Teasing Apart How Food Can Make Us Well

“Let food be thy medicine,” Hippocrates counseled two millennia ago, and most   today would agree. Nutrition research is booming, and disease-preventing “breakthroughs” a media staple.

Neuroscience is a relative newcomer to the feeding frenzy; the first nutrition-brain conference was just over 20 years ago. But we’re making up for lost time, as anyone who reads the papers or spends time online can attest. Given how much nutrition news is exaggerated, ephemeral, or plain foolishness, it’s natural to ask: from a serious scientific perspective, just how important are food and its components to brain health?

Very, according to Irwin H. Rosenberg, professor of nutrition at Tufts University and keynote speaker at a recent symposium at New York Academy of Sciences. “The consideration of nutrition and lifestyle factors for prevention or amelioration of age-related cognitive decline and dementia is truly an imperative,” he said. “It deserves priority in our research.”

Many of the presentations that followed substantiated what Rosenberg called “the nexus of nutrition, aging, and dementia,” and summarized research suggesting how the first might slow the second and prevent the third.

Keeping the brain well fed

Several speakers focused on changes in how the aging brain uses nutrients, glucose in particular.

“Deteriorating brain glucose metabolism in Alzheimer’s disease (AD) is traditionally viewed as a consequence of neuron dysfunction,” said Stephen Cunnane, professor of medicine at Université de Sherbrooke, in Canada. “I want to make the case that it’s also part of the problem: the horse as well as the cart.”

Cunnane cited studies showing diminished glucose utilization in populations at increased risk of AD: people whose parent had the disease; carriers of genes, including ApoE4, who by their 30s frequently show changes in brain regions linked to the disease.

“Failing neurons use less glucose, but problems with glucose may contribute to neuron failure as well,” he said. The energy shortfall accelerates neuropathology and synapse loss, in a “vicious cycle of neuron exhaustion.”

“If we want to develop effective treatments or preventive strategies for dementia, we have to think of the energy part of the equation. Neurons can’t profit from pharmaceuticals, exercise, or cognitive training if they don’t have enough energy to talk to each other,” he said.

The brain can use other energy sources, Cunnane pointed out; up to 65% of its needs can be met by ketones. But usual ketone production, from fats, and metabolism require insulin, whose production  falls in many people as they age.

An alternative, he says, is medium-chain triglycerides (often extracted from palm kernel and coconut oils), which are readily converted to ketones and taken up by brain cells, even when insulin function is suboptimal.

In a pilot study, their ketone levels rose and memory improved when people with mild cognitive impairment were given MCT supplements.

Gary Gibson, professor of neuroscience at Weill Cornell Medical College, noted that reduced glucose utilization is a better biomarker of AD progression than the familiar plaques and tangles, and may, in fact, drive plaque and tangle production, cognitive changes, and oxidative stress.

What exactly reduces glucose metabolism is unclear, he said; many key enzymes are apparently affected in AD. His talk focused on the alpha-ketoglutarate- dehydrogenase complex (KGDHC), a rate-limiting enzyme in the energy-producing Krebs cycle that also modifies other proteins and buffers cells against oxidative stress.

KDGHC and other enzymes depend on thiamine (vitamin B1), Gibson said, noting that severe thiamine deficiency produces cognitive deficits resembling those of AD, along with a similar pattern of glucose hypometabolism.

Might supplementation help? High doses of thiamine itself elevate blood levels only briefly, but benfotiamine, a derivative, produces a more sustained effect. Preclinical studies link benfotiamine with plaque reduction and memory improvements in mice genetically engineered to produce amyloid plaques, Gibson noted.

He is a principal investigator in a clinical trial, now recruiting people with amnestic mild cognitive impairment or early AD, who will be given benfotiamine supplements while their cognitive function and brain glucose utilization are compared with people with similar memory deficits who receive placebo.

Does B make a difference?

The relationship between the other B vitamins and brain aging has become highly controversial. A widely-cited Oxford-led meta-analysis last year concluded that B supplementation “doesn’t slow mental decline as we age, nor is it likely to prevent AD,” but many experts, including two speakers at the conference, argue otherwise.

Key data, including baseline B vitamins levels, were not determined in most trials in the meta-analysis, said Helga Refsum, professor of nutrition at University of Oslo, Norway. Many people in the study were too young and trial periods too short for meaningful separation from controls.

“Studies on nutrients and brain function have to take into account the existing state of the nutrient in the body,” said A. David Smith, professor emeritus of pharmacology at University of Oxford. “You can’t expect to see effects if you give a nutrient to people whose blood levels are close to optimal.”

The amino acid homocysteine plays a mediating role in B vitamin effects, Smith suggested. Elevated blood levels are associated with brain atrophy, cognitive impairment and conversion to dementia; and also with white matter damage, neurofibrillary tangle density, and rate of cognitive decline in established AD.

Homocysteine metabolism is regulated by folate, B12 and B6; supplementation can reduce levels of the compound by 25-35%. Whether this affects cognitive function or dementia risk is the question: the Oxford meta-analysis said no, but Smith pointed out that most studies it included did not take baseline homocysteine into account.

A three-year trial of folate supplementation in 818 people with elevated homocysteine and low folate intake found they performed better on cognitive tests, compared with controls, he said. In another trial, B vitamins slowed brain atrophy and improved cognitive performance–in the subgroup whose homocysteine levels were raised at baseline.

Refsum reviewed studies linking vitamin B12, brain aging, and dementia. Only recently, she observed, have low-normal levels of B12, rather than outright deficiency, been investigated, and functional B12 status examined closely.

She cited research investigating brain atrophy. In one study of 107 cognitively healthy elderly people, brain volume loss was twice as rapid in the lowest B12 quartile, compared with the highest.

Other studies linked B12 supplementation to reduced white matter lesions, and eating patterns high in vitamins B12 and D with reduced amyloid deposits.

In one trial, supplementation with folate, B12, and B6 was associated with significantly reduced brain atrophy, particularly in regions affected by AD. Though the role of each vitamin was unclear, people with low baseline B12 were most likely to respond, Refsum said.

You are what you eat

Some speakers took a broader view. “Many nutrients are important for protecting the brain,” said Katherine L. Tucker, professor of nutritional epidemiology at University of Massachusetts, Lowell. “We need mechanistic studies of single nutrients, but when thinking of public health, we really need to think about total exposure to all in the food matrix. I like to look at [nutrition] in terms of diet, rather than supplements.”

Tucker cited a study that found significant associations between fruit and vegetable intake and memory, attention, and executive function. “Variety was more significant than total consumption,” she said.

Fruits and vegetables may simply indicate good diet, she said, “but there are a lot of phytonutrients we haven’t been thinking about that may be associated with cognitive function.”

Martha Clare Morris, professor of epidemiology at Rush University, described two well-known diets that show apparent cognitive benefits, and presented data on a new eating plan specifically designed to preserve brain function.

Among food groups, fish and vegetable consumption and a low saturated/unsaturated fat ratio have been associated with slower cognitive decline. Data on the Mediterranean and DASH (Dietary Approaches to Stop Hypertension) diets, which were primarily developed for cardiovascular protection, suggest brain benefits as well, she said.

These include better scores on tests of cognitive function after 6.5 years on the Mediterranean diet, compared with controls, and less cognitive decline on average among adherents to the DASH diet.

“We developed the MIND [Mediterranean-DASH Intervention for Neurodegenerative Delay] diet by combining major features of those diets, and modifying them, based on the literature, with features specific to brain health,” Morris said. Their diet calls for one daily serving of green leafy vegetables, two of other vegetables, one of berries, and three of whole grains. Fish should be eaten at least once weekly; consumption of olive oil, nuts, and beans is encouraged, and cheese, sweets, red meats, and fast foods minimized.

Morris described findings from a study that scored the diets of 923 people according to the MIND pattern and followed them for up to 10 years. “Those in the highest tertile had the slowest decline in cognitive function, almost double the protective association seen in Mediterranean and DASH diets,” she said.

The effect on AD incidence, over a mean of 4.5 years, was particularly striking: a 53% reduction in the highest MIND tertile, and 35% reduction with just moderate adherence.

“We see this as an important step toward a diet geared specifically toward healthy brain aging,” Morris said. “As the literature develops, it can be modified.”

Our understanding of individual nutrients, food groups, and diet patterns “have to evolve together,” she said.