First Evidence Dietary Flavonols Linked to Lower Alzheimer Risk

Damian McNamara

January 30, 2020

For the first time, dietary flavonols, which are components of many fruits, vegetables, and tea, have been linked to a significantly lower risk of developing Alzheimer disease (AD). However, some experts are calling for healthy skepticism when interpreting the findings.

Kaempferol, isorhamnetin, and myricetin may not be household names, but investigators at Rush University Medical Center in Chicago, Illinois, found that for those who reported diets highest in these flavonols, the rate of incident AD was 48% lower than that of their counterparts who consumed the lowest levels of these dietary compounds.

Kale, beans, spinach, apples, olive oil, and tomato sauce are among the sources richest of these flavonols.

"Eat your fruits and vegetables, particularly dark leafy greens, and drink some tea every now and again. A healthy diet that contains various fruits and vegetables is critical for continued health, especially brain health," study investigator Thomas M. Holland, MD, Rush Institute for Healthy Aging, told Medscape Medical News.

The study was published online January 29 in Neurology.

Novel Research

A number of flavonoid classes, including flavonols, are known to have antioxidant and anti-inflammatory properties.

Previous research has linked total flavonoid intake to a lower risk for AD. For example, Nurses' Health Study investigators reported higher global cognitive scores among women with higher flavonoid consumption in comparison with others after 6 years of follow-up. In addition, work in animals has linked higher flavonol intake to a lower risk of developing dementia.

However, to date, no researchers have explored the potential cognitive benefits of the flavonol subclass in humans.

To fill this research gap, investigators studied 921 participants from the ongoing Rush Memory and Aging Project (MAP), which started in 1997 and includes community-dwelling seniors living in the Chicago area. The participants' mean age was 81 years, and they were all free from dementia at baseline.

The majority (75%) of the study participants were women. All participants underwent annual neurologic evaluations and dietary assessments that utilized a validated food frequency questionnaire.

A total 220 participants developed AD over a mean follow-up of 6 years.

After adjusting for age, sex, education, APOE-ε4 positivity, late-life cognitive activity, and physical activity, the results showed that those in the highest quintile of total flavonol intake had a 48% lower risk for incident AD vs individuals in the lowest quintile.

Three of four individual flavonols were linked to a reduction in incident AD risk. Compared to persons in the lowest quintile of intake, those who consumed the highest level of kaempferol had a 50% reduction in risk, for example. High intake of isorhamnetin and myricetin were each associated with a 38% risk reduction.

Only dietary intake of quercetin was not associated with a substantially reduced risk for incident AD.

Top Flavonol Sources

Kale, beans, tea, spinach, and broccoli were the top food sources for kaempferol. Tea, wine, kale, oranges, and tomatoes led the list for myricetin. Pears, olive oil, wine, and tomato sauce were associated with the highest intake of isorhamnetin. Top sources of quercetin included tomatoes, kale, apples, and tea.

"However, this list is not exhaustive," Holland said. Total flavonol sources include more than 30 various fruits, vegetables, and beverages such as tea that contribute to the beneficial association with risk for AD dementia, he added.

"In our study, due to its overall consumption, black teas' flavonoid profile was used. Nevertheless, green tea also has a robust flavonol concentration," he said.

The investigators ran a series of adjustments to rule out other potential contributors to their findings.

For example, they found that intake of vitamin E, saturated fat, folate, leutin, and omega-3 fatty acids did not materially change AD risk estimates.

They also found that assessing the role of comorbidities such as diabetes, hypertension, myocardial infarction, and stroke did not markedly change the results. Similarly, the analysis showed that higher body mass index and depression did not worsen AD risk.

The only statistically significant modification of effect was by sex.

Total flavonol intake was stronger in men (quintile 5 [Q5] vs Q1: hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.08 – 0.76) than in women (Q5 vs Q1: HR, 0.59; 95% CI, 0.35 – 0.99).

Only One Piece of the Puzzle

"In this community-based prospective study of older persons, we found evidence that higher flavonol intake through food sources, and kaempferol and isorhamnetin in particular, may be protective against the development of Alzheimer dementia. The associations were independent of many diet and lifestyle factors and cardiovascular-related conditions," the investigators write.

Holland said the association of flavonols with decreased AD risk did not surprise him. "However, I was pleasantly surprised by the percent rate reduction being as strong as it was," he said.

"It is generally known that the vitamins and minerals found in these food items are important. But we are now understanding that it's the entire composition of the food, inclusive of bioactives, like flavonols, that render these foods as beneficial," Holland added.

The investigators note that the findings are only associations and do not support causation.

The current findings build on a previous study, also conducted by Rush University investigators, that linked kaempferol in leafy green vegetables to a slower rate of cognitive decline, as previously reported by Medscape Medical News.

The lead author of the leafy greens study was Martha Clare Morris, ScD, who is also Holland's mentor. She conducted a study published in 2015, which was also reported by Medscape Medical News, that linked the MIND diet (a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension [DASH] diet) with a lower risk for cognitive decline.

"My research is one piece of the diet puzzle," Holland said, "with overall diet being a large component of a healthy lifestyle ― inclusive but not limited to physical, social, and cognitively stimulating activity, good sleep, and stress reduction."

Going forward, Holland and colleagues want to confirm their findings through other prospective cohort studies that feature a more diverse population. In addition, a clinical trial to establish effect "would be quite valuable and informative," he said.

Although the researchers believe the antioxidant and anti-inflammatory actions of flavonols are behind the reduction in AD risk, "it is imperative to elucidate through what specific biologic mechanisms flavonols are working in our bodies," Holland added.

Healthy Skepticism

Commenting on the findings for Medscape Medical News, Thomas Vidic, MD, a neurologist at Elkhart Clinic in Indiana and a fellow of the American Academy of Neurology, described the research as a good "concept study."

"There are many limitations, as spelled out in the article," he added. "But the overall theme is very consistent with the message that we have been providing for years ― eat right and exercise."

Because pharmaceutical options for the prevention of AD are "not currently viable, we must do the 'little things' right," he added.

Also commenting on the study, Gunter Kuhnle, professor of nutrition and food science, University of Reading, United Kingdom, in a release stated, "The mode of action of flavonols is not known and it is likely that the observed associations are simply due to a dietary pattern rich in specific foods and vegetables.

"A risk reduction of almost 50% is of course impressive, but there are currently no data that suggest that flavonols as a compound could have such an effect," Kuhnle added. He said it is important to keep in mind that other compounds in the diet could have contributed to the benefits observed in this research.

"The advice remains that exercise and a healthy diet rich in vegetables probably reduces risk of Alzheimer's disease along with other health problems," David Curtis, honorary professor of genetics, evolution, and environment at University College London, United Kingdom, said in a release. "But on the basis of this study I would not be urging people to drink more tea or eat more kale.

"Dementia represents a huge public health problem," he added, "and it is essential that adequate resources are directed towards following up promising findings such as this one."

The National Institutes of Health, the National Institute on Aging, and the USDA Agricultural Research Service supported the study. Holland, Vidic, and Curtis have disclosed no relevant financial relationships. Kuhnle has conducted studies on associations between flavan-3-ols and health that are funded by Mars.

Neurology. Published online January 29, 2020. Abstract

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