dementia

Montessori for Alzheimer's patients

Cameron Camp, director of the Myers Research Institute, began looking at the Montessori method as a way of helping Alzheimer's patients some 10 years ago. The Montessori method, developed for young children, is rooted in the senses, and involves manipulating everyday objects and following highly structured activities that engage children but rarely allow them to fail. Camp adapted these activities for Alzheimer's patients, tailoring them to the individual's background and interests. You can read about the program and its success in improving the quality of life for Alzheimer's patients and their caregivers in a number of online articles:

http://www.aarp.org/bulletin/longterm/Articles/alzheimer.html

http://www.providermagazine.com/pdf/cover-12-2005.pdf (pdf document)

http://www.nursinghomesmagazine.com/Past_Issues.htm?ID=3815

http://www.vcu.edu/vcoa/ageaction/AGEfa03.htm

Below are several manuals co-written by Cameron Camp. You can also read about these books at the Myers Research Institute site at http://www.myersresearch.org/manuals.html and listen to radio interviews given by Dr Camp at http://www.myersresearch.org/media.html

A Montessori Program is also now used at Truman Medical Center Lakewood for its Alzheimer residents. The program focuses on Montessori activities that will help each resident continue to be independent as long as possible. You can read about it here: http://www.trumed.org/sections/content.aspx?id=217&SID=92

Preventing Dementia: Mental stimulation

Stimulating activities

A 5-year study1 involving 488 people age 75 to 85 found that, for the 101 people who developed dementia, the greater the number of stimulating activities (reading, writing, doing crossword puzzles, playing board or card games, having group discussions, and playing music) they engaged in, the longer rapid memory loss was delayed. Similarly, a study2 involving 1321 randomly selected people aged 70 to 89, of whom 197 had mild cognitive impairment, has found that reading books, playing games, participating in computer activities or doing craft activities such as pottery or quilting was associated with a 30 to 50% decrease in the risk of developing memory loss compared to people who did not do those activities.

Moreover, two activities during middle age (50-65) were also significantly associated with a reduced chance of later memory loss: participation in social activities and reading magazines. The value of social activities is consistent with another, small, study3 that found that social networks, like education, offers a 'protective reserve' capacity that spares individuals the clinical manifestations of Alzheimer's disease. As the size of the social network increased, the same amount of Alzheimer’s pathology in the brain had less effect on cognitive test scores. For those without much pathology (plaques and tangles), social network size had little effect on cognition.

This supports another study4 involving 469 people aged 75 and older, that found that those who participated at least twice weekly in reading, playing games (chess, checkers, backgammon or cards), playing musical instruments, and dancing were significantly less likely to develop dementia. Although the evidence on crossword puzzles was not quite statistically significant, those who did crossword puzzles four days a week had a much lower risk of dementia than those who did one puzzle a week.

Similarly, a study5 of 700 seniors found that more frequent participation in cognitively stimulating activities, such as reading books, newspapers or magazines, engaging in crosswords or card games, was significantly associated with a reduced risk of Alzheimer’s disease. On average, compared with someone with the lowest activity level, the risk of disease was 47% lower for those whose frequency of activity was highest.

In the first comprehensive review6 of the research into 'cognitive reserve', which looks at the role of education, occupational complexity and mentally stimulating activities in preventing cognitive decline, researchers concluded that complex mental activity across people’s lives almost halves the risk of dementia. All the studies also agreed that it was never too late to build cognitive reserve. The review covered 29,000 individuals across 22 studies.

A review7 of research on the impact of cognitive training on the healthy elderly (not those with mild cognitive impairment or Alzheimer's disease), has found no evidence that structured cognitive intervention programs affects the progression of dementia in the healthy elderly population.

Post-mortem analysis of participants in a large, long-running study8 has provided more support for the idea that mental stimulation protects against Alzheimer’s. The study found a cognitively active person in old age was 2.6 times less likely to develop dementia and Alzheimer’s disease than a cognitively inactive person in old age. This association remained after controlling for past cognitive activity, lifetime socioeconomic status, and current social and physical activity. Frequent cognitive activity during old age was also associated with reduced risk of mild cognitive impairment.

Research involving genetically engineered mice9 has found that mice whose brains had lost a large number of neurons regained long-term memories and the ability to learn after their surroundings were enriched with toys and other sensory stimuli, pointing to the importance of maintaining cognitive stimulation as long as possible. Similarly, another mouse study10 found that short but repeated learning sessions can slow the development of those hallmarks of Alzheimer's, beta amyloid plaques and tau tangles. And another11 found that an enriched environment, with more opportunities to exercise, explore and interact with others, dramatically reduces levels of beta-amyloid peptides.

Education & iq

A study12 involving some 6,500 older Chicago residents being interviewed 3-yearly for up to 14 years (average 6.5 years), has found that while at the beginning of the study, those with more education had better memory and thinking skills than those with less education, education was not related to how rapidly these skills declined during the course of the study. The result suggests that the benefit of more education in reducing dementia risk results simply from the difference in level of cognitive function.

Another study13 has come out supporting the view that people with more education and more mentally demanding occupations may have protection against the memory loss that precedes Alzheimer's disease, providing more evidence for the idea of cognitive reserve. The 14-month study followed 242 people with Alzheimer's disease, 72 people with mild cognitive impairment, and 144 people with no memory problems.

Another study14 has come out confirming that people with more years of education begin to lose their memory later than those with less education, but decline faster once it begins. Researchers note that since the participants were born between 1894 and 1908, their life experiences and education may not represent that of people entering the study age range today.

A study15 of 312 New Yorkers aged 65 and older, who were diagnosed with Alzheimer's disease and monitored for over 5 years, found that overall mental agility declined faster for each additional year of education, particularly in the speed of thought processes and memory, and was independent of age, mental ability at diagnosis, or other factors likely to affect brain function, such as depression and vascular disease. It’s suggested this may reflect the greater ability of brains with a higher cognitive reserve to tolerate damage, meaning the damage is greater by the time it becomes observable in behavior.

The Nun Study16 found that nuns who completed 16 or more years of formal education or whose head circumference was in the upper two-thirds were four times less likely to be demented than those with both smaller head circumferences and lower education.

Post-mortem study17 of the brains of 130 participants in the Religious Orders Study found that the relationship between cognitive performance and the number of amyloid plaques in the brain changed with level of formal education. The more years education you had, the less effect the same number of plaques had on actual cognitive performance. It’s worth noting that this considerable difference was observed in a population where even the least educated had some college attendance; presumably the difference would be even more marked in the general population.

A long-running Finnish study18 has found that compared with people with five or less years of education, those with six to eight years had a 40% lower risk of developing dementia and those with nine or more years had an 80% lower risk. Generally speaking, people with low education levels seemed to lead unhealthier lifestyles, but the association remained after lifestyle choices and characteristics such as income, occupation, physical activity and smoking had been taken into account.

An analysis of high school records and yearbooks from the mid-1940s19, and interviews with some 400 of these graduates, now in their 70s, and their family members, has found that those who were more active in high school and who had higher IQ scores, were less likely to have mild memory and thinking problems and dementia as older adults.

An analysis20 of 184 people with dementia found that the mean age of onset of dementia symptoms in the 91 monolingual patients was 71.4 years, while for the 93 bilingual patients it was 75.5 years — a very significant difference.

A study21 of 122 people with Alzheimer's and 235 people without the disease found that people with Alzheimer's are more likely to have had less mentally stimulating careers than their peers who do not have Alzheimer's.

 

A study22 of 173 people from the Scottish Mental Survey of 1932 who have developed dementia has found that, compared to matched controls, those with vascular dementia were 40% more likely to have low IQ scores when they were children than the people who did not develop dementia. This difference was not true for those with Alzheimer's disease. The findings suggest that low childhood IQ may act as a risk factor for vascular dementia through vascular risks rather than the "cognitive reserve" theory. 

References: 
  1. Hall, C.B. et al. 2009. Cognitive activities delay onset of memory decline in persons who develop dementia. Neurology, 73, 356-361.
  2. Geda, Y.E. et al. 2009. Cognitive Activities Are Associated with Decreased Risk of Mild Cognitive Impairment: The Mayo Clinic Population-Based Study of Aging. Presented April 28 at the American Academy of Neurology's 61st Annual Meeting in Seattle.
  3. Bennett, D.A., Schneider,J.A., Tang,Y., Arnold,S.E. & Wilson,R.S. 2006. The effect of social networks on the relation between Alzheimer's disease pathology and level of cognitive function in old people: a longitudinal cohort study. Lancet Neurology,5, 406-412.
  4. Verghese, J., Lipton, R.B., Katz, M.J., Hall, C.B., Derby, C.A., Kuslansky, G., Ambrose, A.F., Sliwinski, M. & Buschke, H. 2003. Leisure Activities and the Risk of Dementia in the Elderly. New England Journal of Medicine, 348 (25), 2508-2516.
  5. Wilson, R.S., de Leon, C.F.M., Barnes, L.L., Schneider, J.S., Bienias, J.L., Evans, D.A. & Bennett, D.A. 2002. Participation in Cognitively Stimulating Activities and Risk of Incident Alzheimer Disease.
    JAMA, 287,742-748.
  6. Valenzuela, M.J. & Sachdev, P. 2006. Brain reserve and dementia: a systematic review. Psychological Medicine, In press
  7. Papp, K.V., Walsh, S.J. & Snyder, P.J. 2009. Immediate and delayed effects of cognitive interventions in healthy elderly: A review of current literature and future directions. Alzheimer's & Dementia, 5 (1), 50-60.
  8. Wilson, R.S., Scherr, P.A., Schneider, J.A., Tang, Y. & Bennett, D.A. 2007. The relation of cognitive activity to risk of developing Alzheimer’s disease. Neurology, published online ahead of print June 27.
  9. Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M. & Tsai, L-H. 2007. Recovery of learning and memory is associated with chromatin remodelling. Nature, 447, 178-182.
  10. Billings, L.M., Green, K.N., McGaugh, J.L. & LaFerla, F.M. 2007. Learning Decreases Aß*56 and Tau Pathology and Ameliorates Behavioral Decline in 3xTg-AD Mice. Journal of Neuroscience, 27, 751-761.
  11. Lazarov, O.et al. 2005. Environmental Enrichment Reduces Aβ Levels and Amyloid Deposition in Transgenic Mice. Cell, 120(5), 701-713.
  12. Wilson, R.S., Hebert, L.E., Scherr, P.A., Barnes, L.L., de Leon, C.F.M. & Evans, D.A. 2009. Educational attainment and cognitive decline in old age. Neurology, 72, 460-465.
  13. Garibotto, V. et al. 2008. Education and occupation as proxies for reserve in aMCI converters and AD: FDG-PET evidence. Neurology, 71, 1342-1349.
  14. Hall, C.B., Derby, C., LeValley, A., Katz, M.J., Verghese, J. & Lipton, R.B. 2007. Education delays accelerated decline on a memory test in persons who develop dementia. Neurology, 69, 1657-1664.
  15. Scarmeas, N., Albert, S.M., Manly, J.J. & Stern, Y. 2006. Education and rates of cognitive decline in incident Alzheimer’s disease. Journal of Neurology Neurosurgery and Psychiatry, 77, 308-316.
  16. Mortimer, J.A., Snowdon, D.A. & Markesbery, W.R. 2003. Head Circumference, Education and Risk of Dementia: Findings from the Nun Study.Journal of Clinical and Experimental Neuropsychology, 25 (5), 671-679.
  17. Bennett, D.A., Wilson, R.S., Schneider, J.A., Evans, D.A., de Leon, M.C.F., Arnold, S.E., Barnes, L.L. & Bienias, J.L. 2003. Education modifies the relation of AD pathology to level of cognitive function in older persons. Neurology, 60, 1909-1915.
  18. Ngandu, T. et al. 2007. Education and dementia: What lies behind the association? Neurology, 69, 1442-1450.
  19. Fritsch, T., Smyth, K.A., McClendon, M.J., Ogrocki, P.K., Santillan, C., Larsen, J.D. & Strauss, M.E. 2005. Associations Between Dementia/Mild Cognitive Impairment and Cognitive Performance and Activity Levels in Youth. Journal of the American Geriatrics Society, 53(7), 1191.
  20. Bialystok, E., Craik, F.I.M. & Freedman, M. 2007. Bilingualism as a protection against the onset of symptoms of dementia. Neuropsychologia, 45 (2), 459-464./li>
  21. Smyth, K.A. et al. 2004. Worker functions and traits associated with occupations and the development of AD. Neurology, 63 (3), 498-503.
  22. McGurn, B., Deary, I.J. & Starr, J.M. 2008. Childhood cognitive ability and risk of late-onset Alzheimer and vascular dementia. Neurology, first published on June 25, 2008 as doi: doi:10.1212/01.wnl.0000319692.20283.10 .

Preventing dementia: Diet & exercise

It's increasingly clear that eating a healthy diet can have a big impact on whether or not you develop dementia.

A study1 of nearly 2000 older adults has found that eating a Mediterranean diet was associated with less risk of developing mild cognitive impairment or of transitioning from MCI to Alzheimer's disease. The third with the highest scores for Mediterranean diet adherence had a 28% lower risk of developing MCI compared to the third with the lowest scores, and of those who already had MCI, those with the highest scores for Mediterranean diet adherence had a 48% less chance of developing Alzheimer’s.

Another, similar-sized study2, has found that those who adhered more strongly to a Mediterranean-type diet had a 40% risk reduction, and those who were very physically active had a 33% risk reduction of Alzheimer's -- doing both gave people a 60% reduction.

A Mediterranean-type diet is typically characterized by high intake of fish, vegetables, legumes, fruits, cereals and monounsaturated fatty acids; relatively low intake of dairy products, meats and saturated fats; and moderate alcohol consumption. Most of these components have been independently associated with reduced dementia risk. Let's look at them one by one.

Fruit & vegetables

A very large study3 of older adults found that those who ate fruits and vegetables daily reduced their risk of dementia by 30% compared to those who didn’t regularly eat fruits and vegetables. Another large, long-running epidemiological study4 found that those who drank three or more servings of fruit and vegetable juices per week had a 76% lower risk of developing Alzheimer’s disease than those who drank juice less than once a week. The benefit seemed greatest for those who carried the so-called “Alzheimer’s gene”.

This may not have anything to do with vitamin C. A five-year study5 involving nearly 3000 people has found that use of Vitamin C or E or both was not associated with a reduced risk of developing dementia or Alzheimer’s. However a study6 involving 4,740 elderly found the greatest reduction in both prevalence and incidence of Alzheimer's in those who used individual vitamin E and C supplements in combination. There was no significant benefit in these vitamins alone.

Of course, it is now well understood that taking vitamins as supplements is not the same as receiving them in food.

Two studies have come out in favor of a diet rich in foods containing vitamin E to help protect against Alzheimer's disease. One study7 involved 815 Chicago residents age 65 and older with no initial symptoms of mental decline, who were questioned about their eating habits and followed for an average of about four years. When factors like age and education were taken into account, those eating the most vitamin E-rich foods had a lower risk of developing Alzheimer’s, provided they did not have the ApoE e4 allele. This was not true when vitamin E was taken as a supplement. The effect of vitamin C was not statistically significant.

The other study8 involved 5,395 people in the Netherlands age 55 and older who were followed for an average of six years. Those with high intakes of vitamins E and C were less likely to become afflicted with Alzheimer's, regardless of whether they had the gene variation. This association was most pronounced for current smokers.

So beneficial effects of these vitamins may depend on genetics, smoking history, and possibly other lifestyle factors. But there are other valuable compounds common in fruits & vegetables. Another class of antioxidant chemicals, polyphenols, are now suspected. Polyphenols generally exist primarily in the skins of fruits and vegetables and are particularly abundant in teas, juices and wines.

A cell study9 also found that quercetin (a flavonoid with greater antioxidant and anticancer properties than vitamin C) protects against cellular damage. Quercetin is particularly abundant in apples (mainly in the skin, and especially the red ones). Other good sources are onions, blueberries and cranberries.

Another cell study10 found that compounds in blackcurrants (anthocyanins as well as polyphenols) strongly protect neuronal cells against the effects of amyloid-beta. Boysenberries contain the same compounds, and those that are darker are likely to be more potent.

The inconsistent findings regarding vitamins C and E may also have to do with the presence of folates. Data from the Baltimore Longitudinal Study of Aging11 revealed that although those with higher intake of folates, vitamin E and vitamin B6 had a lower risk of developing Alzheimer’s, statistical analysis showed it was only folate consumption that was significant. Those who had at least 400mcg of folates a day (the recommended daily allowance) had a 55% reduction in risk of developing Alzheimer’s. Unfortunately, most people who reached that level did so by taking supplements, suggesting the difficulty of doing so through diet alone.

Folates are abundant in foods such as liver, kidneys, yeast, fruits (like bananas and oranges), leafy vegetables, whole-wheat bread, lima beans, eggs and milk; however, they are often destroyed by cooking or processing.

The benefits of folates probably has to do with its effect on homocysteine. A mouse study12 indicates that increased levels of homocysteine are produced by low intake of folate and B vitamins, and impair cognition through microvascular changes. 

High levels of homocysteine are associated not only with deficiencies in vitamin B12 and folate, but also with smoking.

High levels of homocysteine were associated in one study13 with a more than five-fold increase in the risk for stroke, a nearly five-fold risk for vascular dementia, and almost triple the risk for Alzheimer's disease. Findings from the long-running Framingham study14 found people with elevated levels of homocysteine in the blood had nearly double the risk of later developing Alzheimer’s disease.

Moreover, evidence from a study15 using genetically engineered mice suggests that increased levels of homocysteine in the brain cause damage to nerve cells in the hippocampus -- which can be repaired when there is an adequate amount of folate, but not when there is a deficiency.
 

Omega-3 oils & fish

One of the clearest findings in this area has been the benefits of regularly consuming omega-3 oils, fish oil, and fish. Several epidemiological studies have indicated that regularly eating fish (at least once a week) reduces risk of dementia. More recently, two very large studies have come out in support. One very large study3 of older adults found that those who regularly consumed omega-3 rich oils, such as canola oil, flaxseed oil and walnut oil, reduced their risk of dementia by 60% compared to people who did not regularly consume such oils. Additionally, those who ate fish at least once a week had a 40% lower risk of dementia -- but only if they did not carry ApoE4 gene.

Moreover, for those who didn’t have the gene, regular use of omega-6 rich oils, but not omega-3 rich oils or fish, were twice as likely to develop dementia compared to those who didn’t eat omega-6 rich oils (e.g., sunflower or grape seed oil).

The second study16 comes from the famous long-running Framingham Heart Study, which found that those with the highest levels of DHA (an omega-3 polyunsaturated fatty acid found in relatively high concentrations in cold-water fish) had a 47% lower risk of developing dementia. Those with these levels tended to eat an average three fish servings a week, as well as an average of .18 grams of DHA a day. Those at lower levels ate markedly less fish.

There is also some suggestion that omega-3 oils might help slow the progression of dementia. A Swedish study17 found that, although fatty acids DHA and EPA didn't slow cognitive decline in those with mild-to-moderate Alzheimer’s, they did slow decline in those with very mild cognitive impairment (a frequent precursor of dementia). It's been suggested that anti-inflammatory effects are an important reason for the benefit, why might explain why benefits only occur in the very early stages, when levels of inflammation seem to be higher.

Similar results were more recently reported18 from a large 18-month trial. This one, however, suggested that genetic status might be a factor -- that those without the “Alzheimer’s gene” ApoE4 might benefit even if impairment had progressed to mild-to-moderate Alzheimer’s.

There are a number of reasons why DHA might help brains.

A study involving genetically engineered mice19 has found that a diet high in DHA dramatically slowed the progression of Alzheimer's by cutting the harmful brain plaques that mark the disease. An earlier study20 showed that DHA protected against damage to the synaptic areas where brain cells communicate and enabled mice to perform better on memory tests. More recent research21 has revealed that DHA increases the production of LR11, a protein that is found at reduced levels in Alzheimer's patients and which is known to destroy the protein that forms the plaques associated with the disease.

Food sources of omega-3 fatty acids include fish such as salmon, halibut, mackerel and sardines, as well as almonds, walnuts, soy, flaxseed, and DHA-enriched eggs. These fish have high levels of DHA because they consume DHA-rich algae. Because these fishes' oiliness makes them absorb more mercury, dioxin, PCP and other metals, a less risky yet more costly strategy is to consume fish oil or purified DHA supplements made from algae.

Possible benefits of wine, tea, and coffee

There have been a number of reports that moderate alcohol consumption (generally defined as 1 drink or less per day for women and 1-2 drinks or less per day for men) may help reduce your risk of developing dementia, and a 2008 review of 44 studies22 supported this conclusion. 

However, given that alcohol has known negative effects on the brain, no one is recommending that non-drinkers take up the habit! All one can say is that there's no reason to alter your habits if you are a moderate drinker. On the other hand, if you drink more than this, you are probably best to knock it back to this level.

However, the evidence suggests that it is wine rather than alcohol in general that is beneficial for the brain. A large Danish study23 found that those who drank wine occasionally in the 1970s had a lower risk of developing dementia in the 1990s (when participants were 65 or older). However, occasional beer drinking was associated with an increased risk of developing dementia. But we cannot draw too hard & fast a conclusion from this, as eating habits were not investigated, and research suggests that wine drinkers may have better dietary habits than beer and liquor drinkers. Moreover, a very large study of older adults3, that found a significant effect of some dietary factors, found no effect of wine.

There are, however, some good reasons for believing regular drinking of red wine may help the aging brain. Red grapes contain several polyphenols that have been shown to significantly reduce cognitive deterioration in genetically engineered mice, by preventing the formation of amyloid beta. One of these is resveratrol; the others are catechin and epicatechin. Resveratrol was much vaunted when its effects were first discovered, but unfortunately it requires extremely high doses. The more recent discovery24 of the catechins is much more exciting, as they appear to be effective at much lower doses. The catechins are also abundant in tea and cocoa.

Tea, most particularly green tea, has also been found25 to inhibit the activity of enzymes associated with the development of Alzheimer's Disease. Green tea also obstructed the activity of beta-secretase.

These inhibitory properties were not found in coffee. However, a large, long-running Finnish study26 has found that those who were coffee drinkers at midlife had lower risk for dementia and Alzheimer’s later in life compared to those drinking no or only little coffee midlife. The lowest risk was found among moderate coffee drinkers (drinking 3-5 cups of coffee/day).

Restricting your calories

There has been some talk that calorie-restricted diets might help prevent Alzheimer's. So far, the only indications have come from experiments with genetically engineered mice. While there have been a number of studies providing evidence that high cholesterol, obesity, and other cardiovascular risk factors increase the likelihood of Alzheimer’s, it is decidedly premature to say whether calorie-restricted diets would benefit humans. Particularly since one of the early signs of Alzheimer's is weight loss. So it is certainly not recommended that people severely restrict their diets. More useful is removing certain food types (e.g., the "bad" oils; sugar -- there is some evidence that Alzheimer's may be a type of diabetes), and increasing consumption of others (fish, "good" oils, fruit & vegetables).

There may also be a genetic link. A four-year study27 of nearly 1000 older adults found that among those who carried the ApoE e4 gene, those who consumed the most calories had a 2.3 times greater chance of developing Alzheimer’s compared to those who ate the fewest calories. But calories weren't a factor for those without the gene.

Cholesterol

A study28 involving nearly 10,000 people who underwent health evaluations between 1964 and 1973 when they were between the ages of 40 and 45, has found that those with total cholesterol levels between 249 and 500 milligrams were one-and-a-half times more likely to develop Alzheimer's disease than those people with cholesterol levels of less than 198 milligrams. People with total cholesterol levels of 221 to 248 milligrams were more than one-and-a-quarter times more likely to develop Alzheimer's disease. High cholesterol increased risk regardless of midlife diabetes, high blood pressure, obesity, smoking and late-life stroke.

A review29 of autopsy cases of patients over 40 years old found that high blood cholesterol levels were correlated with the presence of amyloid deposits in the brain in the youngest subjects (aged 40-55).

An analysis30 of data on 1037 older women who had participated in a clinical trial of hormone replacement therapy found that high cholesterol levels increase the risk of cognitive impairment.

A large-scale Finnish study31 following 1449 men and women over 21 years found that raised systolic blood pressure and high serum cholesterol concentration, particularly in combination, in midlife, increase the risk of Alzheimer's disease in later life. Raised diastolic blood pressure had no significant effect.

However, the long-running, large-scale Framingham Heart study32 found that, after adjustment for age, sex, APOE genotype, smoking, body mass index, coronary heart disease, and diabetes, there was no significant association between AD risk and cholesterol level.

Previous studies suggesting that fat may be involved in the development of dementia and Alzheimer’s disease have been contradicted by a new study33 involving over 5,000 elderly people over a period of six years. The study found no correlation between fat and cholesterol intake and risk of dementia, and no evidence for a reduction in risk for those taking cholesterol lowering medication.

A cell study34 provides more understanding of why there might be a link between cholesterol and Alzheimer's disease. The study found that proteins which help control cholesterol levels in arterial walls were also present in neurons, and when the genes for these proteins were over-expressed, production of amyloid beta protein fell. The finding suggests a new approach to slowing Alzheimer’s. The study also showed that the apoE protein is extremely good at regulating cholesterol removal from neurons — the gene for this protein is a well-known genetic risk factor for Alzheimer's.

Diabetes

A large Swedish study35 has found that men with low insulin secretion capacity at age 50 were nearly one-and-a-half times more likely to develop Alzheimer’s disease than men without insulin problems. The risk was strongest in those who didn't have the APOE4 gene. Another large study36 found that diabetes was related to a significantly higher risk of developing amnestic mild cognitive impairment in older seniors (average age 76), after controlling for other risk factors. And a large study37 of post-menopausal women (mean age 67 years) found that those with poor blood sugar control were four times more likely to develop MCI or dementia. Findings38 from the long-running Religious Orders Study also support a link between diabetes and an increased risk of developing Alzheimer's disease.

Evidence from a mouse study39 suggests that diabetes might increase risk because elevated blood glucose levels interact with beta amyloid in a way damaging to blood vessels in the brain.
In fact it has been suggested that Alzheimer’s could be considered a third form of diabetes. Another study40 provides evidence that amyloid oligomers remove insulin receptors from nerve cells, rendering those neurons insulin resistant. Another mouse study41 suggests that low levels of insulysin, an enzyme that degrades insulin, are a factor. The enzyme, it seems, also degrades amyloid-beta peptides, and even a partial decrease in insulysin activity was found to raise amyloid-beta peptide levels in the brain.

Obesity

A review42 of 10 international studies published since 1995, covering just over 37,000 people, has found that obesity increased the relative risk of dementia by an average of 42% compared with normal weight. Being underweight increased the risk by 36%. For Alzheimer's Disease and vascular dementia, specifically, obesity was an even more significant risk: 80% and 73%, respectively. With regards to Alzheimer’s, obesity was more likely to be a risk factor for women, but men were more affected when it came to vascular dementia.

A very large study43 that measured abdominal fat at age 40 to 45 and dementia occurrence some 36 years later, found that those with the highest amount of abdominal fat were nearly three times more likely to develop dementia than those with the lowest amount of abdominal fat. Having a large abdomen increased the risk of dementia regardless of overall weight and existing health conditions, although being obese as well did increase the risk. Those more likely to have abdominal obesity, were women, non-whites, smokers, people with high blood pressure, high cholesterol or diabetes, and those with less than a high school level of education. And another large study44 found that those who at 40 were obese, or had high blood pressure, or high cholesterol levels, were twice as more likely to develop dementia by the age of 60. Having all three of these risk factors increased their chances six-fold.

And just to be really scary, when45 genetically engineered mice were fed a diet rich in fat, sugar and cholesterol for a mere nine months (although that is, of course, much longer for a mouse than it is for us!), they developed a preliminary stage of Alzheimer's pathology in their brains, suggesting that a ‘fast food’ diet could be a contributory factor in those with the Alzheimer’s gene.

Physical exercise & fitness

A number of studies have found that physical fitness reduces the risk of dementia. One way physical exercise can help fight dementia is through its ability to grow neurons in the hippocampus. This is well-established in rodent studies, and has been confirmed in small human studies. One such study46 found the association between physical fitness and hippocampus size was specifically associated with performance on certain spatial memory tests.  Another47 found that those with early Alzheimer's disease who were less physically fit had four times more brain shrinkage when compared to normal older adults than those who were more physically fit, suggesting the value of physical fitness extends to slowing down the progression of the disease.

Another reason for exercise to prevent dementia is through its effect on cardiovascular fitness, and a reasonably large four-year study48 did indeed find that the most active (top third) were significantly less likely to develop vascular dementia than the least active (bottom third). Interestingly, no such association was found with Alzheimer’s disease. However, at least two large studies have found a significantly reduced risk of dementia in those who had higher levels of fitness49 or exercised three or more times a week50. It may be that exercise has a greater effect on vascular dementia, but many cases of Alzheimer's dementia are actually mixed dementia, with a vascular component.

References: 
  1. Scarmeas, N. et al. 2009. Mediterranean Diet and Mild Cognitive Impairment. Archives of Neurology, 66(2), 216-225.
  2. Scarmeas, N. et al. 2009. Physical Activity, Diet, and Risk of Alzheimer Disease. Journal of the American Medical Association, 302(6), 627-637.
  3. Barberger-Gateau, P. et al. 2007. Dietary patterns and risk of dementia: The Three-City cohort study. Neurology, 69, 1921-1930.
  4. Dai, Q. et al. 2006. Fruit and Vegetable Juices and Alzheimer's Disease: The Kame Project. The American Journal of Medicine, 119 (9), 751-759
  5. Gray, S.L. et al. 2008. Antioxidant Vitamin Supplement Use and Risk of Dementia or Alzheimer's Disease in Older Adults. Journal of the American Geriatrics Society, 56 (2), 291–295.
  6. Zandi, P.P., Anthony, J.C., Khachaturian, A.S., Stone, S.V., Gustafson, D., Tschanz, J.T., Norton, M.C., Welsh-Bohmer, K.A. & Breitner, J.C.S. 2004. Reduced Risk of Alzheimer Disease in Users of Antioxidant Vitamin Supplements: The Cache County Study. Archives of Neurology, 61, 82-88.
  7. Engelhart, M.J., Geerlings, M.I., Ruitenberg, A., van Swieten, J.C., Hofman, A., Witteman, J.C.M. & Breteler, M.M.B. 2002. Dietary Intake of Antioxidants and Risk of Alzheimer Disease. JAMA, 287, 3223-3229.
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  9. Heo, H.J. & Lee, C.Y. 2004. Protective Effects of Quercetin and Vitamin C against Oxidative Stress-Induced Neurodegeneration. Journal of Agricultural and Food Chemistry, 52 (25), 7514–7517.
  10. Ghosh, D., McGhie, T.K., Zhang, J., Adaim, A. & Skinner, M. 2006. Effects of anthocyanins and other phenolics of boysenberry and blackcurrant as inhibitors of oxidative stress and damage to cellular DNA in SH-SY5Y and HL-60 cells. Journal of the Science of Food and Agriculture, in press.
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  12. Troen, A.M. et al. 2008. B-vitamin deficiency causes hyperhomocysteinemia and vascular cognitive impairment in mice. Proceedings of the National Academy of Sciences, 105, 12474-12479.
  13. McIlroy, S.P., Dynan, K.B., Lawson, J.T., Patterson, C.C. & Passmore, A.P. 2002. Moderately Elevated Plasma Homocysteine, Methylenetetrahydrofolate Reductase Genotype, and Risk for Stroke, Vascular Dementia, and Alzheimer Disease in Northern Ireland. Stroke, 33, 2351–2356.
  14. Seshadri, S., Beiser, A., Selhub, J., Jacques, P.F., Rosenberg, I.H., D'Agostino, R.B., Wilson, P.W.F. & Wolf, P.A. 2002. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. The New England Journal of Medicine, 346, 476-483.
  15. Kruman, I.I., Kumaravel, T.S., Lohani, A., Pedersen, W.A., Cutler, R.G., Kruman, Y., Haughey, N., Lee, J., Evans, M. & Mattson, M.P. 2002. Folic Acid Deficiency and Homocysteine Impair DNA Repair in Hippocampal Neurons and Sensitize Them to Amyloid Toxicity in Experimental Models of Alzheimer's Disease. Journal of Neuroscience, 22, 1752-1762.
  16. Schaefer, E.J. et al. 2006. Plasma Phosphatidylcholine Docosahexaenoic Acid Content and Risk of Dementia and Alzheimer Disease. Archives of Neurology, 63, 1545-1550.
  17. Freund-Levi;, Y. et al. 2006. w-3 Fatty Acid Treatment in 174 Patients With Mild to Moderate Alzheimer Disease: OmegAD Study: A Randomized Double-blind Trial. Archives of Neurology, 63, 1402-1408.
  18. Quinn, J.F. et al. 2009. A clinical trial of docosahexaenoic acid (DHA) for the treatment of Alzheimer's disease. Presented at the Alzheimer's Association International Conference on Alzheimer's Disease July 11-16 in Vienna.
    Yurko-Mauro, K. et al. 2009. Results of the MIDAS Trial: Effects of Docosahexaenoic Acid on Physiological and Safety Parameters in Age-Related Cognitive Decline. Presented at the Alzheimer's Association International Conference on Alzheimer's Disease July 11-16 in Vienna.
  19. Lim, G.P., Calon, F., Morihara, T., Yang, F., Teter, B., Ubeda, O., Salem, N.Jr, Frautschy, S.A. & Cole, G.M. 2005. A Diet Enriched with the Omega-3 Fatty Acid Docosahexaenoic Acid Reduces Amyloid Burden in an Aged Alzheimer Mouse Model. Journal of Neuroscience, 25(12), 3032-3040.
  20. Calon, F. et al. 2004. Docosahexaenoic Acid Protects from Dendritic Pathology in an Alzheimer's Disease Mouse Model. Neuron, 43 (5), 633-645.
  21. Ma, Q-L. et al. 2007. Omega-3 Fatty Acid Docosahexaenoic Acid Increases SorLA/LR11, a Sorting Protein with Reduced Expression in Sporadic Alzheimer's Disease (AD): Relevance to AD Prevention. Journal of Neuroscience, 27 (52), 14299 - 14307.
  22. Collins, M.A. et al. 2008. Alcohol in Moderation, Cardioprotection, and Neuroprotection: Epidemiological Considerations and Mechanistic Studies. Alcoholism: Clinical and Experimental Research, Published Online 20 November.
  23. Truelsen, T., Thudium, D. & Grønbæk, M. 2002. Amount and type of alcohol and risk of dementia: The Copenhagen City Heart Study. Neurology, 59, 1313-1319.
  24. Wang, J. et al. 2008. Grape-Derived Polyphenolics Prevent Aβ Oligomerization and Attenuate Cognitive Deterioration in a Mouse Model of Alzheimer's Disease. Journal of Neuroscience, 28, 6388-6392.
  25. Okello, E.J., Savelev, S.U. & Perry, E.K. 2004. In vitro Anti-beta-secretase and dual anti-cholinesterase activities of Camellia sinensis L. (tea) relevant to treatment of dementia. Phytotherapy Research, 18 (8), 624-627.
  26. Eskelinen, M.H. et al. 2009. Midlife Coffee and Tea Drinking and the Risk of Late-Life Dementia: A Population-based CAIDE Study. Journal of Alzheimer's Disease, 16(1).
  27. Luchsinger, J.A. et al. 2002. Caloric Intake and the Risk of Alzheimer Disease. Archives of Neurology, 59 (8), 1258-1263.
  28. Solomon, A. et al. 2008. Midlife Serum Total Cholesterol and Risk of Alzheimers Disease and Vascular Dementia Three Decades Later. Presented at the American Academy of Neurology Annual Meeting in Chicago, April 16. Abstract
  29. Pappolla, M.A. et al. 2003. Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology. Neurology, 61, 199-205.
  30. Yaffe, K., Barrett-Connor, E., Lin, F. & Grady, D. 2002. Serum Lipoprotein Levels, Statin Use, and Cognitive Function in Older Women. Archives of Neurology, 59,378-384.
  31. Kivipelto, M., Helkala, E., Laakso, M. P., Hanninen, T., Hallikainen, M., Alhainen, K., Soininen, H., et al. (2001). Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. BMJ, 322(7300), 1447-1451.  http://www.bmj.com/cgi/content/full/322/7300/1447
  32. Tan, Z.S., Seshadri, S., Beiser, A., Wilson, P.W.F., Kiel, D.P., Tocco, M., D'Agostino, R.B. & Wolf, P.A. 2003. Plasma Total Cholesterol Level as a Risk Factor for Alzheimer Disease: The Framingham Study. Archives of Internal Medicine, 163, 1053-1057.
  33. Engelhart, M.J., Geerlings, M.I., Ruitenberg, A., van Swieten, J.C., Hofman, A., Witteman, J.C.M. & Breteler, M.M.B. 2002. Diet and risk of dementia: Does fat matter?: The Rotterdam Study. Neurology, 59, 1915-1921.
  34. Kim, W.S. et al. 2007. Role of ABCG1 and ABCA1 in Regulation of Neuronal Cholesterol Efflux to Apolipoprotein E Discs and Suppression of Amyloid-β Peptide Generation. Journal of Biological Chemistry, 282, 2851-2861.
  35. Rönnemaa, E. et al. 2008. Impaired insulin secretion increases the risk of Alzheimer disease. Neurology, first published on April 9 as doi: doi:10.1212/01.wnl.0000310646.32212.3a
  36. Luchsinger, J.A. et al. 2007. Relation of Diabetes to Mild Cognitive Impairment. Archives of Neurology, 64, 570-575.
  37. Yaffe, K. et al. 2006. Glycosylated Hemoglobin Level and Development of Mild Cognitive Impairment or Dementia in Older Women. Journal of Nutrition, Health, and Aging, 10 (4).
  38. Arvanitakis, Z., Wilson, R.S., Bienias, J.L., Evans, D.A. & Bennett, D.A. 2004. Diabetes Mellitus and Risk of Alzheimer Disease and Decline in Cognitive Function. Archives of Neurology, 61, 661-666.
  39. Burdo, J.R. et al. 2008. The pathological interaction between diabetes and presymptomatic Alzheimer's disease. Neurobiology of Aging, Available online 26 March 2008 .
  40. Zhao,W-Q. et al. 2007. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB Journal, published online ahead of print August 24.
  41. Miller, B.C., Eckman, E.A., Sambamurti, K., Dobbs, N., Chow, K.M., Eckman, C.B., Hersh, L.B. & Thiele, D.L. 2003. Amyloid-β peptide levels in brain are inversely correlated with insulysin activity levels in vivo. PNAS, 100, 6221-6226. published online before print.
  42. Beydoun, M.A., Beydoun, H.A. & Wang, Y. 2008. Obesity and central obesity as risk factors for incident dementia and its subtypes: a systematic review and meta-analysis. Obesity Reviews, 9 (3), 204–218.
  43. Whitmer, R.A., et al. 2008. Central obesity and increased risk of dementia more than three decades later. Neurology, published online ahead of print March 26.
  44. Kivipelto,M. et al. 2006. Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Lancet Neurology, advance online publication 3 August
  45. Akterin, S. 2008. From cholesterol to oxidative stress in Alzheimer's disease: A wide perspective on a multifactorial disease. Doctoral thesis, Karolinska Institutet. http://diss.kib.ki.se/2008/978-91-7409-172-4/
  46. Erickson, K.I. et al.  2009. Aerobic fitness is associated with hippocampal volume in elderly humans. Hippocampus, Published online 2 January.
  47. Burns, J.M. et al. 2008. Cardiorespiratory fitness and brain atrophy in early Alzheimer disease. Neurology, 71, 210-216.
  48. Ravaglia, G. et al. 2007. Physical activity and dementia risk in the elderly. Findings from a prospective Italian study. Neurology, published online ahead of print December 19.
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  50. Larson, E.B., Wang, L., Bowen, J.D., McCormick, W.C., Teri, L., Crane, P., & Kukull, W. 2006. Exercise Is Associated with Reduced Risk for Incident Dementia among Persons 65 Years of Age and Older. Annals of Internal Medicine, 144 (2), 73-81.

Dementia: Risk Factors

Genes

Several genes have been implicated in Alzheimer's, but the big one is the e4 allele of the ApoE gene (on chromosome 19). This variant is found in about a quarter of the population.

Having it doesn't mean you are foreordained to develop Alzheimer's, but it certainly increases the risk substantially. The risk goes up considerably more if both of your genes are the e4 variant (remember you inherit two: one from each parent).

It also increases if you have both the ApoE-e4 and the D10S1423 234-bp allele (found on chromosome 10). The combined risk of these two gene variants has been described as being greater than the increased risk of lung cancer caused by smoking1. Chromosome 10 has also been implicated in setting the age at which it begins, for both Alzheimer's and Parkinson's diseases, in those genetically disposed.

Another gene that has been linked to Alzheimer's is the KIBRA gene (on chromosome 5) — carriers of the T-allele have a 25% lower risk of developing Alzheimer's compared to those who carry the C-allele2.

It does seem that having the right, or wrong, genes is more important than we believed. Data from the Swedish Twin Registry3, involving nearly 12,000 people aged 65 and older, estimated that genetic influence accounted for 79% of Alzheimer's risk, with 95% probability of being within the range 67 to 88%.

But it's not just a matter of genes. Not everyone with the 'wrong' genes will develop dementia, and not everyone who develops dementia has the wrong genes. There are a number of lifestyle actions that affect it.

Even the genetic picture is not as simple as it sounds. One study4, for example, found indications that having a mother who had Alzheimer's is more significant than father's status. Data from the long-running Framingham Heart Study has found5 that cognitive impairment is more likely in those whose who have the ApoE ε4 gene — but only if they had a parent with dementia (particularly if it was Alzheimer's). There was no effect of parental dementia in those who didn’t have the ApoE ε4 gene.

For those who carry the “Alzheimer’s” APOE-4 gene, and those who later develop dementia, there is an association between smaller head size and lower educational achievement6. In other words, having both a small head size and low educational achievement in early life makes it more likely that a person will develop Alzheimer’s — probably because of their lack of cognitive reserve.

Cardiac & Blood Pressure Problems

A very large study7 found that those with atrial fibrillation, regardless of age, were 44% more likely to develop dementia, with those younger than 70 particularly at risk (130% more likely to develop dementia). Previous studies have connected atrial fibrillation with vascular dementia; this finding extends it to all dementia types.

Another, smaller, study8 (135 patients) found that memory declined significantly faster in those with high blood pressure or atrial fabrillation.

Atrial fibrillation, the most common heart rhythm problem, has a strong genetic link, and is also a risk factor for stroke.

Smoking

A very large seven-year study9 found that older adults who smoked were 50% more likely to develop dementia than people who had never smoked or no longer smoked. Smoking did not increase the risk for those with the Alzheimer’s gene apolipoprotein E4, but for those without the gene, smoking increased the risk by nearly 70%. Another large study10 found that heavy smokers developed the disease 2.3 years sooner, while heavy drinkers developed Alzheimer’s nearly 5 years earlier than those who were not. Those with the APOE e4 gene developed the disease three years sooner than those without the gene variant. These three risk factors were additive — those with all three developed the disease 8.5 years earlier than those with none of the risk factors.

A large national study11 also found that exposure to second-hand smoke also increases your risk.

Depression, stress & anxiety

Several studies12 have found evidence that depression, high level of stress or anxiety, and even loneliness, increase the risk of later developing dementia.

Other Possible Risk Factors

Findings from a study13 using genetically engineered mice suggests that people genetically predisposed to Alzheimer's disease or with excessive amounts of beta amyloid in their brains are at increased risk of developing the disease earlier if they receive high concentrations of oxygen, for example during or after surgery.

A large long-running study14 has found that women with both the lowest and the highest levels of thyrotropin (a hormone secreted by the pituitary gland that helps regulate thyroid gland function) had more than double the risk of developing Alzheimer's disease. No such association was found in men.

References: 
  1. Zubenko, G.S., Hughes, H.B. III & Stiffler, J.S. 2001. D10S1423 identifies a susceptibility locus for Alzheimer's disease in a prospective, longitudinal, double-blind study of asymptomatic individuals. Molecular Psychiatry, 6 (4), 413-419.
  2. Corneveaux, J.J. et al. In press. Evidence for an association between KIBRA and late-onset Alzheimer's disease. Neurobiology of Aging.
  3. Gatz, M. et al. 2006. Role of Genes and Environments for Explaining Alzheimer Disease. Archives of General Psychiatry, 63, 168-174.
  4. Mosconi, L. et al. 2007. Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism. PNAS, 104, 19067-19072.
  5. Debette, S. et al. 2009. Parental Dementia and Alzheimer Disease Are Associated with Poorer Memory in Middle-Aged Adults: The Framingham Offspring Study. Presented April 29 at the American Academy of Neurology's 61st Annual Meeting in Seattle, Washington.
  6. Mortimer, J,A., Snowdon, D.A.  & Markesbery, W.R. 2008. Small Head Circumference is Associated With Less Education in Persons at Risk for Alzheimer Disease in Later Life. Alzheimer Disease & Associated Disorders, 22(3), 249-254.
  7. Bunch, T.J. et al. 2009. Atrial Fibrillation is Independently Associated with Senile, Vascular, and Alzheimer's Dementia. Presented Friday, May 15, at "Heart Rhythm 2009," the annual scientific sessions of the Heart Rhythm Society in Boston.
  8. Mielke, M.M. et al. 2007. Vascular factors predict rate of progression in Alzheimer disease. Neurology, 69, 1850-1858.
  9. Reitz, C., den Heijer, T., van Duijn, C., Hofman, A. & Breteler, M.M.B. 2007. Relation between smoking and risk of dementia and Alzheimer disease: The Rotterdam Study. Neurology, 69, 998-1005.
  10. Harwood, D. et al. 2008. Impact of Alcohol Use, Smoking and Apolipoprotein-E Epsilon 4 Allele (APOE 4) on Age of Onset of Late Onset Alzheimers Disease (LOAD). Presented at the American Academy of Neurology 60th Annual Meeting in Chicago, April 16. Abstract P04.071
  11. Llewellyn, D.J. et al. 2009. Exposure to secondhand smoke and cognitive impairment in non-smokers: national cross sectional study with cotinine measurement. British Medical Journal, 338, 462. Full text available here.
  12. Peavy, G.M. et al. 2007. The Effects of Prolonged Stress and APOE Genotype on Memory and Cortisol in Older Adults. Biological Psychiatry, 62 (5), 472-478.
    Rapp, M.A. et al. 2006. Increased Hippocampal Plaques and Tangles in Patients With Alzheimer Disease With a Lifetime History of Major Depression. Archives of General Psychiatry, 63,161-167.
    Wang, H. -X. et al. 2009. Personality and lifestyle in relation to dementia incidence. Neurology, 72, 253-259.
    Wilson, R.S., Arnold, S.E., Beck, T.L., Bienias, J.L. & Bennett, D.A. 2008. Change in Depressive Symptoms During the Prodromal Phase of Alzheimer Disease. Archives of General Psychiatry, 65(4), 439-445.
    Wilson, R.S., Schneider, J.A., Boyle, P.A., Arnold, S.E., Tang, Y. & Bennett, D.A. 2007. Chronic distress and incidence of mild cognitive impairment. Neurology, 68, 2085-2092.
    Wilson, R.S., Krueger, K.R., Arnold, S.E., Schneider, J.A., Kelly, J.F., Barnes, L.L., Tang, Y. & Bennett, D.A. 2007. Loneliness and Risk of Alzheimer Disease. Archives of General Psychiatry, 64, 234-240.
    Wilson, R.S., Evans, D.A., Bienias, J.L., Mendes de Leon, C.F., Schneider, J.A. & Bennett, D.A. 2003. Proneness to psychological distress is associated with risk of Alzheimer’s disease. Neurology, 61, 1479-1485.
    Wilson, R.S., Barnes, L.L., de Leon, C.F.M., Aggarwal, N.T., Schneider, J.S., Bach, J., Pilat, J., Beckett, L.A., Arnold, S.E., Evans, D.A. & Bennett, D.A. 2002. Depressive symptoms, cognitive decline, and risk of AD in older persons. Neurology, 59, 364-370.
  13. Arendash, G.W. et al. 2009. Oxygen treatment triggers cognitive impairment in Alzheimer's transgenic mice. NeuroReport, 20 (12), 1087-1092.
  14. Tan, Z.S. et al. 2008. Thyroid Function and the Risk of Alzheimer Disease: The Framingham Study. Archives of Internal Medicine, 168(14), 1514-1520.

Mild Cognitive Impairment

Except in the cases of stroke or traumatic brain injury, loss of cognitive function is not something that happens all at once. Cognitive impairment that comes with age may be thought of as belonging on a continuum, with one end being no cognitive impairment and the other end being dementia, of which Alzheimer's is the most common type.

Most older adults are actually at the "no impairment" end of the continuum. A further 30-40% of adults over 65 will have what is called "age-related memory impairment", which is the type of cognitive loss we regard as a normal consequence of age -- a measurable (but slight) decline on memory tests; a feeling that you're not quite as sharp or as good at remembering, as you used to be.

Only about 1% of these people will develop Alzheimer's.

But around 10% of adults over 65 develop "mild cognitive impairment", and this is a precursor of Alzheimer's. This doesn't mean someone with MCI will inevitably get Alzheimer's in their lifetime, but their likelihood of doing so is substantially increased.

Whether you are one of those 10% depends in part on your age and your level of education. A study2 of nearly 4000 people from the general population of a Minnesota county, run by the Mayo Clinic, indicates 9% of those aged 70 to 79 and nearly 18% of those 80 to 89 have MCI. The prevalence decreased with years of education: it was 25% in those with up to eight years of education, 14% in those with nine to 12 years, 9% in those with 13 to 16 years, and 8.5% in those with greater than 16 years.

Whether or not this will develop into Alzheimer’s can be predicted with a reasonably high level of accuracy (75%) by the rate at which brain tissue is being lost, and in particular the rate at which it is being lost in the hippocampus (arguably the most important region for memory in the brain). Whether actions known to build brain tissue (physical exercise, mental stimulation) can counteract that in this population is not yet known — but it certainly can’t hurt!

Mild cognitive impairment doesn’t necessarily mean memory problems. There are two types of MCI: those with the amnesic subtype (MCI-A) have memory impairments only, while those with the multiple cognitive domain subtype (MCI-MCD) have other types of mild impairments, such as in judgment or language, and mild or no memory loss. Both sub-types progress to Alzheimer's disease at the same rate, but they do have different pathologies in the brain.

Mild cognitive impairment is not necessarily obvious to outside observers. A person with it can function perfectly well, and although they may feel their impairment is obvious to all around them, it's not likely to be obvious to anyone not living with them.

A person suffering from mild cognitive impairment may find that they have problems with:

  • finding the right words
  • making decisions
  • remembering recent events
  • placing things in space (for example, getting the proportions right when drawing a simple object such as a box).

Essentially, age-related cognitive impairment might be thought of as slight, non-important, cognitive impairment, while mild cognitive impairment is a condition where significant cognitive impairment exists which nevertheless doesn't affect daily functioning. Dementia is significant cognitive impairment that does interfere with daily life.

References: 
  1. Becker, J.T. et al. 2006. Three-dimensional Patterns of Hippocampal Atrophy in Mild Cognitive Impairment. Archives of Neurology, 63, 97-101.
  2. Petersen, R. et al. 2006. Study presented April 4 at the American Academy of Neurology meeting in San Diego. Press release
  3. Quinn, J.F. & Kaye, J.A. 2004. Study presented at the 56th annual meeting of the American Academy of Neurology in San Francisco. Press release
  4. Small, G.W. 2002.What we need to know about age related memory loss. British Medical Journal, 324, 1502-1505.

Alzheimer's Disease

Alzheimer's disease currently affects one in 10 people over age 65 and nearly half of those over age 85.

More than 19 million Americans say they have a family member with the disease, and 37 million say they know somebody affected with Alzheimer's.

In the United States, the average lifetime cost per Alzheimer patient is US$174,000. (These figures are from the U.S. Alzheimer's Association).

Resources:

For information about Alzheimer's, see the Alzheimer's Disease Education and Referral (ADEAR) Center's website (www.alzheimers.org). ADEAR is run by the National Institute on Aging (one of the US Government's National Institutes of Health).

Other useful resources include:

The Alzheimer Research Forum: "A scientific knowledge base on Alzheimer disease, with research news, expert commentaries, and databases for peer-reviewed articles, drugs, research reagents, grants, jobs, conferences, and more."
www.alzforum.org

Cognitive Neurology and Alzheimer's Disease Center at Northwestern University
http://www.brain.northwestern.edu/mdad/index.html

Medline Plus
http://www.nlm.nih.gov/medlineplus/alzheimersdisease.html

Links to national organizations that offer support:

http://www.alz.org/ Site of the U.S. Alzheimer’s Association.

http://www.alzheimers.org.uk/ Site of the U.K. Alzheimer's Society

http://www.alzheimer.ca/ Site of the Canadian Alzheimer's Association

http://www.alzheimers.org.au/ Site of the Australian Alzheimer's Association

www.alzheimers.org.nz Site of Alzheimer's New Zealand

Some articles of interest:

a good introduction from the Harvard Mahoney Neuroscience Newsletter:

http://www.med.harvard.edu/publications/On_The_Brain/Volume2/Special/SPAlz.html

Montessori for Alzheimer's patients

Movement with Meaning

Vascular & Mixed Dementia

Prevalence

Vascular dementia, as its name suggests, is caused by poor blood flow, produced by a single, localized stroke, or series of strokes.

It is the second most common dementia, accounting for perhaps 17% of dementias. It also co-occurs with Alzheimer's in 25-45% of cases. Although there are other types of dementia that also co-occur with Alzheimer's, mixed dementia generally refers to the co-occurrence of Alzheimer's and vascular dementia.

Risk factors

In general, unsurprisingly, vascular dementia has the same risk factors as cerebrovascular disease.

A study1 of 173 people from the Scottish Mental Survey of 1932 who have developed dementia has found that, compared to matched controls, those with vascular dementia were 40% more likely to have low IQ scores when they were children than the people who did not develop dementia. Because this was not true for those with Alzheimer's disease, it suggests that low childhood IQ may act as a risk factor for vascular dementia through vascular risks rather than the "cognitive reserve" theory.

Prevention

The exciting thing about vascular dementia is that it is far more preventable than other forms of dementia. As with risk, as a general rule, the same things that help you protect you from heart attacks and stroke will help protect you from vascular dementia. This means diet, and it means exercise.

A four-year study2 involving 749 older adults has found that the top one-third of participants who exerted the most energy in moderate activities such as walking were significantly less likely to develop vascular dementia than those people in the bottom one-third of the group.

Treatment

Apart from normal medical treatment for cerebrovascular problems, there are a couple of interesting Chinese studies that have looked specifically at vascular dementia.

The herb gastrodine has been used in China for centuries to treat disorders such as dizziness, headache and even ischemic stroke. A 12-week, randomized, double-blind trial3 involving 120 stroke patients who were diagnosed with mild to moderate vascular dementia has found that  gastrodine and Duxil® (a drug used to treat stroke patients in China) produced similar overall levels of cognitive improvement -- although more patients showed 'much improvement' with gastrodine (23% vs 14%).

A Chinese pilot study4 involving 25 patients with mild to moderate vascular dementia found that ginseng compound significantly improved their average memory function after 12 weeks, but more research (larger samples, placebo-controls) is needed before this finding can be confirmed. Five years on I have still not seen such a study.

References: 
  1. McGurn, B., Deary, I.J. & Starr, J.M. 2008. Childhood cognitive ability and risk of late-onset Alzheimer and vascular dementia. Neurology, first published on June 25, 2008 as doi: doi:10.1212/01.wnl.0000319692.20283.10
  2. Ravaglia, G. et al. 2007. Physical activity and dementia risk in the elderly. Findings from a prospective Italian study. Neurology, published online ahead of print December 19.
  3. Tian, J.Z. et al. 2003. A double-blind, randomized controlled clinical trial of compound of Gastrodine in treatment of mild and moderate vascular dementia in Beijing, China. Presented at the American Heart Association's Second Asia Pacific Scientific Forum in Honolulu on June 10.
  4. Tian, J.Z. et al. 2003. Presented at the American Stroke Association's 28th International Stroke Conference on February 14 in Phoenix. Press release

Dementia with Lewy Bodies

LBD: What is it?

Lewy Body Dementia is so called because the brains of affected people develop abnormal spherical masses of protein, called Lewy bodies, inside nerve cells. Lewy bodies are associated with Parkinson’s disease as well as dementia. Thus Lewy body dementia can refer to both Parkinson’s disease dementia and “dementia with Lewy bodies”. Lewy bodies are also often found in the brains of those with Alzheimer’s disease.

Unlike Alzheimer’s, however, dementia with Lewy bodies characteristically (but not invariably) begins with visual hallucinations.

Prevalence of LBD

Estimates of its prevalence are complicated by the lack of clearly defined clinical criteria, and vary widely. A 2005 review1 concluded that the range probably falls between 0 to 5% in the general population, and from 0 to 30.5% of all dementia cases (the very broad range reflects the confusion between Parkinson’s disease dementia (PDD), dementia with Lewy bodies, and Alzheimer’s where Lewy bodies are present).

How does LBD differ from Alzheimer's & PDD?

A comparison of these three disorders found that cognitive impairment in those with Alzheimer's disease and those with Lewy body dementia was similar, and more severe than in those with Parkinson's disease dementia.

The 1997 study2 also found that a simple test, in which patients are asked to draw and copy a clock face, distinguished those with Alzheimer’s and those with Lewy body dementia — of all the groups, only those with Lewy body dementia had equally poor scores in the “copy” part of the test compared to the “draw” part.

For more information:

Mayo Clinic: http://www.mayoclinic.com/health/lewy-body-dementia/DS00795

Lewy Body Dementia Association: http://www.lewybodydementia.org/

References: 
  1. Zaccai, J., McCracken, C. & Brayne, C. 2005. A systematic review of prevalence and incidence studies of dementia with Lewy bodies. Age and Ageing, 34(6), 561-566.
  2. Gnanalingham, K.K. et al. 1997. Motor and cognitive function in Lewy body dementia: comparison with Alzheimer's and Parkinson's diseases. Journal of Neurology, Neurosurgery, and Psychiatry, 62, 243-252.

Frontotemporal Dementia

What is it?

Frontotemporal dementia is a disorder of the frontal lobes and includes what was known as primary progressive aphasia. Although it occurs far less often than Alzheimer's disease, among dementia sufferers younger than 65 it is estimated to occur at about the same rate. In other words, frontotemporal dementia is, unlike the most common dementias, not a disorder of age. Most sufferers become symptomatic in their 50s and 60s.

Frontotemporal dementia generally begins with a focal symptom, such as aphasia, before (usually a number of years later) progressing to more generalized dementia.

There are several types of frontotemporal dementia. The most common (around 60% of FTD cases) is known as the behavioral variant (also, Pick's disease). This is characterized by impairment in social and emotional skills. The other 40% of FTD cases have language impairments -- about half of these suffer from semantic FTD, characterized by difficulties in remembering the meanings of words; the other half suffer from progressive nonfluent aphasia, characterized by difficulties in producing language (although they understand what they're trying to say).

In around 15% of FTD cases (most usually the behavioral variant), motor neurone disease also develops.

Prevalence

A large-scale epidemiological study1 in the Netherlands indicated frontotemporal dementia occurs at a rate of 1.1 per 100,000, with the prevalence highest among those ages 60 to 69, at 9.4 per 100,000. The prevalence among people ages 45 to 64 was estimated to be 6.7 per 100,000 (this was after autopsies caused the number of diagnosed cases to go up, with 17 of 50 patients undiagnosed in life). Unlike other forms of dementia, where most occurrences begin in older adults, symptoms began after age 65 in only 22% of patients. The median age of onset was 58, with a range from 33 to 80.

A family history of dementia was present in 43% of patients. Interestingly, whites accounted for 99% of all cases despite an ample nonwhite population.

A large U.K. study2 found prevalences of early-onset FTD and Alzheimer's were the same in the 45-64 population: 15 per 100,000. The mean age at onset of FTD was 52.8 years and there was a striking male preponderance (14:3).

This rate is notably higher than that found in the Dutch study, and it has been suggested that the reason is ethnicity -- the Dutch study, as mentioned, had a significant proportion of non-Caucasians, while the British (Cambridge) study explicitly mentioned that minorities were under-represented.

It has been estimated that frontotemporal dementia accounts for approximately 8% of patients with dementia, but this is now thought to be an underestimation.

Genes as a factor

There is a high level of genetic involvement in this type of dementia.

As mentioned, the Dutch study found a family history of dementia in 43% of FTD patients. Another large Dutch study3 found 38% of FTD patients had one or more first-degree relatives with dementia before age 80 compared to 15% of age-matched controls; 10% had two or more first-degree relatives with dementia compared with 0.9% of the controls. FTD patients were also three times more likely to have 2 "Alzheimer's genes" (2 e4 alleles of the ApoE gene) than the controls: 7% vs 2.3%.

This study also supports findings with other dementias that earlier-onset is more likely to have genetic causes. First-degree relatives of FTD patients (who had twice the risk of dementia before age 80 compared with relatives of controls) were much more likely to develop dementia early: age of onset of dementia in affected first-degree relatives of FTD patients averaged was just under 61, compared to 72.3 for affected first-degree relatives of controls.

The genes implicated in familial cases of FTD are on chromosome 17, in the gene for the tau protein, and in the gene for the progranulin protein. Research4 has now confirmed that people with these hereditable defects produce only half of the normal amount of progranulin, and recently a simple test for measuring the quantity of progranulin in the blood was developed. The test reveals whether someone has the mutations that carry an increased risk of FTD.

A recent study5 involving 225 FTD patients found 41.8% of patients had some family history, although only 10.2% had a clear autosomal dominant history (at least 3 cases within the last 2 generations). However, the importance of genes varied across the different clinical subtypes of the disease, with the behavioral variant being the most heritable and FTD–motor neuron disease and the language syndromes (particularly semantic dementia) the least heritable.

For more information:

http://emedicine.medscape.com/article/1135164-overview

http://memory.ucsf.edu/ftd/

References: 
  1. Rosso, S.M. et al. 2003. Frontotemporal dementia in The Netherlands: Patient characteristics and prevalence estimates from a population-based study. Brain, 126, 2016-22. Full text available at http://brain.oxfordjournals.org/cgi/content/full/126/9/2016
  2. Ratnavalli, E., Brayne, C., Dawson, K. & Hodges, J.R. 2002. The prevalence of frontotemporal dementia. Neurology, 58, 1615-1621.
  3. Stevens, M. et al. 1998. Familial aggregation in frontotemporal dementia. Neurology, 50(6), 1541-5.
  4. Sleegers, K. et al. 2009. Serum biomarker for progranulin-associated frontotemporal lobar degeneration. Annals of Neurology, Published online March 13.
  5. Rohrer, J.D. et al. 2009. The heritability and genetics of frontotemporal lobar degeneration. Neurology, 73(18), 1451-1456.

Dementia: A general introduction

Prevalence of dementia

Dementia is estimated1 to afflict over 35.5 million people worldwide -- this includes nearly 10 million people in Europe, nearly 4.4 million in North America, nearly 7 million in South and Southeast Asia, about 5.5 million in China and East Asia and about 3 million in Latin America.

The estimated prevalence for over 60s is 4.7% worldwide. Because this is a disorder of age, prevalence is of course greatly affected by the proportion of people reaching their senior years. Hence the prevalence is higher in the more developed countries: the estimated prevalence in Western Europe and North America is 7.2% and 6.9% respectively, compared to 2.6% in Africa.

What kinds of dementia are most common?

The prevalence of the various dementia types is a complicated story. Certainly Alzheimer's disease is by far the most common type of dementia, accounting for perhaps 70% of all dementias (although a 2006 study13 suggested that non-Alzheimer dementias were as common as Alzheimer's — however this was based on dementia among military veterans). The second most common dementia is almost certainly vascular dementia, which may account for some 17% of dementias. However, the actual numbers are made uncertain by the fact that these two dementias often occur together.

At minimum, around a quarter of Alzheimer's cases have been found, on autopsy, to also have vascular pathology; this proportion reaches higher levels when the samples are not restricted to dementia clinics. One such community-based study2, for example, found 45% of the Alzheimer's cases also showed significant vascular pathology. Another, U.K., study3 found a similar proportion (46%).

Another, large long-running, study14 has found that only 30% of people with signs of dementia had Alzheimer’s disease alone. 42% had Alzheimer’s disease with cerebral infarcts (strokes) and 16% had Alzheimer’s disease with Parkinson’s disease (including two people with all three conditions). Infarcts alone caused another 12% of the cases. Vascular dementia caused another 12%.

Although there are other types of dementia that also co-occur with Alzheimer's, mixed dementia generally refers to the co-occurrence of Alzheimer's and vascular dementia.

The other important dementia type that co-occurs with Alzheimer's at a high rate is dementia with Lewy bodies, also considered to be one of the most common dementias (although, due to inconsistent criteria, estimates of its actual prevalence vary wildly). It is estimated to co-occur with Alzheimer's pathology around half the time. At a lesser frequency, but still high, is Parkinson's disease dementia — about 20% of Alzheimer's patients also have Parkinson's disease.

But it is probably fair to say that the distinction between these dementia types is not clear-cut. Lewy bodies are found in a high proportion of both Alzheimer's and Parkinson's patients — the number of cases of 'pure' Lewy body dementia is much smaller. It's been said, in fact, that the main difference between Lewy body dementia and Parkinson's disease dementia lies in the timing — Parkinson's disease dementia will be preceded by at least a year and more likely a number of years, by full-blown Parkinson's disease.

Regardless of the difficulties in establishing clear clinical criteria, however, there is no doubt that Alzheimer's co-occurs with vascular pathology or Lewy body pathology at a startlingly high rate.

One of the problems with clearly distinguishing between these types of dementia is a happy one: vascular and Alzheimer's pathology can be found, at autopsy, in many elderly brains that have not shown symptoms of dementia.

For example, in one community-based study4, in which the median age at death was around 85 for the 209 individuals, 48% had had dementia, of whom 64% showed Alzheimer's pathology. However, 33% of those who had not had dementia showed similar levels of Alzheimer's plaques. Similarly, some amount of tau tangles (another aspect of Alzheimer's pathology) was found in 61% of the demented and 34% of the non-demented individuals. Finally, multiple vascular pathology was found in 46% of the demented group and 33% of the non-demented, and vascular lesions were equally common in both.

And in the large long-running study mentioned earlier14, in those without dementia, brain autopsy revealed the presence of Alzheimer’s in 24% of cases, and infarctions in 18%.

How likely am I to develop dementia?

The question of how likely any person is to develop dementia must begin with estimates of prevalence, but this of course is only the very beginning of the story.

Estimating prevalence is complicated by the fact that dementia is greatly affected by lifestyle, environmental, and genetic factors, and consequently prevalence varies a lot depending on geographic region.

Different dementia sub-types have different causes, and some give a much greater weight to genetic or environmental factors than others. However, the finding that dementia risk is much greater in those with more than one pathology, and that Alzheimer’s pathology with cerebral infarcts is a very common combination, adds to growing evidence that dementia risk might be reduced with the same tools we use for cardiovascular disease such as control of blood cholesterol levels and hypertension.

Age as a factor

The first American study to use nationally representative data5 (rather than extrapolating from regional data) came up with a figure of 13.9% of those aged 71 and older (one in seven). But age of course makes all the difference in the world. The study found 5% of those aged 71 to 79, rising to 37.4% of those age 90 and older.

Although all the dementia types show an increase with age, Alzheimer's is particularly a disorder of age: although the study found only 46.7% of those with dementia in their 70s had Alzheimer's, for those in their 90s, Alzheimer's was the dementia type for 79.5% of them.

An Italian study of over 2000 seniors over 80 years old6 confirms that dementia does indeed keep increasing with age (it had been thought that risk leveled off for those who reached their 90s). The study found that 13.5% of those aged 80 to 84 had dementia, rising sharply to 30.8% of those 85 to 89, 39.5% of those 90 to 94, and 52.8% among those older than 94.

Gender as a factor

A number of studies have found differences between men and women, or between difference ethnicities, but this large, nationally representative study found that, although on the face of it there were race and gender differences, these differences disappeared once age, years of education, and presence of at least one "Alzheimer's gene" was taken into account.

However, an American study of over 900 seniors over 90 years old7 found that women of this age were much more likely to have dementia than men (some 45% of them, compared to 28% of the men), and that the likelihood of having dementia kept increasing with age for the women, but not for the men. Of course, more women than men survive to this age (some two-thirds of the participants were women).

Interestingly, education was protective for the women (the risk of dementia decreasing the more years of education the individual had had) but not for the men. The study participants were not, however, a random sampling -- they all came from the same retirement community, and most were white and of high socioeconomic status. Given that, and considering the times in which they were born, it seems likely that there would be far more variability in educational level among the women than the men. The men, while less likely to develop dementia, did tend to decline faster if they did develop it.

The Italian oldest-old study, too, found more women than men had dementia: across all ages, 25.8% of the women and 17.1% of the men.

These figures don't of course tell us how many develop dementia at those ages. Obviously, survival rates are a factor, and as we saw in the other study, male and female survival rates do vary. The figures for new cases of dementia developing in these age bands were:

  • 6% at 80 to 84 years;
  • 12.4% at 85 to 89 years;
  • 13.1% from 90 to 94 years; and
  • 20.7% among those over 94.

These figures make even more clear what was apparent in the earlier figures: dementia jumps suddenly in the later half of the 80s, and again in the later half of the 90s.

Importantly, however, the incidence of new cases shows us how important the gender difference in survival rates is: the difference in prevalence is much smaller in these terms --9.2% among women and 7.2% among men.

The study, which canvassed everyone in the age group within a specific geographical area and had an 88% response rate, had a ratio of 74 women to 26 men. Because the number of men at the very highest ages was so small, we can't draw any firm conclusions about gender differences at those ages.

The Italian study involves a very different population from that of the American study: Varese is in a heavily industrialised part of northern Italy, with a high immigrant population, and the average amount of education was only 5.1 years.

A review of 26 studies looking at dementia prevalence in Europe8 confirmed rates for men rising from 1.8% in the 65-69 years age range up to 30% in the over 90 years age group, and for women rising from 1.5% to 30% in the 80-85 years age band. However (and confirming the American study), rates in the oldest old for women rose to over 50% in those over 95 years.

Early onset of dementia

The average age at the onset of dementia is around 80 years. Early-onset dementia is defined arbitrarily (and variably) as occurring before 60-65. Early-onset cases have been estimated to make up about 6-7% of all cases of Alzheimer's disease, and though a lot of attention has been given to them, only about 7% of early-onset cases are in fact familial9.

Familial cases involve mutations in specific genes (the APP or presenilin genes); they do not include what is popularly referred to as the "Alzheimer's gene" — variants of APOE. A 1995 study10 calculated that a person with no family history of Alzheimer's disease who has an e4 allele has a lifetime risk of 29%, compared to a risk of 9% if they don't have an e4 allele. In other words, if you don't have any of the Alzheimer's risk genes, or any family history, you only have a 9% risk of developing Alzheimer's, and even if you do have the "Alzheimer's gene", your chance of not getting Alzheimer's is still over 70%. Your risk does, however, go up dramatically if both your APOE alleles are e4.

A large study11 found, however, that there were both ethnic and gender differences for the risk of this genetic factor. The effect of having an e4 allele was much greater among Japanese compared to Caucasian, and greater for Caucasian compared to African American and Hispanic. Additionally, the effect of having an e4 allele becomes less significant after 70.

There is evidence12 that the age of onset for both Alzheimer's and Parkinson's diseases, for those genetically disposed, is controlled by genes on chromosome 10.

References: 
  1. From the 2009 World Alzheimer's Report: http://www.alz.co.uk/research/worldreport/
  2. Lim A, Tsuang D, Kukull W, et al. 1999. Cliniconeuropathological correlation of Alzheimer’s disease in a community-based case series. Journal of the American Geriatric Society, 47, 564-569.
  3. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). 2001. Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Lancet, 357, 169-175.
  4. Langa, K.M., Foster, N.L. & Larson, E.B. 2004. Mixed Dementia: Emerging Concepts and Therapeutic Implications. JAMA, 292(23), 2901-2908.
  5. Plassman, B.L. et al. 2007. Prevalence of Dementia in the United States: The Aging, Demographics, and Memory Study. Neuroepidemiology, 29, 125-132. 
  6. Lucca, U. et al. 2009. Risk of dementia continues to rise in the oldest old: The Monzino 80-plus Study. Presented on July 14, 2009, at the annual International Conference on Alzheimer's Disease in Vienna. http://www.alz.org/icad/documents/abstracts/abstracts_prev_ICAD09.pdf
  7. Corrada, M.M. et al. 2008. Prevalence of dementia after age 90: Results from The 90+ Study. Neurology, 71 (5), 337-343.
  8. Reynish, E. et al. 2009. Systematic Review and Collaborative Analysis of the Prevalence of Dementia in Europe. Presented on July 14, 2009, at the annual International Conference on Alzheimer's Disease in Vienna. http://www.alz.org/icad/documents/abstracts/abstracts_prev_ICAD09.pdf
  9. Nussbaum, R.L. & Ellis, C.E. 2003. Alzheimer's Disease and Parkinson's Disease. New England Journal of Medicine, 348 (14), 1356-1364. http://content.nejm.org/cgi/content/full/348/14/1356#R23
  10. Seshadri S, Drachman DA, Lippa CF. 1995. Apolipoprotein E epsilon 4 allele and the lifetime risk of Alzheimer's disease: what physicians know, and what they should know. Archives of Neurology, 52, 1074-1079. http://tinyurl.com/ya7vss7 
  11. Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. JAMA 1997;278:1349-1356. http://tinyurl.com/yb9tdju
  12. Li, Y. et al. 2002. Age at Onset in Two Common Neurodegenerative Diseases Is Genetically Controlled. American Journal of Human Genetics, 70, 985-993. Press release
  13. Ross, E.D. et al. 2006. Changing Relative Prevalence of Alzheimer Disease versus Non-Alzheimer Disease Dementias: Have We Underestimated the Looming Dementia Epidemic? Dementia and Geriatric Cognitive Disorders, 22 (4), 273-277.
  14. Schneider, J.A., Arvanitakis, Z., Bang, W. & Bennett, D.A. 2007. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology, published ahead of print June 13.

 

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