A progressive form of senile dementia, Alzheimer’s disease damages areas of the brain involved in memory, intelligence, judgment, language and behavior. The disease is characterized by the presence of neurofibrillary tangles and beta-amyloid plaques in the nerve cells. Beta amyloid is a polypeptide consisting of 36-43 amino acids and is the main constituent of those plaques (deposits) found in the brains of people with Alzheimer’s disease. There are two types of Alzheimer’s disease; early onset and late onset. The early onset form, which strikes people between the ages of 30 and 60, is much rarer than the late onset form and affects only about 5% of all people who develop Alzheimer’s disease.
The appearance of Alzheimer’s disease is preceded by mild cognitive impairment (MCI), which affects about 16 % of people over the age of 70 and is characterized by increasing problems with memory, language and the performance of other mental functions. This condition goes beyond the normal forgetfulness usually associated with aging. Symptoms of MCI include forgetting important appointments, losing a train of thought midstream and exercising increasingly poor judgment. People are essentially losing their minds and about half of those with MCI will go on to develop Alzheimer’s disease within 5 years. So what could be causing this loss in mental capacity? Several factors have come under the spotlight.
1. Genetics
Some cases of early onset Alzheimer’s disease, also known as Familial Alzheimer’s disease (FAD) are linked to chromosomal DNA mutations which result in the formation of abnormal proteins. Affected are chromosomes 1, 14, and 21 and the proteins that result are abnormal forms of presenilin 2, presenilin 1, and amyloid precursor protein (APP) respectively. Each of these mutations will cause an increased amount of beta amyloid protein to be produced which is a major component of the plaques observed in Alzheimer’s disease (1).
These gene mutations are not involved in late-onset Alzheimer’s disease which develops after age 60. An increased risk of this form of the disease is related to the Apolipoprotein E (APOE) gene located on chromosome 19 (1). This gene codes for a protein that carries cholesterol in the blood. There are different versions of this gene and the one that may predispose to Alzheimer’s diseases is Apolipoprotein epsilon 4 (APOE e4). Carrying this form of the gene increases the risk of developing late-onset AD but does not guarantee it (1). The gene occurs in about 40% of all those who develop late onset Alzheimer’s disease. Other possible risk-factor genes are currently being investigated.
2. Prior Brain Injury
The possible involvement of brain injury as a precursor to Alzheimer’s disease has been extensively studied and there have been conflicting results. The current consensus is that the more severe the head injury, the greater the risk for Alzheimer’s disease. This would be the case if the injury was repeated or involved a loss of consciousness, and if the person already had other risk factors for the disease (2, 3). Precautions to take would include the use of a seatbelt while driving an enclosed vehicle and wearing a helmet for an exposed vehicle. Those engaged in contact sports where the head is at risk of injury should wear appropriate protection and homes should be fall-proofed as much as possible.
3. Insufficient Exercise
There is growing evidence to suggest that regular exercise can ward off dementia. A new analysis from the Framingham study found that participants who spent at least one hour every day engaged in moderate to heavy physical activity had a 45% lower risk of developing dementia, including Alzheimer’s disease (4).
Increased physical activity has also been shown to counteract brain shrinkage in late adulthood. It was shown that walking at least 72 blocks each week resulted in greater volumes in the frontal, occipital, entorhinal, and hippocampal regions of the brain 9 years later and this in turn reduced the risk of cognitive impairment (5).
4. Obesity
As well as being a major risk factor for Type 2 diabetes, high blood pressure, coronary heart disease, stroke and certain cancers (6), obesity has now been shown to predispose to cognitive decline and dementia, including Alzheimer’s disease (7). Being overweight or obese has also been found to be associated with brain shrinkage in otherwise healthy, middle-aged adults. The higher the body mass index (BMI), waist circumference, waist-to-hip ratio and amount of abdominal fat, the smaller was the brain volume and the body weight indicator which correlated the most with reduced brain size was the amount of abdominal fat (8). MRI images of obese individuals who possess a certain variant of the fat mass and obesity-associated (FTO) gene displayed structural brain atrophy with an 8% reduction in the volume of the frontal lobes and a 12% deficit in occipital lobe volume (9).
5. Diabetes
In a study conducted at Uppsala University in Sweden, the health of 2,269 men aged 50 years in 1970 was followed for a median of 32 years. At the beginning of the study, the men were tested for their insulin responsiveness and glucose tolerance. At the end of the study, it was found that 102 (4.5%) of the men had developed Alzheimer’s disease, 57 (2.5%) had developed vascular dementia, and 235 (10.4%) had been diagnosed with other forms of dementia. Those men who had exhibited a poor response to insulin at the beginning of the study were much more likely to develop Alzheimer’s disease than those with a normal insulin response and this was after adjusting for other factors such as body mass index (BMI), serum cholesterol and systolic blood pressure . Men in the bottom 25% for insulin responsiveness were almost twice as likely to develop Alzheimer’s disease as those in the top 25%. Impaired glucose tolerance was not found to be associated with Alzheimer’s disease but instead with vascular dementia in which impaired blood flow to the brain causes the loss of mental capacity (10, 11)
A study performed in New York showed that elderly individuals with type 2 diabetes were also at greater risk of developing mild cognitive impairment (MCI) when compared with people who did not have diabetes. This difference was maintained even after adjusting for stroke and vascular disease, suggesting that the relationship between diabetes and MCI was independent of any cerebrovascular disease (12).
6. Diet
A) High Plasma Homocysteine Levels
In a rigorous prospective study of 1092 elderly subjects who were initially free of dementia, it was found after 8 years of follow-up that 111 of the subjects developed dementia, most cases being Alzheimer’s disease (13). It was discovered that an elevated level of plasma homocysteine could be a predictor of the disease with the risk nearly doubled for those with the highest concentrations. Homocysteine is formed in the liver from the amino acid methionine, a building block of protein, and this amino acid is present in 2-3 times higher concentrations in dietary animal protein compared to plant protein. The authors concluded that “an increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer’s disease.”
An association has also been reported between elevated levels of plasma homocysteine and cognitive impairment (reduced mental capacity) (14). The investigators found serum homocysteine to be “an early and sensitive marker for cognitive impairment”. Thirty-nine percent of their patients with mild cognitive impairment had pathological serum homocysteine levels. Homocysteine is formed in the liver from the amino acid methionine, a building block of protein, and this amino acid is present in 2-3 times higher concentrations in dietary animal protein compared to plant protein.
B) Folate, Vitamin B6 and B12 Deficiency
A deficiency in Vitamins B6, B12 and folate correlates with higher plasma homocysteine levels and when the deficiency is remedied, the levels of homocysteine fall. This is because these vitamins act as cofactors or substrates for enzymes involved in the metabolism of homocysteine. In view of the association between high plasma homocysteine levels and an increased risk of mild cognitive impairment and dementia, it was decided to study the effects of long-term administration of high concentrations of these vitamins on the rate of brain atrophy in elderly subjects with MCI.
It was found that administration of B vitamins over a 2-year period significantly reduced the rate of brain atrophy. When adjustments were made for age, the rate of brain atrophy per year as determined by MRI analysis was nearly 30% less in subjects receiving B vitamins compared to those receiving placebo (15) and this reduction in the rate of brain atrophy also correlated with a reduction in total homocysteine levels.
C) Plant-Based Diet
There is growing evidence to suggest that eating a predominantly plant-based diet reduces the risk of getting Alzheimer’s disease. As the animal and caloric content of the diet increase, so also does the risk of Alzheimer’s, except in the case of eating fish or taking supplements rich in the omega 3 fatty acid DHA, which may confer some protection (16). It has been shown that adherence to a Mediterranean-Type Diet is associated with a reduced risk of Alzheimer’s disease (17,18). This diet is characterized by a high intake of vegetables, legumes, fruits, and cereals; a high intake of unsaturated fatty acids (mostly olive oil), and a low intake of saturated fatty acids; a moderately high intake of fish; a low to moderate intake of dairy products (mostly cheese or yogurt); a low intake of meat and poultry; and a regular but moderate intake of alcohol, mainly wine and with meals. The study found that the greater the adherence to the diet, the lower the risk of Alzheimer’s disease. There was a significant dose – response relationship.
D) Turmeric, Curcumin and Curry
Turmeric is best known as the bright yellow powder that is available in the spice section of the grocery store. It is produced by boiling the underground stems of the turmeric plant and then drying them in ovens before grinding. Ground turmeric is an important constituent of curry powder, giving it its yellow color, and is commonly used in Indian, Southeast Asian and Middle Eastern cuisine. The bright orange-yellow stem can also be grated fresh and added to salads and to dishes as they are cooking. For some time now it has been apparent that turmeric, like its close relative ginger, conveys medicinal properties and health benefits. Most of the pharmacological effects of turmeric have been attributed to curcumin, a polyphenol responsible for the bright orange-yellow color.
There is growing evidence to suggest that turmeric and curcumin may protect against neurodegenerative diseases such as Alzheimer’s disease. Their anti-oxidant and anti-inflammatory properties are believed to protect brain cells from oxidative damage (19). The prevalence of Alzheimer’s disease in a group of elderly people aged 70-79 in India was found to be 4.4 times less than in a similar group of people in the U.S. (20). When the cognitive level in 1010 Asians aged between 60 and 93 was compared to curry consumption, it was found that those who occasionally ate curry (less than once a month) and more often (more than once a month) performed better on a standard test of cognitive function than those who rarely or never ate curry (21).
Macrophages ( a type of white blood cell ), isolated from Alzheimer’s disease patients and pre-incubated with curcumin, were found to be more effective in ingesting beta amyloid than macrophages that has not been previously exposed to curcumin (22) and studies in a mouse model for Alzheimer’s disease have shown that curcumin can cross the blood brain barrier and bind to the beta amyloid plaques. It can also inhibit beta amyloid aggregation and destabilize the polymer (23). Further research and clinical trials are underway to determine if curcumin and related compounds can have therapeutic value in treating Alzheimer’s disease as well as contributing to prevention.
7. Vitamin D
A study of 1,766 individuals aged 65 and over in England found that cognitive function and serum levels of vitamin D3 were inversely related. Individuals with the lowest levels of vitamin D3 were more than twice as likely to be cognitively impaired as those with the highest levels and the effect was more marked in men than in women (24). This inverse relationship between serum vitamin D3 levels and cognitive function in the elderly was confirmed in a prospective study conducted on an Italian population over a 6 year period. Low levels of vitamin D3 were associated with substantial cognitive decline (25).
In an effort to understand how vitamin D might influence cognitive function, it has been recently shown that vitamin D3 interacts with curcuminoids to stimulate the clearance of beta amyloid by macrophages of patients with Alzheimer’s disease (26).
Conclusion
It is clear that the pursuit of a healthy lifestyle that includes keeping physically and mentally active, eating a diet that draws from the Mediterranean and East Indies, maintaining adequate vitamin D levels and taking precautions to avoid head injury are all key factors in avoiding dementia later in life.
References
1. http://www.nia.nih.gov/Alzheimers/Publications/geneticsfs.htm
2. http://www.mayoclinic.com/health/alzheimers-disease/AN01710
3. Van Den Heuvel1 C, et al. (2007) Traumatic Brain Injury and Alzheimer’s Disease: A Review. Progress in Brain Research. 161:303.
4. http://www.medpagetoday.com/MeetingCoverage/ICAD/21178
5. http://www.neurology.org/content/75/16/1415.abstract
6. https://www.healthyaddress.com/obesity-and-how-it-can-affect-our-health.html
7. Elias, M.F. et al. (2005) Obesity, Diabetes and
Cognitive Deficit: The Framingham Heart Study. Neurobiol Aging 26 (Suppl 1):11–16.
8. http://scienceblogs.com/neurophilosophy/2010/06/obesity_linked_to_brain_shrinkage_and_dementia.php
9. http://www.pnas.org/content/early/2010/04/02/0910878107.full.pdf+html
10. http://www.neurology.org/content/71/14/1065.abstract
11. http://alzheimers.about.com/od/whatisalzheimer1/a/diabetesandad.htm
12. http://archneur.ama-assn.org/cgi/content/abstract/64/4/570
13. Shadri, S et al. (2002) Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer’s Disease. N. Eng. J. Med. 14, 346 (7), 476-483.
14. Gottfries C. G. et al. (1998) Early Diagnosis of Cognitive Impairment in the Elderly with the Focus on Alzheimer’s Disease. J. Neural Transm. 105:8-9, 773-786.
15. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012244
16. https://www.healthyaddress.com/diet-and-alzheimer%e2%80%99s-disease.html
17. Scarmeas, N. et al. (2006) Mediterranean Diet and Risk for Alzheimer’s Disease. Ann. Neurol. 59 (6), 912-921.18.
18. Hitti, M. (2006) Mediterranean Diet may cut Alzheimer’s.
http://www.webmd.com/alzheimers/news/20060418/mediterranean-diet-cut-alzheimers
19. Mishra, S. and Palanivelu, K. (2008) The Effect of Curcumin (Turmeric) on Alzheimer’s Disease: An Overview. Ann. Indian Acad. Neurol. 11:13-19.
http://www.annalsofian.org/article.asp?issn=0972-2327;year=2008;volume=11;issue=1;spage=13;epage=19;aulast=Mishra
20. Pandav, R., Belle, S.H. and DeKosky, S.T. (2000) Apolipoprotein E Polymorphism and Alzheimer’s Disease: The Indo-US Cross-National Dementia Study. Arch. Neurol. 57:824-830.
21. Ng, T.P. et al. (2006) Curry Consumption and Cognitive Function in the Elderly. Am. J. Epidemiol. 164:898-906.
22. Zhang, L. et al. (2006) Curcuminoids enhance Amyloid-Beta Uptake by Macrophages of Alzheimer’s Disease Patients. J. Alzheimer’s Disease 10:1-7.
23. Yang, F. et al. (2005) Curcumin inhibits Formation of Amyloid Beta Oligomers and Fibrils, binds Plaques, and reduces Amyloid in vivo. J. Biol. Chem. 280:5892-5901.
24. Llewellyn, D. J., Langa, K. M. & Lang, I. A. (2009) Serum 25-Hydroxyvitamin D Concentration and Cognitive Impairment. J. Geriatric Psychiatry Neurol. 22 (3) 188-195. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2730978
25. Llewellyn, D. J. et al. (2010) Vitamin D and Risk of Cognitive Decline in Elderly Persons. Arch Intern Med. 2010; 170 (13):1135-1141. http://archinte.ama-assn.org/cgi/content/abstract/170/13/1135
26. Masoumi A. et al. (2009) 1 Alpha,25-Dihydroxyvitamin D3 interacts with Curcuminoids to stimulate Amyloid-Beta Clearance by Macrophages of Alzheimer’s Disease Patients. J. Alzheimer’s Disease 17(3):703-717.
http://www.ncbi.nlm.nih.gov/pubmed/19433889
© Christopher J. Jones, M.Sc., Ph.D.
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