The Role of Nutrition in Dementia Prevention and Management

Podcast and Video

Can We Prevent Dementia Through Our Diet?
This Academy podcast explores whether dementia can be prevented by making dietary changes.

Nestlé Health Science Video
This Nestlé Health Science short video provides an overview of the March 26–27 conference with speaker interviews.

Journal Articles

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Buell JS, Scott TM, Dawson-Hughes B, et al. Vitamin D is associated with cognitive function in elders receiving home health services. J Gerontol A Biol Sci Med Sci. 2009;64(8):888-95.

Castellano CA, Nugent S, Paquet N, et al. Lower brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism in mild Alzheimer's disease dementia. J Alzheimers Dis. 2015;43(4):1343-53.

Clarke R, Bennett D, Parish S, et al. Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals. Am J Clin Nutr. 2014;100(2):657-66.

Clarke R, Smith AD, Jobst KA, et al. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol. 1998;55(11):1449-55.

Crane PK, Walker R, Larson EB. Glucose levels and risk of dementia. N Engl J Med. 2013;369(19):1863-4.

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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):9523-8.

Dumont M, Ho DJ, Calingasan NY, et al. Mitochondrial dihydrolipoyl succinyltransferase deficiency accelerates amyloid pathology and memory deficit in a transgenic mouse model of amyloid deposition. Free Radic Biol Med. 2009;47(7):1019-27.

Durga J, van Boxtel MP, Schouten EG, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007;369(9557):208-16.

Hemarajata P, Versalovic J. Effects of probiotics on gut microbiota: mechanisms of intestinal immunomodulation and neuromodulation. Therap Adv Gastroenterol. 2013;6(1):39-51.

Hin H, Clarke R, Sherliker P, et al. Clinical relevance of low serum vitamin B12 concentrations in older people: the Banbury B12 study. Age Ageing. 2006;35(4):416-22.

Hooshmand B, Polvikoski T, Kivipelto M, et al. Plasma homocysteine, Alzheimer and cerebrovascular pathology: a population-based autopsy study. Brain. 2013;136(Pt 9):2707-16.

Kang JH, Cook N, Manson J, et al. A randomized trial of vitamin E supplementation and cognitive function in women. Arch Intern Med. 2006;166(22):2462-8.

Keller H, Beck AM, Namasivayam A, International-Dining in Nursing home Experts (I-DINE) Consortium. Improving food and fluid intake for older adults living in long-term care: a research agenda. J Am Med Dir Assoc. 2015;16(2):93-100.

Keller HH, Schindel Martin L, Dupuis S, et al. Mealtimes and being connected in the community-based dementia context. Dementia. 2010;9(2):191-213.

Kerti L, Witte AV, Winkler A, et al. Higher glucose levels associated with lower memory and reduced hippocampal microstructure. Neurology. 2013;81(20):1746-52.

Kopelman MD. Frontal dysfunction and memory deficits in the alcoholic Korrsakoff syndrome and Alzheimer-type dementia. Brain. 1991;114 (Pt 1A):117-37.

Krikorian R, Shidler MD, Dangelo K, et al. Dietary ketosis enhances memory in mild cognitive impairment. Neurobiol Aging. 2012;33(2):425.e19-27.

Littlejohns TJ, Henley WE, Lang IA, et al. Vitamin D and the risk of dementia and Alzheimer disease. Neurology. 2014;83(10):920-8.

Mangialasche F, Kivipelto M, Solomon A, Fratiglioni L. Dementia prevention: current epidemiological evidence and future perspective. Alzheimers Res Ther. 2012;4(1):6.

Morris MC, Evans DA, Tangney CC, et al. Associations of vegetable and fruit consumption with age-related cognitive change. Neurology. 2006;67(8):1370-6.

Morris MC, Tangney CC, Wang Y, et al. MIND diet associated with reduced incidence of Alzheimer's disease. Alzheimers Dement. 2015. [Epub ahead of print]

Morris MC, Tangney CC. A potential design flaw of randomized trials of vitamin supplements. JAMA. 2011;305(13):1348-9.

Morris MS, Selhub J, Jacques PF. Vitamin B-12 and folate status in relation to decline in scores on the mini-mental state examination in the Framingham heart study. J Am Geriatr Soc. 2012;60(8):1457-64.

Nilsen LH, Shi Q, Gibson GE, Sonnewald U. Brain [U-13 C] glucose metabolism in mice with decreased α-ketoglutarate dehydrogenase complex activity. J Neurosci Res. 2011;89(12):1997-2007.

Norton S, Matthews FE, Barnes DE, et al. Potential for primary prevention of Alzheimer's disease: an analysis of population-based data. Lancet Neurol. 2014;13(8):788-94.

Nugent S, Tremblay S, Chen KW, et al. Brain glucose and acetoacetate metabolism: a comparison of young and older adults. Neurobiol Aging. 2014;35(6):1386-95.

Phillips CV, Goodman KJ. The missed lessons of Sir Austin Bradford Hill. Epidemiol Perspect Innov. 2004;1(1):3.

Riggs KM, Spiro A, Tucker K, Rush D. Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr. 1996;63(3):306-14.

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Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002;346:476-83.

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Tot Babberich Ede N, Gourdeau C, Pointel S, et al. Biology of subjective cognitive complaint amongst geriatric patients: vitamin D involvement. Curr Alzheimer Res. 2015;12(2):173-8.

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Websites

Max Lugavere: Official Site

National Institute on Aging, National Institutes of Health. Alzheimer's Disease Research Summit 2015: Path to Treatment and Prevention.

Shock NW, Greulich RC, Andres R, et al. Normal Human Aging: The Baltimore Longitudinal Study of Aging. National Institute on Aging. National Institutes of Health. NIH Publication No. 84-2450. 1984.

Sponsors

Today, it is possible to live a longer and healthier life than ever before thanks to advances in technology and medicine. However, increased life expectancy has also led to more cases of diseases that disproportionately affect the elderly, such as Alzheimer's disease (AD). According to the World Health Organization (WHO), in 2011, 35.6 million people were living with dementia, an umbrella term for brain disorders that result in memory loss and degradation of cognitive skills. AD, the most common and widely discussed form of dementia, represents 50%–70% of cases.

The dementia population is expected to double by 2030 and triple by 2050, further burdening stressed health, social, and economic systems. Thus research must move rapidly to prevent a global crisis. If high-income countries find it challenging to manage the growing societal and fiscal costs of dementia and cognitive decline, low- and middle-income countries will find these costs unmanageable. Most research focuses on targeting pathological changes in the AD brain—particularly tangles of hyperphosphorylated tau protein and plaques of β-amyloid. This conference presented work on strategies to prevent and manage dementia—nutritional and lifestyle interventions.

Cases of dementia are expected to triple in the next 35 years worldwide, imposing particularly high burdens on low- and middle-income countries. (Image courtesy of Irwin H. Rosenberg)

In the opening session, speakers discussed epidemiological evidence for the role of diet and lifestyle in cognitive function. Keynote speaker Irwin H. Rosenberg emphasized that nutrition can slow the onset of disability and extend healthy life. Speakers explained how impaired glucose metabolism may affect AD onset, how the gut microbiome is connected to cognitive health, and how a ketogenic diet may alleviate glucose metabolism problems in people at risk for AD. The audience also heard an update on U.S. National Institute on Aging recommendations from the 2015 Alzheimer's Disease Research Summit.

Keynote speaker A. David Smith opened the second session with an argument for the role of homocysteine, an amino acid, in AD and other illnesses. Speakers explored individual nutrients, including vitamin D and B vitamins, and the role of whole diet in cognitive function, concluding with a presentation on dietary patterns and dementia. In a panel discussion, speakers debated whether available evidence supports individual or broad recommendations on diet, lifestyle, or nutrient supplementation.

In the final session, keynote speaker Miia Kivipelto described strategies to delay or prevent cognitive impairment and AD, such as a Nordic diet, exercise, and cognitive training. Speakers discussed the effects of low blood glucose and hemoglobin A1c (HbA1c), a marker of glucose, on memory and hippocampal connectivity, and presented the benefits of a ketogenic diet for memory and cognitive health. The session looked at how to improve quality of life for dementia patients and caregivers and concluded with a clinical studies panel discussion.

Keynote Speaker:
Irwin H. Rosenberg, Tufts University
 
Speakers:
Gary E. Gibson, Weill Cornell Medical College; Burke Medical Research Institute
Kirsten Tillisch, David Geffen School of Medicine, UCLA
Stephen Cunnane, Université de Sherbrooke, Canada
Lenore J. Launer on behalf of Suzana Petanceska, National Institute on Aging, NIH

Highlights

• Nutrition and lifestyle are key determinants of quality of life; nutrition research for aging aims to extend lifespan while delaying cognitive decline.
• Impaired glucose metabolism is a ubiquitous finding in the AD brain, and preliminary clinical studies suggest that repairing glucose uptake could help prevent AD.
• The gut microbiome and the brain are known to interact, but more work is needed to make recommendations for probiotic supplementation or other microbe-targeting treatment strategies for brain health.
• In February 2015 the National Institute of Aging updated its priorities and recommendations for AD research.

Keynote address: aging and the nutrition imperative

Dementia interventions aim to extend healthy life and delay cognitive decline. Keynote speaker Irwin H. Rosenberg of Tufts University explained that the key objective is to reduce the time between the onset of disability and death. "What environmental factor can change the slope of that line?" he said. "Nutrition."

Prevention strategies could delay the onset of age-related cognitive decline. (Image courtesy of Irwin H. Rosenberg)

Rosenberg emphasized the need for nutritional and lifestyle interventions as we age, which he called the "nutrition imperative" in dementia research. Nutrition has long been recognized as important in aging, but large research consortia on brain aging and nutrition are only recent. Several research activities in the 1980s and 1990s—including a 1992 conference on vitamins and brain function and a research article on B vitamins, homocysteine, and cerebrovascular disease—are now being acknowledged for their forward-thinking contributions to the field.

Rosenberg's group and others focus on the nutrition–cerebrovascular disease connection. Research on vascular dementia highlights the role of vascular factors in brain health. Current findings in this area reveal that nutrient metabolism can affect cognitive function by modulating the integrity of the cerebrovascular system. Moreover, the risk factors for cardiovascular disease and age-related dementia are similar, as are the nutritional factors (such as plasma homocysteine levels) underlying both conditions.

Early descriptions of AD pathology noted substantial vascular impairment, originally described as "strangulation of brain vessels." Studies of elderly cohorts later revealed a strong relationship between high blood homocysteine (a product of protein metabolism) and incident dementia, establishing homocysteine as a potential factor in dementia pathology. Research by Rosenberg's group and others showed a link between elevated homocysteine levels and declining cognitive function in individuals with vascular pathology (small vessel infarcts).

"[There is ample] evidence that challenges us to think of the nexus of nutrition, aging, and dementia as something that has a significant vascular component," Rosenberg said. "The use of nutritional and lifestyle techniques to influence the progression of this condition ... [is] a global imperative."

The mitochondrial component of AD and its relation to nutrition

Only 1%–3% of patients have a clear genetic link to AD, and researchers do not understand how genetic changes affect disease manifestation in those cases. Up to 30% of the healthy control participants in clinical trials have enough amyloid plaques to meet the definition for AD, and there is no clear correlation between plaques and cognitive function. Thus some researchers theorize that plaques do not cause AD but instead are a disease outcome.

Gary E. Gibson of Weill Cornell Medical College and Burke Medical Research Institute pointed out that reduced glucose metabolism is consistently noted in AD; it is linked with declining cognitive function and can be observed as early in life as the 20s in people with a genetic predisposition. The causes of reduced glucose metabolism in AD are largely unknown. One contributor is loss of brain cells, which have high glucose utilization. Gibson described the effects of glucose metabolism, mitochondrial function, and oxidative stress in exacerbating cognitive decline, plaque and tangle formation, and calcium abnormalities.

Certain metabolic changes increase the production of reactive oxygen species and increase oxidative stress in the AD brain. "There's a lot more oxidative stress than there are plaques and tangles," Gibson said. His group postulated that oxidative damage stalls a critical step of glucose metabolism that depends on the α-ketoglutarate dehydrogenase complex (KGDHC), a rate-limiting enzyme that is highly sensitive to oxidative damage. KGDHC inactivity has downstream effects on critical cell processes, and low levels of this single protein reduces brain adaptability, memory, and neurogenesis, while correlating with amyloid plaque formation and hyperphosphorylation of tau.

Restoring KGDHC function could jumpstart glucose metabolism in AD. Gibson and others have shown that KGDHC and two other enzymes involved in brain glucose metabolism are dependent on thiamine, vitamin B1. He proposed that treatment with benfotiamine, a drug derived from thiamine, might improve memory and treat plaques and tangles.

A phase IIa clinical trial is underway at the Burke Rehabilitation Center of Weill Cornell Medical College and the Alzheimer's Disease Research Center at Columbia University to explore whether benfotiamine treatment slows cognitive decline and neurodegeneration in patients with mild cognitive impairment (MCI) or mild AD.

The microbiome and the mind

The human body contains 10 times more bacterial cells than human cells; bacteria perform so many necessary functions that some people have described the microbiome as an organ. Studies have linked changes in human gut flora to cancer, autism, and dementia, among other conditions. Kirsten Tillisch of the David Geffen School of Medicine at UCLA described the role of the microbiome in brain health.

Signaling between gut microbiota and the brain influences behavior and emotion. Studies in germ-free rodents show the microbiome modulates NMDA and serotonin receptors, promotes plasticity, and decreases risk-taking behaviors. Dietary changes that increase the diversity of beneficial bacterial species improve cognitive performance in rats, and fecal transplants can transfer anxiety phenotypes between rats.

Despite person-to-person variations in microbial composition—and independent of geography, age, body mass index, or sex—most people have core clusters of gut microbes in common. Tillisch and colleagues report that these clusters affect brain structure and function and that dietary probiotics can influence the microbiota–gut–brain axis. A study in humans linked probiotic consumption to blunted reactivity of the interoceptive and somatosensory brain regions during an activity designed to assess response to visual displays of emotion. Further work revealed significantly lower anxiety and depression scores, as well as lower scores in a general measure of psychopathology (SCL-90), in humans who consumed a probiotic for 30 days compared with a placebo.

Microbiota clusters have structural brain signatures. (Image courtesy of Kirsten Tillisch)

The gut microbiota has been implicated in risk factors for cognitive decline, including obesity, mood disorder, inflammation, hypertension, diabetes, and sedentary lifestyle. Future interventions might include stool transplants from the young to the elderly and, with further research, recommendations for nutrition and lifestyle changes to promote beneficial gut microflora.

Deteriorating brain glucose uptake: implications for AD

Declining brain glucose metabolism has often been viewed as a consequence of neuronal dysfunction. However, Stephen Cunnane of the University of Sherbrooke made the case that it could instead be a driver of the dysfunction. Glucose metabolism is 15% lower in cognitively normal adults with a family history of AD, relative to others of similar age and education, and drops to approximately 25% of baseline values in the early stages of AD. The brain normally relies on ketone bodies for fuel when glucose reserves are depleted. But although ketone uptake is normal in AD patients, with impaired glucose metabolism the brain eventually enters a state of exhaustion, kicking off a cycle of neuropathology, clinical symptoms, and further exhaustion.

Neuropathology, functional connectivity, and glucose metabolism are linked. Areas of β-amyloid accumulation in AD (top left) are linked with the default mode network (top right), and tend to require high levels of glucose (bottom). (Image courtesy of Stephen Cunnane)

Impaired glucose metabolism is linked to amyloid accumulation and both interferes with neuronal firing and reduces the amount of energy available for use in the brain. In young people at risk for AD, Cunnane noted, "the brain is suffering from that chronically, slowly, and over many decades." An estimated 65% of the brain's energy needs can be met by ketones, but replacing glucose with ketones works well only in patients with insulin sensitivity. Insulin resistance, which is common in patients with AD, blocks glucose utilization and ketone production from stored fatty acids.

The infant brain provides a useful model to understand energy use in the brain. Infants do not produce enough glucose to fuel brain function, so 30% of the normal developing brain's energy needs are met by ketones derived from medium-chain fatty acids in breastmilk. Similar ketone levels would be achieved in the adult brain only after fasting for 1 to 2 days.

Viewing the glucose uptake problem in people at risk for AD as a "clogged gasoline filter" suggests strategies to prevent cognitive decline. One strategy involves dietary supplementation with medium-chain fatty acids to promote ketone production by the liver. Recent brain ketone PET studies show that after only 4 days on the ketogenic diet—a high-fat, low-carbohydrate regimen that forces the body to derive energy from fat rather than carbohydrates—patients' ketone uptake increases by about 15-fold, without changes in glucose metabolism. Cunnane's group recently received funding to investigate the diet as a treatment strategy in AD patients.

New strategies for Alzheimer's prevention

Alzheimer's disease has multiple causes, prodromal phenotypes, and progression trajectories: complex approaches will be needed for prevention and treatment. Lenore J. Launer, on behalf of Suzana Petanceska, gave an overview of National Institute on Aging (NIA) initiatives.

The U.S. National Alzheimer's Plan prioritized finding an effective treatment for AD by 2025 and set goals for care quality, patient support, public awareness, and research. In May 2012, the NIH Path to Treatment and Prevention Summit spurred work in biomarker clinical trials, optogenetics, quantitative systems, pharmacology, and other areas.

By 2014, however, researchers had voiced concerns, noting that drug candidates did not engage intended targets, interventions were mistimed, translatable pharmacodynamic biomarkers were lacking, and animal model preclinical testing had poor predictive power for success in humans. A second summit in February 2015 highlighted the need to understand AD as a heterogeneous condition. It called for new drug development and prevention strategies; innovations in disease monitoring, assessment, and care; better patient and public engagement; and partnerships for open innovation.

Current areas of nutrition research include environment-wide association and microbiome studies as well as epigenomics, epigenetics, 'omics, and translational work. Nutrition researchers are also using bioinformatics and network-biology approaches to develop predictive models of wellness and disease.

Keynote Speaker:
A. David Smith, University of Oxford, UK
 
Speakers:
Helga Refsum, University of Oslo, Norway
Cédric Annweiler, Angers University Hospital, France
Katherine L. Tucker, University of Massachusetts, Lowell
Martha C. Morris, Rush University
 
Moderator:
Joshua W. Miller, Rutgers, The State University of New Jersey

Highlights

• New studies suggest the homocysteine hypothesis of brain disease may be valid, with important implications for public health.
• Optimal levels of vitamin B12 and folate may protect brain regions that are typically affected in AD.
• Vitamin D supplementation is associated with improved cognitive performance, but further studies are needed to link intervention to outcome.
• An overall healthy diet, including one serving per day of green leafy vegetables and at least one serving per week of fatty fish, could help prevent cognitive decline.

Keynote address: how valid is the homocysteine hypothesis of brain disease?

Keynote speaker A. David Smith of the University of Oxford opened the second session with an argument for the role of amino acid homocysteine in AD and other illnesses.

Abnormal levels of homocysteine in blood plasma have been observed in several neurological conditions, including schizophrenia and vascular dementia. Homocysteine is a product of methionine metabolism that is not consumed in the diet. It is regulated by three B vitamins—folate, B12, and B6. In clinical studies, supplementation with folic acid lowered homocysteine 25%–35%. Supplementation has also been shown to affect brain outcomes, improving negative symptoms in schizophrenia and preventing a second stroke in patients not taking anti-platelet drugs. Fortification of bread products with B vitamins has coincided with decreased stroke mortality rates in the U.S. and Canada.

Smith took issue with a 2014 press release from the University of Oxford about a meta-analysis published by Robert Clarke and colleagues, which claimed, "Taking B vitamins doesn't slow mental decline as we age, nor is it likely to prevent Alzheimer's disease, conclude Oxford University researchers who have assembled all the best clinical trial data involving 22 000 people to offer a final answer on this debate."

"Today, Helga and I will show that the 'final answer' is not supported by evidence," Smith said, arguing that several other important studies in the field do show a connection between B vitamins and mental decline, via homocysteine regulation. In 1998 early studies by Clarke et al. and Diaz-Arrastia strongly associated elevated homocysteine and low-normal folate and vitamin B12 with histologically confirmed AD and vascular dementia. A number of prospective studies, including one by Ravaglia et al. in 2005, associated elevated homocysteine with initiation of cognitive impairment, conversion from cognitive impairment to dementia, incidence of dementia and AD, and density of neurofibrillary tangles, as well as increased rates of cognitive decline in AD, brain atrophy, and white matter damage. A 2014 meta-analysis estimated that 22% of AD cases might be caused by elevated homocysteine.

Design flaws are common in vitamin supplementation trials, Smith argued. When participants begin a trial with near-optimal biological function, it is difficult to measure a response to the clinical intervention. Thus, trials should enroll participants whose biological function is much lower than normal. He pointed to a study by Durga et al. as a clinical trial that circumvented these design challenges.

Methodological limitations of clinical trial designs: supplementation trials should enroll participants with below-optimal levels to demonstrate a vitamin's effects. (Image courtesy of A. David Smith)

The VITACOG trial by Smith and colleagues recently explored whether B vitamin supplementation slows cognitive decline and brain atrophy by lowering brain homocysteine in elderly participants with MCI. Results suggest that the 25% of the U.S. elderly population with elevated homocysteine might benefit most from B vitamin supplementation: participants with baseline homocysteine levels higher than ~11 mmol/L experienced a 53% slower atrophy rate during a period of B vitamin supplementation, compared with other groups in the study, particularly in brain regions that atrophy in AD. That group also had marked improvements in episodic memory, semantic memory, global cognition, clinical dementia scores, and IQCODE scores.

Smith proposed that the homocysteine hypothesis of brain disease is valid and has important implications for public health. In the U.S., about 3.2 million patients with MCI have high homocysteine levels. Offering B vitamins to these patients could slow progression to dementia. A public health policy decision is needed, Smith argued, saying clinicians can either act now in memory clinics or wait for results of more trials. He posited that the benefits of acting now could be spectacular.

Vitamin B12 and the brain

Helga Refsum of the University of Oslo, who first developed a method for measuring homocysteine levels in 1989, supported Smith's argument with information on vitamin B12. Even marginally low B12 levels can have a detrimental effect on the central nervous system (CNS). Metabolic insufficiency and low-normal B12 are linked to CNS abnormalities including neural tube defects, stroke, depression, cognitive impairment, white matter damage, deposition of β-amyloid, and brain atrophy.

Refsum pointed to seemingly contradictory data on B12 and cognition. While 6 prospective studies, on 4607 subjects, associated low-normal B12 levels with lower cognitive function, 10 studies, on 7537 subjects, found no association. Refsum argued that the lack of association may reflect the multifactorial causes of cognitive decline, the study design challenges noted earlier by Smith, and the difficulty recruiting an appropriate study population. She also noted that total plasma B12 may not be an ideal marker of functional B12 status. Functional markers such as holotranscobalamin, serum levels of homocysteine, and methylmalonic acid (MMA) may be more effective because they more accurately reflect B12 status in the blood.

A careful balance between folate and B12 may be needed to prevent cognitive decline. (Image courtesy of Helga Refsum)

Landmark studies on the importance of folate, such as the National Health and Nutrition Examination Survey (NHANES), found the risks for anemia and cognitive impairment are higher when low B12 is combined with normal folate—and dramatically higher when folate is elevated, although increasing B12 to normal levels then has a protective effect. The balance between these vitamins may thus be critical to the outcome of interventions for cognitive decline.

Refsum cited further evidence of B12's protective effects in the brain. The Rotterdam Study and a 2005 study by Vry et al. both found that improved B12 status can reverse white matter damage (vitamin B12 deficiency is known to cause demyelinating disease and white matter changes). Vry et al. reported reversal of white matter damage in a 39-year-old women after only 4 months of treatment. The VITACOG study found brain regions affected in AD are protected by B12 supplementation, reporting a 9-fold lower rate of atrophy in those regions with supplementation.

Brain regions (green) where B vitamin supplementation significantly (P < 0.05) reduced the loss of grey matter, compared to placebo, correspond to regions that show atrophy in early AD. (Image presented by Helga Refsum courtesy of Douaud et al. PNAS. 2013.)

Refsum concluded by noting limitations in the Clarke meta-analysis: the analysis did not investigate dementia as an outcome, cognitive decline did not occur during the trials, and cognitive tests were performed at baseline in only a quarter of the studies included. Moreover, some participants in the analysis were unlikely to show an effect, because they were too young, had a short trial duration, or exhibited low baseline levels of homocysteine. More than 80% of the population used aspirin, which was shown in the VITACOG study to block the effects of B vitamins on cognitive decline. In the two cohorts with trial duration and baseline cognitive data sufficient to investigate cognitive function, participants with poor B vitamin status at baseline demonstrated the beneficial effects of folic acid, B6, and B12 supplementation.

Vitamin D in dementia prevention

Vitamin D is a neurosteroid hormone synthesized in the skin via UV rays, and a small amount is obtained in the diet. It is involved in neurophysiology, neuroprotection, and vasculoprotection, and participates in the genetic regulation of proteins such as neurotropic factors. Cédric Annweiler of Angers University Hospital explained that aging is associated with changes in the mechanisms of vitamin D production and action.

Studies have linked vitamin D to cognitive and executive function. Vitamin D can cross the blood–brain barrier, and appears to exert particular effects on the hippocampus, hypothalamus, cortex, subcortex, and spinal cord. Low vitamin D status is associated with a 2.4-fold increased risk of cognitive impairment in the general population and is often observed before AD onset. In contrast, higher vitamin D is associated with higher Mini-Mental State Examination (MMSE) scores.

Vitamin D may enhance neuroprotection. (Image courtesy of Cédric Annweiler)

But, Annweiler noted, it is unclear whether vitamin D supplementation could prevent cognitive decline or delay AD. Interventional studies to date suggest it could: a correlation between dietary vitamin D intake and cognitive performance has been noted in several studies after 2–16 months of supplementation. However, these studies did not definitively link the intervention to the improvement. Stronger trials are needed to clarify the relationship.

Nutrients and foods associated with cognitive function

Katherine L. Tucker of the University of Massachusetts, Lowell, presented three cohort studies on nutrients and cognitive outcomes and described how the findings should be integrated into recommendations for an overall healthy diet. "If you consider each nutrient separately, you might come to the conclusion that we should take B vitamins or vitamin D. But the truth is that cognitive decline is multifactorial, so it may depend on who you are and what your particular deficiency is," she said.

The Normative Aging Study looked at vitamin B6, homocysteine, and cognitive function, finding a dose-response relationship between homocysteine and executive function in older men, and a strong decline in that measure for 3 years following the original study, correlating with levels of homocysteine, folate, and B12. It also correlated vitamin B6, which affects homocysteine levels, with cognitive scores. Inadequate dietary intake of B6 was at least partly responsible for its low plasma levels, showing that poor diet and lifestyle contributed to the insufficiency. Tucker reported that few studies have looked at vitamin B6 and cognitive decline.

The Boston Puerto Rican Health Study examined a disadvantaged population—42% percent diabetic, 71% hypertensive, and many obese, with low education levels, high rates of depression, and low cognitive function scores. Participants' folate levels were sufficient (the study was initiated after folate fortification began), but 30% were deficient in B6 and 5% were deficient in B12. Cognitive function was 60% more likely to decline after 2 years in those deficient in vitamin B6.

Finally, the Nutrition, Aging, and Memory in Elders (NAME) study examined a low-income, minority elderly population from the greater Boston area. Participants had at least one unmet need related to food or personal care. Those with higher dietary intake of omega-3 fatty acids had better immediate recall and improved executive function, memory, attention, and brain volume. Furthermore, those with sufficient vitamin D levels were less likely than others to experience dementia, stroke, and AD.

Tucker concluded by pointing to the need to place findings on individual nutrients in a dietary context. For example, eating fatty fish like mackerel can help maintain sufficient omega-3 fatty acid levels, and reducing sugar intake in nondiabetic patients may lower their risk for cognitive impairment. Her team associated food insecurity, low fruit and vegetable intake, and poor dietary variety with cognitive decline. Their data on whole diet, using measures such as Mediterranean diet score and Healthy Eating Index-2015 score, show associations with improved cognitive function. "We need these mechanistic studies of single nutrients," she said, "but [for public health] we really need to think more broadly than a single supplement here or a single supplement there.... Food is the best available source."

The NAME study linked higher vitamin D levels to higher cognitive scores in an elderly population. (Image courtesy of Katherine L. Tucker)

Dietary patterns and dementia prevention

Martha C. Morris of Rush University described data on dietary patterns and dementia. She began by reviewing nutrients such as food-derived vitamin E, DHA, and folate, shown to protect against brain aging. It may be surprising, she noted, to see media reports claiming that supplementation with some of these nutrients has no effect on cognitive function. Clinical studies often fail to draw out the nuances of data; neglecting, for example, to consider participants' baseline dietary intake of nutrients when reporting findings. In the Women's Health Study, for example, the effects of supplementation on cognitive function were seen only in participants with below- or above-median intake of α-tocopherol (vitamin E), but these effects were obscured when the groups were analyzed together.

Individual nutrients strongly and moderately associated with cognitive function can be obtained through diet. (Image courtesy of Martha C. Morris)

Describing findings on particular foods and diets, Morris showed data demonstrating that fish intake is negatively correlated with AD and one daily serving of green leafy vegetables may confer the equivalent of an 11-year younger brain. A study by her team tested a diet known as the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND), a brain-focused diet taking cues from the Mediterranean diet and the Dietary Approaches to Stop Hypertension (DASH) diet—both shown to mitigate cognitive decline in previous studies. Elderly Chicago residents in the intervention group had slower cognitive decline (double the protection from cognitive change) compared with those who followed either diet alone.

Methodological challenges hinder progress in the field, and Morris described flaws in studies relying on Mediterranean diet pattern scoring. Several prospective studies found no association between a Mediterranean-type diet and cognitive decline, but the studies analyzed dietary patterns based on within-population median food intake, rather than intake levels found in the Mediterranean population (which tend to be much higher for foods such as fish and vegetables compared to inner-city populations). These methods led to crude estimates of the link between nutrition and brain aging. Serving medians from the Mediterranean population are needed to produce meaningful adherence scores and interpret findings across studies.

Morris argued future research should focus on the roles of individual nutrients, foods, and diets. Studies should report the amount of a nutrient or food per serving that is needed for protective effects. Brain-specific diets should be modified as research progresses, and dietary intervention trials should be emphasized.

Panel: can we give at-risk patients specific nutritional advice now, or do we need more trials?

Panel moderator Joshua W. Miller opened the discussion with a quote from The missed lessons of Sir Austin Bradford Hill, a 2004 article by Carl Phillips and Karen Goodman that summarized Hill's lecture to the Royal Society in 1965. Hill presented criteria for determining whether something is causative in the absence of a randomized controlled trial: "Policy actions that appear to create net benefit should be taken even without statistical proof of an association, while actions that entail great costs should only be taken with sufficient certainty of substantial benefit."

Irwin Rosenberg answered the panel's discussion question—Can we give at-risk patients specific nutritional advice now, or do we need more trials?—with a resounding, "We must." He argued that there is enough evidence to provide specific recommendations to patients in the clinical setting, but that making general recommendations to the population outside the clinical setting is a different story. "There, I would defer to the very convincing observations that Martha Morris has given us," he said. "I think you can, on the basis of those studies, make some recommendations about healthy diets that will be beneficial."

The panelists agreed that Morris's data on omega-3 supplementation point to practical and realistic recommendations to consume one fish meal a week. Obtaining omega-3s from the diet is considered far superior to supplementation. Helga Refsum added that previous work suggests 6–10 µg of vitamin B12, much higher than the recommended daily intake, confers optimal effects on homocysteine levels. She suggested that elderly patients consider taking B12 supplements to achieve these beneficial effects. Rosenberg emphasized the importance of obtaining B12 from crystalline sources, such as supplements or fortified foods, to circumvent problems with nutrient absorption.

Gary Gibson said that selecting the target population for an intervention is very important, and A. David Smith reminded the panel that broad dietary recommendations would require additional research, because a recommendation based on a cognitive study might be contraindicated for another health condition. This issue came up in discussions with the U.S. Food and Drug Administration during the debate on folic acid fortification, Rosenberg reported. The panelists agreed that exposing the population to a supplementation or fortification requires policy makers to carefully weigh the risks to specific subgroups.

Cédric Annweiler noted that while there are no interventional data to support recommendations about vitamin D consumption, no toxic effects are associated with supplementation. Patients with low vitamin D levels are known to benefit, and Annweiler supplements his older patients who have insufficiencies.

Keynote Speaker:
Miia Kivipelto, Karolinska Institute, Sweden
 
Speakers:
Agnes Flöel, Charité–University Hospital Berlin, Germany
Richard S. Isaacson, Weill Cornell Medical College; New York Presbyterian Hospital
Heather H. Keller, University of Waterloo, Canada
Max Lugavere, Independent documentary filmmaker

Highlights

• Preliminary findings suggest interventions such as a Nordic diet, an exercise regimen, cognitive training, and social activities may help stave off cognitive decline.
• Elevated blood glucose is associated with hippocampal and amygdalar atrophy and with cognitive decline; caloric restriction may improve verbal memory and ameliorate cognitive decline.
• Social facilitation at mealtimes encourages nutrition resiliency in dementia patients.
• A documentary by independent filmmaker Max Lugavere will explore how lifestyle choices affect AD onset.

Keynote address: can diet and lifestyle prevent cognitive impairment?

Keynote speaker Miia Kivipelto of the Karolinska Institute noted that everyone can do something to delay or prevent AD. The research community has identified seven risk factors that contribute to AD besides aging: diabetes, hypertension, smoking, obesity, physical inactivity, depression, and lower education. Reducing these collective risk factors by 20% could lower AD incidence by 15%, or more than 16 million cases globally by 2050. There is controversy about the degree to which AD incidence can be lowered by environmental and behavioral interventions, but studies suggest that 30% of AD cases might be related to these seven modifiable risk factors, and might therefore be preventable. The challenge is that little is known about the interplay between risk factors, in part because of a lack of long-term randomized controlled trials to examine them together.

Kivipelto's group is targeting several risk factors simultaneously, hoping to maximize preventive effects. This strategy is effective in diabetes prevention: in the multimodal Finnish Diabetes Prevention Study, diabetes incidence decreased by 58% with dietary counseling and physical activity. An AD study by Kivipelto and colleagues—the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)—used a multi-domain approach to assess how risk factors for cognitive impairment contribute to long-term outcomes such as dementia, depression, and vascular disease. The group implemented three interventions over 2 years: nutritional guidance using a Nordic diet, an exercise regimen, and cognitive training and social activities. Participants were at risk for dementia, with average or lower cognitive performance as well as high cholesterol, high blood pressure, high BMI, low education, or low physical activity scores.

The intervention group participated in all three interventions and had improvements of 25% in cognitive scores, 80% in executive function, and 150% in processing speed compared with a control group. The intervention group also had a 40% better performance on complex tasks, while the control group had a 30% higher risk of cognitive impairment. After 1 year, the intervention group had lower blood pressure, BMI, and total and LDL cholesterol. Kivipelto noted that many participants maintained the recommended fish and vegetable intake and level of physical activity after the 2-year study ended. FINGER is the first large, long-term trial to demonstrate that a multi-domain intervention can maintain cognition and prevent cognitive decline in older at-risk individuals. Long-term outcomes will be monitored over 7 years.

Kivipelto hopes FINGER will be a "pragmatic model that can be tested and adapted in various settings and populations." She sees value in similar ongoing studies in Europe and hopes findings will be made available in a large database, similar to the European Dementia Prevention Initiative and MIND-AD databases. Because of the lack of AD drugs on the horizon, Kivipelto considers the multimodal approach a promising path for prevention research.

Harmful effects of high-normal glucose on the brain in dementia prevention

Agnes Flöel of Charité–University Hospital Berlin studies how dementia is influenced by glucose, using clinical measurements of glucose and glycated hemoglobin levels. In diabetes it is well established that impaired glucose control contributes to vascular outcomes, such as atherosclerosis and stroke, and that glucose toxicity can induce broad changes in cognition and brain structure, accelerating brain aging. Flöel's group explores whether similar outcomes apply to nondiabetic patients who have slightly elevated glucose levels. She cited studies in 2013 (Crane et al.) and 2012 (Cherbuin et al.) that linked elevated glucose in nondiabetic patients to dementia and hippocampal and amygdalar atrophy.

In nondiabetic older adults her group linked higher HbA1c levels (a marker of glucose control) and higher glucose levels with lower memory and consolidation scores (including delayed recall), reduced learning ability, and decreased hippocampal volume and density (measured via magnetic resonance imaging, MRI), demonstrating that short- and long-term elevations in glucose affect the structure of the hippocampus, an area of the brain that controls memory. Other brain measures, such as gray matter volume, were unchanged, suggesting the hippocampus may be among the first areas affected by elevated glucose, possibly via decreased neurotransmitter signaling. Lowering glucose levels, even within the normal range, may thus improve cognition in older adults.

Caloric restriction slows aging and reduces age-related brain atrophy. In a proof-of-concept dementia study, Flöel's group found that caloric restriction improved verbal memory and that memory improvements were linked to C-reactive protein (a marker of inflammation), fasting glucose levels, and low insulin. To assess whether caloric restriction works independently of body composition, the group tested cognitive performance and grey matter density after a period of weight loss, and then post-intervention after a period of weight maintenance. The subjects had better attention, memory, and verbal fluency and increased grey matter density after the weight maintenance period, suggesting that caloric restriction is the controlling factor.

In clinical situations, however, caloric restriction must be closely monitored in dementia patients, because the disease itself causes weight loss. As an alternative, the group tested compounds that mimic caloric restriction, such as resveratrol, which yields similar glucose levels and increases synaptic plasticity and gene longevity. Older adults who consumed resveratrol supplements for 26 weeks performed better on a 30-minute word retention task and had declining HbA1c levels, which may mirror increased functional connectivity in the hippocampus.

Before and after the resveratrol intervention/control period, subjects underwent memory tasks and neuroimaging to assess volume, microstructure, and functional connectivity of the hippocampus. (Image courtesy of Agnes Flöel)

Dietary intervention to prevent and slow memory loss due to AD (DIPLOMA)

Is AD preventable? Should doctors target risk reduction in 30-year-olds? Is it possible to customize AD risk-reduction strategies based on lifestyle and epigenetic factors? Richard S. Isaacson of Weill Cornell Medical College and New York Presbyterian Hospital asks these questions at his Alzheimer's Prevention Clinic. "Twenty to thirty years ago, we couldn't prevent a heart attack and we couldn't prevent a stroke," he said. "So, in 2015, I'd like to talk about Alzheimer's and prevention in the same sentence." Prevention is not about any one factor, he argued, but involves strategic risk reduction, risk stratification, and clinical intervention.

His patients get a full workup—interviews, cognitive testing, and biomarker assessment—and receive customized prevention plans. Isaacson tries to "get under the hood of the engine," he said, reviewing modifiable and non-modifiable risks, and at times blurring the two. Science suggests gene expression can be modified by exercise, for example, and he described exercise interventions as a "tug of war against genes."

The clinic, which tracks patients via the Comparative Effectiveness Dementia & Alzheimer's Registry, is conducting a phase I prospective cohort study, Dietary Intervention to Prevent and Slow Memory Loss due to Alzheimer's, to assess multimodal interventions based on genetic testing and biomarker assessments. The cohort of 27- to 91-years-olds includes patients with preclinical and mild AD, as well as a cognitively normal population. The trial investigates nutritional and pharmaceutical interventions tailored to the individual's genome, including a modified MIND diet, and assesses risk reduction by evaluating cognitive performance, biomarkers, and adherence.

Next, the researchers will conduct a randomized controlled phase II trial using the best interventions from phase I to assess whether dietary ketosis and other strategies improve memory and reduce AD risk. The team is also launching online initiatives such as the AD-Nutrition Tracking System, a free tool that helps individuals track brain-healthy dietary and lifestyle choices using an evidence-based personalized approach. It provides real-time monitoring and feedback on social, physical, and mental health choices, tracking social networking and engagement, musical training (known to improve cognition), diet, exercise, and physiological markers. The group is also building a comprehensive online database, Alzheimer's Universe, set to launch in late 2015.

Features of the AD-Nutrition Tracking System. (Image courtesy of Richard S. Isaacson)

Interventions to improve food intake

In the U.S., one person is diagnosed with AD every minute. Caregivers provide unpaid assistance that would, if compensated, cost eight times the revenue McDonald's Corporation makes every year. In Canada, of the 1 in 10 people transferred from long-term to acute care facilities, 60% have dementia. Most people are moved from home care to long-term care because caregivers are overwhelmed; the burden placed on caregivers is huge, and evidence-based recommendations are needed. Heather H. Keller of the University of Waterloo discussed the need to maintain quality of life for dementia patients by combating weight loss, a common health outcome that affects factors such as cognitive decline, physical decline, and rate of falling. Keller described a strategy to prevent weight loss by increasing food intake via improved mealtime interactions.

Patients tend to decrease food intake for behavioral and emotional reasons (such as agitation, social isolation, and depression) and physiological reasons associated with swallowing and food texture. Keller reported that challenging behaviors at mealtimes often leads to a decision to place AD patients in long-term care. Studies aiming to improve knowledge among caregivers often focus on training in weight monitoring and stress coping and on increasing protein and energy consumption. Keller posited that targeting stress and social behaviors could be more important; there is "more to food than nutrients," she said, citing the cultural, social, and cognitive benefits of mealtimes.

Redefining mealtimes as opportunities to embrace social, cultural, behavioral, and symbolic meaning. (Image courtesy of Heather H. Keller)

"Soft factors" such as hospitality, meal choice, staff attitude, and environment are important at mealtimes. We need to move beyond thinking of mealtimes as a task, Keller noted; in a 6-year longitudinal study she conducted, caregivers got as much enjoyment from a successful mealtime as people with dementia. Qualitative studies show mealtime experience can be improved through simple changes, such as homelike décor, music, structured conversation, intimate space, meal choice, and staff interaction. Keller's theory of nutrition resiliency, "The Life Nourishment Theory—being connected, honoring identity, and adapting to evolving life," advocates improving food intake through such social facilitation. She called for more research to overcome challenges in long-term care facilities, such as highly heterogeneous populations, poor data, and limited transferability.

According to Keller, the long-term care system, and staff perceptions, need to change. She is implementing the largest study to date, called M3, to identify drivers of food intake on which to base multimodal interventions.

Patient perspective: why 30-somethings should get serious about brain health

Max Lugavere, an independent documentary filmmaker, described his efforts to understand how young people can reduce their AD risk. When his mother began to show signs of cognitive decline and memory loss 3 years ago at age 59, without a family history of dementia, he questioned his assumption that dementia is a disease of the old. After learning that changes in the brain can occur decades before signs of the disease, he began looking for diet and lifestyle interventions for the young.

Lugavere, a storyteller by trade, aims to take the public on a journey through the science and personal experience of dementia—portraying it as a cascade of events throughout life. With $130 000 from his Kickstarter crowdfunding campaign, Lugavere is building a documentary around a simple question: "What if America's most feared disease were a choice we made at checkout?" He showed a short clip, in which he highlights his experience and interviews researchers such as Suzanne Delamonte, a neuropathologist at Brown University who coined the term "type 3 diabetes" as a synonym for AD. In the clip, Lugavere emphasizes that genes are not our destiny; AD occurs in part because of the lifestyle choices we make.

Clinical studies panel

The conference concluded with a panel discussion featuring a debate on three clinical studies presented by Isaacson. The discussion touched on topics including cholesterol in brain health, statin use, physical activity, cardiovascular risks, brain-healthy diets, and optimal vitamin D levels. It highlighted the array of lifestyle, genetic, environmental, and other factors whose interplay affects brain health and the risk of AD, reinforcing the need for multifaceted approaches to prevention and treatment.

What additional studies are needed to inform broad dietary recommendations for brain health?

Is there a need to establish guidelines for the methodological design of trials that assess nutritional interventions?

How can we design more effective long-term trials to determine if nutritional interventions can prevent cognitive decline or dementia?

What preventive strategies would mitigate brain glucose hypometabolism in young adults at risk for AD?

Are further studies needed to characterize the merits of vitamin supplementation versus dietary consumption of nutrients?

How might further research explore which lifestyle changes could mitigate cognitive impairment and dementia?

Are further studies needed to resolve the recent questions regarding the homocysteine hypothesis of brain disease?

Can interventions targeting the human gut microbiome be designed to improve cognitive health?

How might additional studies explore keto-therapeutics for dementia?

Is there sufficient evidence to support vitamin D supplementation in adults at risk for dementia?

How do understudied food groups such as legumes, meats, nuts, and whole grains affect the cognitive health of elderly populations?

Can lifestyle interventions that target glucose control improve brain function in patients with mild cognitive impairment?