and calcium.

Alzheimer’s patients have significantly lower blood levels of eight out of 10 antioxidants investigated––though, of course, this could just be a consequence of demented individuals eating diets poor in fruits and vegetables. When put to the test, the PREADViSE study found no benefit for vitamin E or selenium in terms of preventing dementia. What about other antioxidants? In the Harvard Physician’s Health Study, nearly 6,000 older men were randomized to beta carotene or placebo. No difference was found after three years. But after 11 years, those unknowingly taking the equivalent of 3/4 cup (150 g) of sweet potato worth of beta carotene a day had slightly yet significantly better overall cognitive performance. A similar study of older women found no cognitive benefit over a period of nine years. Maybe they just didn’t wait long enough?

Vitamin E and C were also tested. Vitamin E similarly flopped throughout, and so did vitamin C, up until the last cognitive assessment at around year nine where the vitamin C group appeared to pull ahead. However, two trials of a combination of vitamin C, E, and beta carotene together versus placebo—one randomizing 1,500 older patients for seven years and another truly massive one randomizing more than 20,000 adults for five years—both failed to show any cognitive benefit for the antioxidant cocktail.

What about a multivitamin? The Physician’s Health Study also tested taking the daily multivitamin/multimineral supplement Centrum Silver for 12 years. Compared to those instead randomized to a placebo, the Centrum group experienced no cognitive benefit.

Souvenaid is a nutritional drink containing a patented formulation of nutrients, branded as Fortasyn Connect, specifically designed to help in Alzheimer’s disease. Unfortunately, it doesn’t work. There have been three randomized controlled trials enrolling more than a thousand people, and those taking Souvenaid were no less likely to develop dementia in the first place, and probably it has little or no effect on measures of memory or other thinking skills in both those with mild cognitive impairment or Alzheimer’s disease.

In terms of specific minerals other than the failed selenium, zinc has similarly flopped to improve overall cognition over months or years of supplementation, and it’s possible calcium supplements could make things worse.

Cross-sectionally, those taking calcium have more “hyperintensity” brain lesions on MRI (denoting evidence of mini-strokes) and longitudinally over time, women taking calcium supplements appear to have twice the odds of developing dementia. The Women’s Health Initiative should have been able to settle the question once and for all. Thousands of older women were randomized to calcium supplements (plus vitamin D) or placebo for about eight years. Thankfully, there was no difference in the risk of developing cognitive impairment or dementia. But, that’s what was originally found for heart attack and stroke rates before pre-existing supplement use was taken into account. See, more than half of the women were already taking personal calcium supplements before entering the study and being randomized to calcium or placebo. You can imagine how this could muddy the results. If you just look at the women who weren’t on calcium beforehand, starting calcium resulted in a significant increase in the risk of cardiovascular events, consistent with a meta-analysis of calcium trials showing a 15 percent increase in heart attacks or strokes among those randomized to calcium supplements over placebo. Unfortunately, such a reanalysis has yet to be performed on the dementia data.

The bottom line is that vitamin and mineral supplements probably aren’t going to help prevent dementia or treat it, but there are tons of other things we can do.