Your Trusted Brand for Over 35 Years

Life Extension Magazine

<< Back to February 2015

Combat Age-Related Brain Atrophy

February 2015

By Barry Volk

Even if you seem perfectly healthy, you may be losing as much as 0.4% of your brain mass every year.1,2 The rate of brain shrinkage increases with age and is a major factor in early cognitive decline and premature death.2-7

Studies show that older adults with significant brain shrinkage are much more likely to have cognitive and movement disorders than similarly aged people with normal brain size. They are also at an increased risk of vascular death and ischemic stroke.4,8-10

In addition, atrophy of specific brain regions has been associated with a variety of cognitive, behavioral, and mental health problems. Shrinkage of the temporal lobes, for example, is associated with a 181% increase in the risk of major depression.7

Perhaps most alarmingly, brain shrinkage sharply increases risk of early death:

  • Younger individuals with overall brain shrinkage have as much as a 70% increase in the chance of dying,5
  • In a study of people aged 85, temporal lobe atrophy is associated with a 60% increase in the risk of dying,2
  • Severe atrophy of the frontal lobe (behind the forehead) increases the risk of death by 30%.2

Brains also shrink from the inside out, resulting in enlargement of the fluid-filled ventricles, or hollow spaces on the interior of the brain; such shrinkage has its own modest effect on early death.2

Even though brain shrinkage is progressive, a growing number of neuroscientists believe that brain shrinkage can be slowed or even reversed.11-13 In this article, we will share with you how lifestyle changes and proper supplementation can help prevent this devastating cause of cognitive decline and premature death.

Brain Shrinkage Is Not Inevitable  

Brain Shrinkage Is Not Inevitable

Like so many of the symptoms of aging, brain shrinkage was long thought to be simply an inevitable consequence of growing older. However, we are learning that brain atrophy is by no means inevitable. A host of conditions—from cardiovascular disease and diabetes to sleep and anxiety disorders to lifestyle choices—have been associated with brain shrinkage. Since many of these are reversible or at least preventable, it’s important to understand their impact on brain shrinkage, cognition, and life span.

What you need to know
The Danger Of Excess Abdominal Fat

Protect Against Brain Shrinkage

  • Your brain is shrinking as you age, costing you memories and mental sharpness.
  • Worse, brain shrinkage has been directly associated with premature death.
  • Causes of brain shrinkage are closely related to symptoms of aging, including cardiovascular disease, obesity, diabetes, and even poor sleep habits and distress.
  • You may be able to prevent brain shrinkage by adopting healthy lifestyle habits and using supplements that target your own aging body’s vulnerabilities.
  • Supplements that reduce your cardiovascular risk, lower your blood sugar, or improve your sleep, for example, may do double duty in slowing or stopping brain shrinkage and improving your chances for a long, mentally fit life.

The Connection Between Cardiovascular Disease And Brain Shrinkage

The Connection Between Cardiovascular Disease And Brain Shrinkage  

Although we don’t often hear about this, there is a strong connection between cardiovascular disease and brain shrinkage.

Perhaps the most obvious connection is the one between blood vessel disease (atherosclerosis) and brain volume. Atherosclerosis occurs when plaque builds up inside your arteries and restricts blood flow throughout the body. Although we typically think of the negative effect atherosclerosis has on the heart, its effect on your brain can be equally devastating.

When blood flow to the brain is restricted, your brain receives less oxygen and fewer nutrients, causing it to shrink. Studies show that people with lower levels of blood flow to the brain have smaller total brain volumes and total thickness of the cortex (the active surface layer of the brain)—resulting in poorer performance on tests of cognitive function.14

In addition, disease of the coronary arteries (the arteries that feed the heart muscle) is also associated with decreased brain volume. When compared to healthy controls, patients with coronary artery disease had significantly smaller gray matter volume in several regions of their brains.15 This is especially significant since gray matter is where all thinking, feeling, sensory, and motor function originates.

The relationship between cardiovascular disease and brain volume operates in both directions: People with smaller brain volumes have been found to have a 58% increase in the risk of death from all causes, a 69% increase in risk of vascular death, and a 96% increase in the risk of stroke, compared with those having normal brain volumes.10

Several other risk factors commonly associated with cardiovascular disease may also predict brain shrinkage. For example, people carrying the ApoE4 gene variant have significantly smaller overall brain size—with a specific decrease in brain areas that process memory and emotion.16

High levels of the amino acid homocysteine, another risk factor typically associated with heart disease, have now also been connected to brain shrinkage (independent of its impact on cardiovascular disease).

Specifically, studies have shown that people with high levels of homocysteine have smaller volumes of gray matter in the brain—and as a result, have worse scores on many tests of cognitive function.17

This was especially evident in a study of a group of people who had recently suffered strokes. The researchers found that those with the highest homocysteine levels had a tremendous 8.8-fold increase in risk of brain shrinkage (compared with those having the lowest).18 Other studies have demonstrated that the higher the level of plasma homocysteine, the greater the rate of brain atrophy and the risk for Parkinson’s and Alzheimer’s diseases.19-22

A deficiency of B vitamins has also been tied to brain shrinkage. This makes sense, since inadequate amounts of vitamins B6, B12, and folic acid can lead to elevated homocysteine levels. This occurs because these vitamins play a role in converting homocysteine into an important protein building block and when there’s a shortage of B vitamins, that conversion process isn’t as efficient, and homocysteine levels increase.13,23

Close associations have been found between low levels of folate, for example, and severe gray matter atrophy and atrophy of the hippocampus, a main memory-processing center in the brain.24,25 Similarly, people with lower vitamin B12 levels have been shown to have progressive brain atrophy, with rates of brain volume loss 517% greater than those with higher levels.13,26

Remarkably, it has been found that brain shrinkage due to high homocysteine levels must reach a critical level before cognitive decline sets in.21 This is another example of the “therapeutic window of opportunity” during which brain shrinkage may be prevented by adequate supplementation, as we’ll see later.27

The Connection Between Diabetes And Brain Shrinkage

The Connection Between Diabetes And Brain Shrinkage  

Diabetes is notorious for causing problems with the peripheral nervous system,28 leading to conditions such as painful diabetic neuropathy and blindness-inducing diabetic retinopathy. New findings suggest that high blood sugar levels—and the advanced glycation end products (AGEs) that they produce—cause damage to the central nervous system as well, specifically neurodegeneration and brain atrophy.29-31

Studies have shown that, when compared to nondiabetic people of similar age, diabetics have an average of 4% smaller hippocampal volume, a nearly 3% reduction in whole brain volume, and double the risk of mild cognitive impairment.32,33

In addition to causing brain shrinkage, studies now suggest that diabetes induces toxic, misfolded proteins quite similar to those found in neurodegenerative diseases such as Alzheimer’s, pointing to yet another way that diabetes can damage brain cells.34 Indeed, diabetes and Alzheimer’s disease share many properties, including defective insulin release and signaling, impaired glucose uptake from the blood, increased oxidative stress, stimulation of brain cell death by apoptosis,35,36 blood vessel abnormalities, and problems with energy production in mitochondria.37,38

Obesity And Your Brain

Like diabetes, obesity is a known cause of brain atrophy.39 Even in people with normal cognition, higher body mass index (BMI, a measure of obesity) is associated with lower brain volume in obese and overweight people.40

Obesity and diabetes share many similar mechanisms, including insulin resistance and oxidative stress, both of which are known to contribute to brain atrophy.38,41 In addition, fat deposits produce huge amounts of inflammatory signaling molecules (cytokines) that may contribute to brain cell death and brain volume loss.39

Additional links between obesity and brain shrinkage may be even more fundamental. About 46% of Western Europeans and their descendants carry a gene variant called FTO, which is associated with fat mass and obesity. People who carry this gene weigh on average about 2.64 pounds more and have an extra half-inch of waist circumference compared to those who lack the gene variant.42 Recent findings show that carriers of the FTO gene variant have approximately 8% smaller frontal lobe volumes, and 12% smaller occipital (back of the brain) volumes than people who don’t carry this gene variant. These changes were not associated with differences in cholesterol levels or blood pressure, suggesting an independent relationship.42

Sleep Disruptions

Sleep disruptions and anxiety also contribute to loss of brain volume. Relatively healthy older adults with short sleep duration have significantly smaller brains than those with longer sleep duration. In addition, for every hour of reduced sleep duration, they experience a 0.59% yearly increase in the size of the blood-filled ventricles, and a 0.67% decrease in cognitive performance.43 Similarly, increases in brain shrinkage are associated with decreased quality of sleep as well.44

Poor sleep and anxiety, of course, are related, and one study has shown that middle-aged women who have had longstanding psychological distress (based on a standard questionnaire) are at a 51% increased risk of moderate-to-severe atrophy of the temporal lobes.6

Smoking And Drinking

Smoking has been recognized as a cause of brain shrinkage since at least 1987.45,46 More recent studies have confirmed and extended this association, with evidence that any lifetime history of smoking (even if you currently do not smoke) is associated with faster brain shrinkage in multiple brain regions, compared with people who never smoked.47

Chronic alcohol consumption has also been associated with brain shrinkage, but in a dose-dependent way. While light-to-moderate drinkers have larger total brain volume than nondrinkers,48 heavy drinkers are 80% more likely than nondrinkers to sustain frontal lobe shrinkage, compared with nondrinkers,49 and 32% more likely to have enlargement of the ventricles, indicating shrinkage from within.50 (A heavy drinker is defined as someone who consumes more than about 15 ounces of pure alcohol per week. A standard drink is equal to 14.0 grams, or 0.6 ounces, of pure alcohol.)

Natural Supplements That Protect Brain Volume

Natural Supplements That Protect Brain Volume  

Even though the array of factors that can cause brain shrinkage can be daunting, there is good news. Since brain shrinkage results from the same basic processes that cause other symptoms of aging, it’s likely that brain shrinkage is preventable—especially when caught early enough.

That’s why we want to provide you with information on key nutrients that have been shown to powerfully protect the brain. Here are four of the most potent brain-protecting nutrients.

B Vitamins

B vitamins are essential for supporting normal metabolic function, especially in the regulation of homocysteine51 (and elevated homocysteine, as we have seen, leads to significant brain shrinkage and dementia, especially when B-vitamins are deficient).18,27,52,53

Elderly people are now generally advised to maintain optimal B-vitamin status—and for good reason.13,54 Studies show that people with higher folate levels have slower rates of brain atrophy and a lower rate of conversion from mild cognitive impairment to actual dementia, and those who take folate or B12 have lower grades of brain white matter abnormalities.53,55

While each of these B vitamins provides its own unique benefits, several recent studies show why it’s beneficial to supplement with a combination of folate, vitamin B6, and vitamin B12. This was clearly seen in a double-blind, placebo-controlled clinical trial in adults over age 70 who had mild cognitive impairment.56

For the study, one group of subjects took folate (800 mcg/day), vitamin B12 (500 mcg/day), and vitamin B6 ( 20 mg/day), while the other group took placebo.56 After two years, supplemented patients’ brains shrank at an annual rate that was 30% slower than those taking the placebo. Supplemented patients whose homocysteine levels were abnormally high at baseline had a 53% slower brain shrinkage rate than unsupplemented patients, showing that supplementing with B vitamins is especially important in people who have high homocysteine levels.

A follow-up study showed that brain areas most susceptible to atrophy in the early development of Alzheimer’s disease are especially well-protected by the same B-vitamin regimen, with supplemented patients experiencing as much as a 7-fold reduction in shrinkage of those regions.57 Another study, using the same doses of B vitamins, found that supplemented patients had 30% lower mean plasma homocysteine levels, and slower rates of cognitive decline on multiple standard tests.58

Omega-3 Fatty Acids

Omega-3 Fatty Acids  

Omega-3 fatty acids comprise a large and important portion of brain cell membranes, where they participate in a wide variety of cellular functions. Indeed, 30 to 50% of the fatty acids in brain cell membranes are long-chain polyunsaturated fatty acids that include the vital omega-3 group. Brain cell membranes are especially rich in DHA, an essential fatty acid derived only from the diet.59,60

Omega-3s have many functions that help protect brain cells. Omega-3 fats are known to enhance the brain’s relaxing functions.61 This protects brain cells from overexcitation, which is a major cause of brain cell damage that occurs with aging.62 Omega-3s also help preserve brain cell function by increasing the production of anti-inflammatory signaling molecules in the brain.59,63 Similarly, omega-3 fats in brain tissue protect cells from damage induced by stress and elevated stress steroids.63

The importance of this protection is especially seen when there’s not enough of this vital nutrient. Indeed, abnormal distributions of fatty acids in brain cells are associated with a variety of mental health disorders, particularly major depression and bipolar disorder.64

It is not surprising, then, that age-related changes in brain cell omega-3 fat composition raise the risk of brain abnormalities as people age.65 By contrast, studies show that a higher omega-3 index (which is the sum of the omega-3 fats EPA plus DHA), is correlated with larger brain volume.66

Unfortunately, aging is associated with a significant decline in DHA levels in the brain, a drop that is sharply worsened in Alzheimer’s disease and possibly other neurodegenerative disorders.67,68 This highlights the importance of protecting your brain by supplementing with omega-3 fats.

Pomegranate

Pomegranates contain very high levels of polyphenols, which are plant-derived molecules with anti-inflammatory and neuroprotective properties.69 Animal studies reveal that supplementing with pomegranate juice slows the development of Alzheimer-like disease, a major cause of brain atrophy.69-71 This protection may arise from the ability of the polyphenols in pomegranate to slow or stop brain cell death.72

Human studies demonstrate significant improvements in cognition and memory with consumption of 8 ounces of pomegranate juice daily, and lab studies with human brain cells in culture show that pomegranate polyphenols protect cells against changes that occur in other neurodegenerative diseases.73,74

Resveratrol

Resveratrol  

Resveratrol is a major component of red grapes and certain other dark fruits; it has seen widespread use in preventing aging and age-related cardiovascular and neurologic conditions. Studies in a mouse model of chronic fatigue syndrome (which can produce brain shrinkage) show that four weeks of resveratrol therapy increased the animals’ daily physical activity by more than 20%, possibly as a result of reduced brain cell death.75 In addition, the volume of the memory-intensive hippocampus was larger following supplementation.

Researchers are also exploring resveratrol as a potent neuroprotectant against the brain-shrinking effects of obesity and a high-fat diet. In studies of obese animals (obesity is a cause of brain shrinkage), resveratrol protected brain tissue from oxidative damage, a precursor to brain cell death.76 And in mice fed a high-fat diet, resveratrol similarly protected against oxidative damage to the vital blood-brain barrier and decreased injury to the endothelial cells in the brain.77

These findings in animals may explain the results of a compelling human study in 2014, which demonstrated that, in healthy overweight older adults, supplementing with 200 mg/day of resveratrol improved the functional connections between the hippocampus and the frontal areas of the brain.78 Such changes were accompanied by improved memory performance as well as better blood sugar control, again pointing to the complex interactions of metabolism and brain performance.

Summary

Brain shrinkage is a silent threat to our health and longevity. Loss of brain volume means loss of brain cells, which in turn means loss of memory and learning.

There are a myriad of threats to brain volume as we age. Virtually all of the chronic symptoms of aging have been associated with, and to some extent implicated in, brain shrinkage. In addition, lifestyle habits such as a high-fat diet, sedentary behavior, and smoking or excess drinking can further complicate matters.

Fortunately, like other symptoms of aging, brain shrinkage appears to be preventable through a combination of lifestyle changes and sensible supplementation. Start by identifying which aging symptoms most directly affect you, and then focus your supplement regimen on controlling or reversing those factors. With proper care, your brain can maintain its youthful volume and function for years to come.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.

References

  1. Enzinger C, Fazekas F, Matthews PM, et al. Risk factors for progression of brain atrophy in aging: six-year follow-up of normal subjects. Neurology. 2005 May 24;64(10):1704-11.
  2. Hedman AM. Human brain changes across the life span: a review of 56 longitudinal magnetic resonance imaging studies. Human Brain Mapping. 2012;33:1987-220.
  3. Olesen PJ, Guo X, Gustafson D, et al. A population-based study on the influence of brain atrophy on 20-year survival after age 85. Neurology. 2011 Mar 8;76(10):879-86.
  4. Guo X, Steen B, Matousek M, et al. A population-based study on brain atrophy and motor performance in elderly women. J Gerontol A Biol Sci Med Sci. 2001 Oct;56(10):M633-7.
  5. Henneman WJ, Sluimer JD, Cordonnier C, et al. MRI biomarkers of vascular damage and atrophy predicting mortality in a memory clinic population. Stroke. 2009 Feb;40(2):492-8.
  6. Johansson L, Skoog I, Gustafson DR, et al. Midlife psychological distress associated with late-life brain atrophy and white matter lesions: a 32-year population study of women. Psychosom Med. 2012 Feb-Mar;74(2):120-5.
  7. Olesen PJ, Gustafson DR, Simoni M, et al. Temporal lobe atrophy and white matter lesions are related to major depression over 5 years in the elderly. Neuropsychopharmacology. 2010 Dec;35(13):2638-45.
  8. Debette S, Seshadri S, Beiser A, et al. Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline. Neurology. 2011 Aug 2;77(5):461-8.
  9. Stoub TR, Detoledo-Morrell L, Dickerson BC. Parahippocampal white matter volume predicts Alzheimer’s disease risk in cognitively normal old adults. Neurobiol Aging. 2014 Aug;35(8):1855-61.
  10. van der Veen PH, Muller M, Vincken KL, Mali WP, van der Graaf Y, Geerlings MI. Brain volumes and risk of cardiovascular events and mortality. The SMART-MR study. Neurobiol Aging. 2014 Jul;35(7):1624-31.
  11. Draganski B, Lutti A, Kherif F. Impact of brain aging and neurodegeneration on cognition: evidence from MRI. Curr Opin Neurol. 2013 Dec;26(6):640-5.
  12. Akinyemi RO, Mukaetova-Ladinska EB, Attems J, Ihara M, Kalaria RN. Vascular risk factors and neurodegeneration in ageing related dementias: Alzheimer’s disease and vascular dementia. Curr Alzheimer Res. 2013 Jul;10(6):642-53.
  13. Grober U, Kisters K, Schmidt J. Neuroenhancement with vitamin B12-underestimated neurological significance. Nutrients. 2013 Dec;5(12):5031-45.
  14. Alosco ML, Gunstad J, Jerskey BA, et al. The adverse effects of reduced cerebral perfusion on cognition and brain structure in older adults with cardiovascular disease. Brain Behav. 2013 Nov;3(6):626-36.
  15. Anazodo UC, Shoemaker JK, Suskin N, St Lawrence KS. An investigation of changes in regional gray matter volume in cardiovascular disease patients, pre and post cardiovascular rehabilitation. Neuroimage Clin. 2013;3:388-95.
  16. Cherbuin N, Leach LS, Christensen H, Anstey KJ. Neuroimaging and APOE genotype: a systematic qualitative review. Dement Geriatr Cogn Disord. 2007;24(5):348-62.
  17. Ford AH, Garrido GJ, Beer C, et al. Homocysteine, grey matter and cognitive function in adults with cardiovascular disease. PLoS One. 2012;7(3):e33345.
  18. Yang LK, Wong KC, Wu MY, Liao SL, Kuo CS, Huang RF. Correlations between folate, B12, homocysteine levels, and radiological markers of neuropathology in elderly post-stroke patients. J Am Coll Nutr. 2007 Jun;26(3):272-8.
  19. Narayan SK, Firbank MJ, Saxby BK, et al. Elevated plasma homocysteine is associated with increased brain atrophy rates in older subjects with mild hypertension. Dement Geriatr Cogn Disord. 2011;31(5):341-8.
  20. Rajagopalan P, Hua X, Toga AW, Jack CR, Jr., Weiner MW, Thompson PM. Homocysteine effects on brain volumes mapped in 732 elderly individuals. Neuroreport. 2011 Jun 11;22(8):391-5.
  21. de Jager CA. Critical levels of brain atrophy associated with homocysteine and cognitive decline. Neurobiol Aging. 2014 Sep;35 Suppl 2:S35-9.
  22. Sapkota S, Gee M, Sabino J, Emery D, Camicioli R. Association of homocysteine with ventricular dilatation and brain atrophy in Parkinson’s disease. Mov Disord. 2014 Mar;29(3):368-74.
  23. Herrmann W, Obeid R. Homocysteine: a biomarker in neurodegenerative diseases. Clin Chem Lab Med. 2011 Mar;49(3):435-41.
  24. Gallucci M, Zanardo A, Bendini M, Di Paola F, Boldrini P, Grossi E. Serum folate, homocysteine, brain atrophy, and auto-CM system: The Treviso Dementia (TREDEM) study. J Alzheimers Dis. 2014;38(3):581-7.
  25. Squire LR. Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev. 1992 Apr;99(2):195-231.
  26. Vogiatzoglou A, Refsum H, Johnston C, et al. Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology. 2008 Sep 9;71(11):826-32.
  27. Nachum-Biala Y, Troen AM. B-vitamins for neuroprotection: narrowing the evidence gap. Biofactors. 2012 Mar-Apr;38(2):145-50.
  28. Cade WT. Diabetes-related microvascular and macrovascular diseases in the physical therapy setting. Phys Ther. 2008 Nov;88(11):1322-35.
  29. Toth C, Martinez J, Zochodne DW. RAGE, diabetes, and the nervous system. Curr Mol Med. 2007 Dec;7(8):766-76.
  30. Biessels GJ, Reijmer YD. Brain changes underlying cognitive dysfunction in diabetes: what can we learn from MRI? Diabetes. 2014 Jul;63(7):2244-52.
  31. Moran C, Munch G, Forbes JM, et al. Type 2 diabetes mellitus, skin autofluorescence and brain atrophy. Diabetes. 2014 Jul 22.
  32. Roberts RO, Knopman DS, Przybelski SA, et al. Association of type 2 diabetes with brain atrophy and cognitive impairment. Neurology. 2014 Apr 1;82(13):1132-41.
  33. Wisse LE, de Bresser J, Geerlings MI, et al. Global brain atrophy but not hippocampal atrophy is related to type 2 diabetes. J Neurol Sci. 2014 Sep 15;344(1-2):32-6.
  34. Ashraf GM, Greig NH, Khan TA, et al. Protein misfolding and aggregation in Alzheimer’s disease and type 2 diabetes mellitus. CNS Neurol Disord Drug Targets. 2014;13(7):1280-93.
  35. Britton M, Rafols J, Alousi S, Dunbar JC. The effects of middle cerebral artery occlusion on central nervous system apoptotic events in normal and diabetic rats. Int J Exp Diabesity Res. 2003 Jan-Mar;4(1):13-20.
  36. Smale G, Nichols NR, Brady DR, Finch CE, Horton WE Jr. Evidence for apoptotic cell death in Alzheimer’s disease. Exp Neurol. 1995 Jun;133(2):225-30.
  37. Adeghate E, Donath T, Adem A. Alzheimer disease and diabetes mellitus: do they have anything in common? Curr Alzheimer Res. 2013 Jul;10(6):609-17.
  38. Moroz N, Tong M, Longato L, Xu H, de la Monte SM. Limited Alzheimer-type neurodegeneration in experimental obesity and type 2 diabetes mellitus. J Alzheimers Dis. 2008 Sep;15(1):29-44.
  39. Kiliaan AJ, Arnoldussen IA, Gustafson DR. Adipokines: a link between obesity and dementia? Lancet Neurol. 2014 Sep;13(9):913-23.
  40. Raji CA, Ho AJ, Parikshak NN, et al. Brain structure and obesity. Hum Brain Mapp. 2010 Mar;31(3):353-64.
  41. Fotuhi M, Hachinski V, Whitehouse PJ. Changing perspectives regarding late-life dementia. Nat Rev Neurol. 2009 Dec;5(12):649-58.
  42. Ho AJ, Stein JL, Hua X, et al. A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly. Proc Natl Acad Sci U S A. 2010 May 4;107(18):8404-9.
  43. Lo JC, Loh KK, Zheng H, Sim SK, Chee MW. Sleep duration and age-related changes in brain structure and cognitive performance. Sleep. 2014 Jul;37(7):1171-8.
  44. Sexton CE, Storsve AB, Walhovd KB, Johansen-Berg H, Fjell AM. Poor sleep quality is associated with increased cortical atrophy in community-dwelling adults. Neurology. 2014 Sep 3.
  45. Kubota K, Matsuzawa T, Fujiwara T, et al. Age-related brain atrophy enhanced by smoking: a quantitative study with computed tomography. Tohoku J Exp Med. 1987 Dec;153(4):303-11.
  46. Durazzo TC, Meyerhoff DJ, Nixon SJ. Chronic cigarette smoking: implications for neurocognition and brain neurobiology. Int J Environ Res Public Health. 2010 Oct;7(10):3760-91.
  47. Durazzo TC, Insel PS, Weiner MW. Greater regional brain atrophy rate in healthy elderly subjects with a history of cigarette smoking. Alzheimers Dement. 2012 Nov;8(6):513-9.
  48. Gu Y, Scarmeas N, Short EE, et al. Alcohol intake and brain structure in a multiethnic elderly cohort. Clin Nutr. 2014 Aug;33(4):662-7.
  49. Kubota M, Nakazaki S, Hirai S, Saeki N, Yamaura A, Kusaka T. Alcohol consumption and frontal lobe shrinkage: study of 1432 nonalcoholic subjects. J Neurol Neurosurg Psychiatry. 2001 Jul;71(1):104-6.
  50. Mukamal KJ, Longstreth WT, Jr., Mittleman MA, Crum RM, Siscovick DS. Alcohol consumption and subclinical findings on magnetic resonance imaging of the brain in older adults: the cardiovascular health study. Stroke. 2001 Sep;32(9):1939-46.
  51. Varela-Moreiras G. Nutritional regulation of homocysteine: effects of drugs. Biomed Pharmacother. 2001 Oct;55(8):448-53.
  52. Polyak Z, Stern F, Berner YN, et al. Hyperhomocysteinemia and vitamin score: correlations with silent brain ischemic lesions and brain atrophy. Dement Geriatr Cogn Disord. 2003;16(1):39-45.
  53. Blasko I, Hinterberger M, Kemmler G, et al. Conversion from mild cognitive impairment to dementia: influence of folic acid and vitamin B12 use in the VITA cohort. J Nutr Health Aging. 2012 Aug;16(8):687-94.
  54. Smith AD, Refsum H. Vitamin B-12 and cognition in the elderly. Am J Clin Nutr. 2009 Feb;89(2):707s-11s.
  55. Healthy Quality Ontario. Vitamin B12 and cognitive function: an evidence-based analysis. Ont Health Technol Assess Ser. 2013;13(23):1-45.
  56. Smith AD, Smith SM, de Jager CA, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS One. 2010;5(9):e12244.
  57. 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 Jun 4;110(23):9523-8.
  58. de Jager CA, Oulhaj A, Jacoby R, Refsum H, Smith AD. Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry. 2012 Jun;27(6):592-600.
  59. Singh RB, Gupta S, Dherange P, et al. Metabolic syndrome: a brain disease. Can J Physiol Pharmacol. 2012 Sep;90(9):1171-83.
  60. Nguyen LN, Ma D, Shui G, et al. Mfsd2a is a transporter for the essential omega-3 fatty acid docosahexaenoic acid. Nature. 2014 May 22;509(7501):503-6.
  61. Sagduyu K, Dokucu ME, Eddy BA, Craigen G, Baldassano CF, Yildiz A. Omega-3 fatty acids decreased irritability of patients with bipolar disorder in an add-on, open label study. Nutr J. 2005 Feb 9;4:6.
  62. Scrable H, Burns-Cusato M, Medrano S. Anxiety and the aging brain: stressed out over p53? Biochim Biophys Acta. 2009 Dec;1790(12):1587-91.
  63. Hennebelle M, Champeil-Potokar G, Lavialle M, Vancassel S, Denis I. Omega-3 polyunsaturated fatty acids and chronic stress-induced modulations of glutamatergic neurotransmission in the hippocampus. Nutr Rev. 2014 Feb;72(2):99-112.
  64. Tatebayashi Y, Nihonmatsu-Kikuchi N, Hayashi Y, Yu X, Soma M, Ikeda K. Abnormal fatty acid composition in the frontopolar cortex of patients with affective disorders. Transl Psychiatry. 2012;2:e204.
  65. Virtanen JK, Siscovick DS, Lemaitre RN, et al. Circulating omega-3 polyunsaturated fatty acids and subclinical brain abnormalities on MRI in older adults: the Cardiovascular Health Study. J Am Heart Assoc. 2013 Oct;2(5):e000305.
  66. Pottala JV, Yaffe K, Robinson JG, Espeland MA, Wallace R, Harris WS. Higher RBC EPA + DHA corresponds with larger total brain and hippocampal volumes: WHIMS-MRI study. Neurology. 2014 Feb 4;82(5):435-42.
  67. Torres M, Price SL, Fiol-Deroque MA, et al. Membrane lipid modifications and therapeutic effects mediated by hydroxydocosahexaenoic acid on Alzheimer’s disease. Biochim Biophys Acta. 2014 Jun;1838(6):1680-92.
  68. Zhang C, Bazan NG. Lipid-mediated cell signaling protects against injury and neurodegeneration. J Nutr. 2010 Apr;140(4):858-63.
  69. Hartman RE, Shah A, Fagan AM, et al. Pomegranate juice decreases amyloid load and improves behavior in a mouse model of Alzheimer’s disease. Neurobiol Dis. 2006 Dec;24(3):506-15.
  70. Kumar S, Maheshwari KK, Singh V. Protective effects of Punica granatum seeds extract against aging and scopolamine induced cognitive impairments in mice. Afr J Tradit Complement Altern Med. 2008;6(1):49-56.
  71. Rojanathammanee L, Puig KL, Combs CK. Pomegranate polyphenols and extract inhibit nuclear factor of activated T-cell activity and microglial activation in vitro and in a transgenic mouse model of Alzheimer disease. J Nutr. 2013 May;143(5):597-605.
  72. Choi SJ, Lee JH, Heo HJ, et al. Punica granatum protects against oxidative stress in PC12 cells and oxidative stress-induced Alzheimer’s symptoms in mice. J Med Food. 2011 Jul-Aug;14(7-8):695-701.
  73. Bookheimer SY, Renner BA, Ekstrom A, et al. Pomegranate juice augments memory and FMRI activity in middle-aged and older adults with mild memory complaints. Evid Based Complement Alternat Med. 2013;2013:946298.
  74. Forouzanfar F, Afkhami Goli A, Asadpour E, Ghorbani A, Sadeghnia HR. Protective effect of Punica granatum L. against serum/glucose deprivation-induced PC12 cells injury. Evid Based Complement Alternat Med. 2013;2013:716730.
  75. Moriya J, Chen R, Yamakawa J, Sasaki K, Ishigaki Y, Takahashi T. Resveratrol improves hippocampal atrophy in chronic fatigue mice by enhancing neurogenesis and inhibiting apoptosis of granular cells. Biol Pharm Bull. 2011;34(3):354-9.
  76. Rege SD, Kumar S, Wilson DN, et al. Resveratrol protects the brain of obese mice from oxidative damage. Oxid Med Cell Longev. 2013;2013:419092.
  77. Chang HC, Tai YT, Cherng YG, et al. Resveratrol attenuates high-fat diet-induced disruption of the blood-brain barrier and protects brain neurons from apoptotic insults. J Agric Food Chem. 2014 Apr 16;62(15):3466-75.
  78. Witte AV, Kerti L, Margulies DS, Floel A. Effects of resveratrol on memory performance, hippocampal functional connectivity, and glucose metabolism in healthy older adults. J Neurosci. 2014 Jun 4;34(23):7862-70.