Alzheimer's & other dementias
Data from 196,383 older adults (60+; mean age 64) in the UK Biobank found that a healthy lifestyle was associated with lower dementia risk regardless of genes.
Both an unhealthy lifestyle and high genetic risk were associated with higher dementia risk.
Lifestyle factors included smoking, physical activity, diet, and alcohol consumption. Bearing in mind that lifestyle factors were self-reported, 68.1% followed a healthy lifestyle, 23.6% were intermediate, and 8.2% followed an unhealthy lifestyle. Regarding genes, 20% were at high risk, 60% were intermediate, and 20% were at low risk.
Of those at high genetic risk, 1.23% developed dementia in the 8-year period (remember that these are people who are still relatively — the average age at study end would still only be 72), compared with 0.63% of those at low genetic risk. Of those at high genetic risk plus an unhealthy lifestyle, 1.78% developed dementia compared to 0.56% of those at low risk with a healthy lifestyle. Among those who had a high genetic risk but a healthy lifestyle, 1.13% developed dementia in the period.
I trust that these people will continue to be followed — it will be very interesting to see the statistics in another 10 years.
There were 1,769 new cases of dementia during the 8-year study period.
 Lourida, I., Hannon E., Littlejohns T. J., Langa K. M., Hyppönen E., Kuźma E., et al.
(2019). Association of Lifestyle and Genetic Risk With Incidence of Dementia.
JAMA. 322(5), 430 - 437.
A very long-running study, in which 800 Swedish women (aged 38-54) were followed for 44 years, found that women with a high level of mental activities in midlife were 46% less likely to develop Alzheimer's disease and 34% less likely to develop dementia overall, compared with women with the low level of mental activities. Women who were physically active were 52% less likely to develop dementia with cerebrovascular disease and 56% less likely to develop mixed dementia, compared with women who were inactive.
Mental activities included intellectual activities, such as reading and writing; artistic activities, such as going to a concert or singing in a choir; manual activities, such as needlework or gardening; club activities; and religious activity.
Participants were given scores in each of the five areas based on how often they participated in mental activities, with a score of zero for no or low activity, one for moderate activity and two for high activity. For example, moderate artistic activity was defined as attending a concert, play or art exhibit during the last six months, while high artistic activity was defined as more frequent visits, playing an instrument, singing in a choir or painting. Low activity was defined as scores of zero to two and high activity as scores of three to 10 (44% and 56% of participants, respectively).
The physically active group ranged from light physical activity such as walking, gardening, bowling or biking for a minimum of four hours per week to regular intense exercise such as running or swimming several times a week or engaging in competitive sports. Most (82%) were in the active group.
Of the 438 women with the high level of mental activity, 104 (23.7%) developed dementia, compared to 90 (25.9%) of the 347 women with the low level of activity. Of the 648 women with the high level of physical activity, 159 (24.5%) developed dementia, compared to 35 (25.5%) of the 137 women who were inactive.
I note that distinction between those with high and low levels of activity seems very broad-brush. I don’t know why the researchers didn’t analyze the data in a more refined manner — comparing the most active with the least active would be more usual, and would be more likely to show a greater effect. But perhaps that's the point — showing that even with this smaller distinction, a significant effect is still found.
During the study, 194 women developed dementia. Of those, 102 had Alzheimer's disease, 27 had vascular dementia, 41 had mixed dementia, and 14 had other dementias. 81 (41.8%) of those with dementia also had cerebrovascular disease.
Full text available at https://n.neurology.org/content/early/2019/02/21/WNL.0000000000007021
 Najar, J., Östling S., Gudmundsson P., Sundh V., Johansson L., Kern S., et al.
(2019). Cognitive and physical activity and dementia.
Neurology. 92(12), e1322.
Various forms of dementia, including Alzheimer's, involve brain network problems. Brain regions are not coordinating as well as they should; white matter is dysfunctional, impairing communications. It has even been suggested that problems in the default mode network (the "resting state" of the brain) may be the ultimate driver of the pathological characteristics of Alzheimer's, such as amyloid plaques, tau tangles, and brain atrophy. Regardless of the order of events, it does seem that network dysfunction is one of the big problems in dementia.
It's with this in mind that a pilot study has investigated the benefits of a program designed to simultaneously recruit networks involved in cognition and motor action.
37 elderly people were divided into four groups based on their level of cognition: 12 with normal levels of cognitive performance; 8 with below-average cognition; 6 with mild-to-moderate impairment; 11 with severe cognitive impairment. They completed a 16-week cognitive-motor training program that consisted of weekly sessions involving playing a videogame that required goal-directed hand movements on a computer tablet. Specifically, players had to slice moving objects by sliding their finger through it. Each object sliced earned a point, and bonus points were awarded for slicing multiple objects in a single movement. Each session lasted 20-30 minutes.
Cognition was assessed using the Dementia Rating Scale and the Montreal Cognitive Assessment questionnaire. Cognitive-motor functioning was assessed using the Brain Dysfunction Indicator. Tests occurred 2 weeks prior to training and 2 weeks after.
Two groups showed significant improvement in their cognitive scores after training: the sub-average group, and those with mild-to-moderate impairment. While those who were severely impaired showed no improvement, neither did they decline over the period.
It’s suggested that the communication between frontal lobe and motor control areas is a crucial factor in the program’s success.
Full text available at https://www.karger.com/Article/FullText/490173
 de Boer, C., Echlin H. V., Rogojin A., Baltaretu B. R., & Sergio L. E.
(2018). Thinking-While-Moving Exercises May Improve Cognition in Elderly with Mild Cognitive Deficits: A Proof-of-Principle Study.
Dementia and Geriatric Cognitive Disorders Extra. 8, 248 - 258.
A French study involving 6,626 older adults (65+) found that having optimal levels in more measures of cardiovascular health (nonsmoking, weight, diet, physical activity, cholesterol, blood glucose and blood pressure) was associated with lower dementia risk and slower rates of cognitive decline. Dementia risk and rates of cognitive decline lowered with each additional metric at the recommended optimal level.
The measures come from an American Heart Association seven-item checklist aimed at preventing cardiovascular disease.
New findings from the large, long-running Whitehall II study revealed that 50-year-olds who had blood pressure that was higher than normal but still below the usual threshold for treating hypertension, were at increased risk of developing dementia in later life.
This increased risk was seen even when they didn’t have other heart or blood vessel-related problems.
The study involved 8,639 people, of whom 32.5% were women. Participants were aged between 35-55 in 1985, and had their blood pressure measured in 1985, 1991, 1997 and 2003. 385 (4.5%) developed dementia by 2017.
Those who had a systolic blood pressure of 130 mmHg or more at the age of 50 had a 45% greater risk of developing dementia than those with a lower systolic blood pressure at the same age. This association was not seen at the ages of 60 and 70, and diastolic blood pressure was not linked to dementia.
Preliminary results from the Systolic Blood Pressure Intervention Trial (SPRINT) has found that aggressive lowering of systolic blood pressure produced significant reductions in the risk of MCI, and MCI/dementia.
The randomized clinical trial compared an intensive strategy with a systolic blood pressure goal of less than 120 mm Hg and a standard care strategy targeting a systolic blood pressure goal of less than 140 mm Hg. The study involved 9,361 hypertensive older adults (mean age 67.9).
The intensive treatment group had a 19% lower rate of new cases of MCI, and the combined outcome of MCI plus probable all-cause dementia was 15% lower. Serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or acute renal failure occurred more frequently in the intensive-treatment group (4.7% vs 2.5%).
Participants were seen monthly for the first 3 months and every 3 months thereafter. Medications were adjusted on a monthly basis and lifestyle modification was encouraged. 30% of the participants were African American and 10% were Hispanic.
Preliminary results from 673 participants in the trial revealed that total white matter lesion (WML) volume increased in both treatment groups, but the increase was significantly less in the intensive treatment group. There was no significant difference in total brain volume change.
The findings were reported at the Alzheimer's Association International Conference (AAIC) 2018 in Chicago.
A long-running study involving 356 older adults (average age 78) found that those with high levels of arterial stiffness were 60% more likely to develop dementia during the next 15 years compared to those with lower levels.
Arterial stiffness is correlated with subclinical brain disease and cardiovascular risk factors, but adjusting for these factors didn't reduce the association between arterial stiffness and dementia — indicating that arterial stiffness and subclinical brain damage markers are independently related to dementia risk.
Arterial stiffening can be reduced by antihypertensive medication and perhaps also healthy lifestyle changes such as exercise. This study found that exercise at an average age of 73 was associated with lower arterial stiffness five years later.
A rat study found that hypertensive rats exhibited larger ventricles, decreased brain volume, and impaired fluid transport. It’s suggested that hypertension interferes with the clearance of macromolecules from the brain, such as amyloid-beta.
Samieri C, Perier M, Gaye B, et al. Association of Cardiovascular Health Level in Older Age With Cognitive Decline and Incident Dementia. JAMA. 2018;320(7):657–664. doi:10.1001/jama.2018.11499
Abell, J. et al. 2018. Association between systolic blood pressure and dementia in the Whitehall II cohort study: role of age, duration and threshold used to define hypertension. European Heart Journal. doi:10.1093/eurheartj/ehy288
 Cui, C., Sekikawa A., Kuller L. H., Lopez O. L., Newman A. B., Kuipers A. L., et al.
(2018). Aortic Stiffness is Associated with Increased Risk of Incident Dementia in Older Adults.
Journal of Alzheimer's Disease. 66(1), 297 - 306.
 Mortensen, K. Nygaard, Sanggaard S., Mestre H., Lee H., Kostrikov S., Xavier A. L. R., et al.
(2019). Impaired Glymphatic Transport in Spontaneously Hypertensive Rats.
Journal of Neuroscience. 39(32), 6365 - 6377.
Although first reported in 1816, the fact that the brain is surrounded by lymphatic vessels, which connect the brain and the immune system, was only rediscovered in 2015.
Lymphatic vessels are part of the body's circulatory system. In most of the body they run alongside blood vessels. They transport lymph, a colorless fluid containing immune cells and waste, to the lymph nodes. Blood vessels deliver white blood cells to an organ and the lymphatic system removes the cells and recirculates them through the body. The process helps the immune system detect whether an organ is under attack from bacteria or viruses or has been injured.
Since then, brain scans have indicated that our brains drain some waste out through lymphatic vessels, and could act as a pipeline between the brain and the immune system.
More recent research suggests the vessels are vital to the brain's ability to cleanse itself. When a compound was used to improve the flow of waste from the brain to the lymph nodes in the neck of aged mice, their ability to learn and remember improved dramatically.
Moreover, obstructing the vessels in mice worsened the accumulation of harmful amyloid plaques in the brain.
 Da Mesquita, S., Louveau A., Vaccari A., Smirnov I., R. Cornelison C., Kingsmore K. M., et al.
(2018). Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease.
Nature. 560(7717), 185 - 191.
Absinta, Ha et al. Human and nonhuman primate meninges harbor lymphatic vessels that can be visualized noninvasively by MRI, October 3, 2017, eLife: 10.7554/eLife.29738
A cell-culture study using rodent microglia found that some of the genes affected by alcohol and inflammation are also implicated in processes that clear amyloid beta, suggesting that alcohol may impede the clearance of amyloid beta in the brain.
In the study, rat microglial cells were exposed either to alcohol, pro-inflammatory chemicals called cytokines, or alcohol and cytokines, for 24 hours. Gene expression was altered for 312 genes under the alcohol condition; for 3,082 for the pro-inflammatory condition, and 3,552 for the alcohol and pro-inflammatory condition. Changes in gene expression ranged from a 50% decrease to a 72% increase. Many of the genes were involved in phagocytosis; just a handful of genes were involved in both phagocytosis and inflammation.
Data from the French National Hospital Discharge database, involving over a million people diagnosed with dementia between 2008 and 2013, found that 38% of the 57,000 cases of early-onset dementia were directly alcohol-related and 18% had an additional diagnosis of alcohol use disorders.
Overall, alcohol use disorders were associated with a three times greater risk of all types of dementia.
The study only looked at people admitted to hospital due to chronic heavy drinking, so it will understate the link between alcohol use and dementia risk.
Moreover, heavy drinkers who had given up alcohol for a time did not reduce their dementia risk (although they were less likely to die early).
 Kalinin, S., González-Prieto M., Scheiblich H., Lisi L., Kusumo H., Heneka M. T., et al.
(2018). Transcriptome analysis of alcohol-treated microglia reveals downregulation of beta amyloid phagocytosis.
Journal of Neuroinflammation. 15(1), 141.
 Schwarzinger, M., Pollock B. G., Hasan O. S. M., Dufouil C., Rehm J., Baillot S., et al.
(2018). Contribution of alcohol use disorders to the burden of dementia in France 2008–13: a nationwide retrospective cohort study.
The Lancet Public Health. 3(3), e124 - e132.
A diet containing compounds found in green tea and carrots reversed Alzheimer's-like symptoms in mice genetically programmed to develop the disease. The two compounds were EGCG (epigallocatechin-3-gallate), a key ingredient in green tea, and FA (ferulic acid), which is found in carrots, tomatoes, rice, wheat and oats.
After three months, the treatment completely restored working memory deficits seen in the Alzheimer's mice. The compounds appeared to help prevent amyloid precursor proteins from breaking up into amyloid beta, as well as reduce neuroinflammation and oxidative stress in the brain.
The amount of EGCG and FA was no more than could be gained from an appropriate diet.
 Mori, T., Koyama N., Tan J., Segawa T., Maeda M., & Town T.
(2019). Combined treatment with the phenolics (−)-epigallocatechin-3-gallate and ferulic acid improves cognition and reduces Alzheimer-like pathology in mice.
Journal of Biological Chemistry. 294(8), 2714 - 2731.
A long-running study involving 8225 adults found that self-reported diet during midlife (mean age 50) was not significantly associated with subsequent risk for dementia.
Dietary intake was assessed in 1991-1993, 1997-1999, and 2002-2004, with follow-up for incident dementia until March 31, 2017. Diet quality was assessed using the Alternate Healthy Eating Index (AHEI), an 11-component diet quality score (score range, 0-110), with higher scores indicating a healthier diet.
There were 344 cases of incident dementia developed in the study period. 69.1% of participants were male.
 Akbaraly, T. N., Singh-Manoux A., Dugravot A., Brunner E. J., Kivimäki M., & Sabia S.
(2019). Association of Midlife Diet With Subsequent Risk for Dementia.
JAMA. 321(10), 957 - 968.
Data from a large, long-running Finnish study, involving some 2,500 men aged 42-60, has found that dietary intake of phosphatidylcholine was associated with a reduced risk of dementia (the risk was 28% lower in men with the highest intake compared to the lowest). Men with the highest intake of dietary phosphatidylcholine also excelled in tests measuring their memory and linguistic abilities.
The key sources of phosphatidylcholine in the study population's diet were eggs (39%) and meat (37%).
Choline is necessary for the formation of the neurotransmitter acetylcholine. Earlier studies have linked choline intake with cognitive processing, and adequate choline intake may play a role in the prevention of cognitive decline and Alzheimer's disease.
There was no interaction with the APOE4 gene.
A study using genetically engineered mice found that when they were given high choline in their diet, their offspring showed improved in spatial memory.
Study of the hippocampus found the choline had reduced microglial activation, and thus brain inflammation, and reduced levels of homocysteine by converting it into the more helpful chemical methionine. These effects, achieved through gene modification, passed on to the next generation.
It has long been recognized that choline is particularly important in early brain development.
Ylilauri, Maija P.T. et al. 2019. Associations of dietary choline intake with risk of incident dementia and with cognitive performance: the Kuopio Ischaemic Heart Disease Risk Factor Study.American Journal of Clinical Nutrition, published online July 30, 2019, https://doi.org/10.1093/ajcn/nqz148
 Velazquez, R., Ferreira E., Winslow W., Dave N., Piras I. S., Naymik M., et al.
(2019). Maternal choline supplementation ameliorates Alzheimer’s disease pathology by reducing brain homocysteine levels across multiple generations.
Molecular Psychiatry. 1 - 10.
Elevated cholesterol levels have been linked to increased risk of Alzheimer's later in life, and APOE4 is known to raise levels of circulating cholesterol, particularly low-density lipoprotein (LDL) ("bad cholesterol"). A new study has investigated whether LDL is also linked to early-onset Alzheimer's.
The study involved genetically testing 2,125 people, 654 of whom had early-onset Alzheimer's, and testing for cholesterol in a subset of 267 participants. It found that APOE4 explained about 10% of early-onset Alzheimer's, which is similar to estimates in late-onset Alzheimer's disease. About 3% of early-onset Alzheimer's cases had at least one of the known early-onset Alzheimer's risk factors (APP, PSEN1, PSEN2).
Those with elevated LDL levels were more likely to have early-onset Alzheimer's disease, compared with patients with lower cholesterol levels. This was true even after the researchers controlled for APOE genotype.
There was no link between HDL (high-density lipoprotein) cholesterol levels and early-onset Alzheimer's, and only a very slight association between the disease and triglyceride levels.
The researchers also found a new possible genetic risk factor for early-onset Alzheimer's disease. Early-onset Alzheimer's cases were higher in participants with a rare variant of a gene called APOB. This gene encodes a protein that is involved in the metabolism of lipids, or fats, including cholesterol.
A long-running study found that women who had normal levels of the “good” cholesterol, HDL, in 1992 had less white matter damage in their brain two decades later.
The data come from 135 participants in the long-running Women's Healthy Ageing Project. The study found that a higher cardiovascular risk score in midlife was associated with a greater degree of white matter hyperintensity lesions 20 years later, but, intriguingly, that this was predominantly driven by HDL cholesterol level, after controlling for age, education, and APOEe4 status.
 Wingo, T. S., Cutler D. J., Wingo A. P., Le N-A., Rabinovici G. D., Miller B. L., et al.
(2019). Association of Early-Onset Alzheimer Disease With Elevated Low-Density Lipoprotein Cholesterol Levels and Rare Genetic Coding Variants of APOB.
JAMA Neurology. 76(7), 809 - 817.
 Aljondi, R., Szoeke C., Steward C., Gorelik A., & Desmond P.
(2018). The effect of midlife cardiovascular risk factors on white matter hyperintensity volume and cognition two decades later in normal ageing women.
Brain Imaging and Behavior.
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