Alzheimer's & other dementias
A mouse study has found that canola oil in the diet was associated with worsened memory, worsened learning ability, and weight gain in Alzheimer's mice.
Canola oil-treated animals also had greatly reduced levels of amyloid beta 1-40 (the “good” version), leading to more amyloid-beta plaques (made from amyloid beta 1-42), and a significant decrease in synapses.
The mice were given the equivalent of about two tablespoons of canola oil daily. The mice began their enriched diet at 6 months of age, before they developed any signs of Alzheimer's.
A previous study by the same researchers found that Alzheimer’s mice fed a diet enriched with extra-virgin olive oil had reduced levels of amyloid plaques and phosphorylated tau and experienced memory improvement.
Moreover, olive oil reduced inflammation in the brain, improved synaptic integrity, and dramatically increased levels of autophagy (the process by which waste products from cells are cleared away).
 Lauretti, E., & Praticò D.
(2017). Effect of canola oil consumption on memory, synapse and neuropathology in the triple transgenic mouse model of Alzheimer’s disease.
Scientific Reports. 7(1), 1 - 9.
 Lauretti, E., Iuliano L., & Praticò D.
(2017). Extra-virgin olive oil ameliorates cognition and neuropathology of the 3xTg mice: role of autophagy.
Annals of Clinical and Translational Neurology. 4(8), 564 - 574.
I rarely report on drugs, but because I do have a number of early reports on the four drugs approved for use with Alzheimer’s, I wanted to provide this update.
The four drugs are donepezil, rivastigmine, galantamine and memantine. This review is said to be the first to rank their comparative safety and effectiveness. It used evidence from 142 clinical trials published between 1996 and 2015. The number of patients in each study ranged from 13 to 2,045, and the review evaluated a total of 33,889 patients.
Donepezil was the most effective medication for Alzheimer's dementia across all effectiveness outcomes, including cognition, behavior and overall health, according to the study. It was also the only cognitive enhancer that produced effects that could be observed clinically, not merely statistically.
However, patients who took donepezil were more likely to experience side effects including nausea, vomiting and diarrhea than those who received a placebo.
Previous research found that these drugs don’t improve cognition or function in people with MCI, and these patients experience significantly more nausea, diarrhea, vomiting and headaches.
A small study found that combining a specific care management program with memantine multiplied the drug’s ability to improve daily function by about 7.5 times.
The Comprehensive, Individualized, Person-Centered Management program (CI-PCM) includes caregiver training, residence assessment, therapeutic home visits, and caregiver support groups.
In the 28-week, blinded, randomized controlled trial, 10 patient-caregiver groups enrolled in the CI-PCM were compared against 10 pairs receiving standard community care. All patients were taking memantine. Participants were assessed at the end of the trial using a recognized tool called Functional Assessment Staging (FAST), which measures losses in the ability of a person to independently carry out daily activities, such as dressing, bathing and toileting.
Caregiver training included "memory coaching" that teaches patients how to accomplish skills they lost.
The findings were presented July 16 at the Alzheimer's Association International Conference 2017 in London.
Tricco, A. C., Ashoor, H. M., Soobiah, C., Rios, P., Veroniki, A. A., Hamid, J. S., … Straus, S. E. (2018). Comparative Effectiveness and Safety of Cognitive Enhancers for Treating Alzheimer’s Disease: Systematic Review and Network Metaanalysis. Journal of the American Geriatrics Society, 66(1), 170–178. https://doi.org/10.1111/jgs.15069
A study involving 2,000 healthy older adults (average age 78) found that mentally stimulating activities were linked to a lower risk or delay of MCI, and that the timing and number of these activities may also play a role.
During the study, 532 participants developed MCI.
Using a computer in middle-age (50-65) was associated with a 48% lower risk of MCI, while using a computer in later life was associated with a 30% lower risk, and using a computer in both middle-age and later life was associated with a 37% lower risk.
Engaging in social activities, like going to movies or going out with friends, or playing games, like doing crosswords or playing cards, in both middle-age and later life were associated with a 20% lower risk of developing MCI.
Craft activities were associated with a 42% lower risk, but only in later life.
Those who engaged in two activities were 28% less likely to develop MCI than those who took part in no activities, while those who took part in three activities were 45% less likely, those with four activities 56% percent less likely and those with five activities were 43% less likely.
It should be noted that activities in middle-age were assessed by participants’ memory many years later.
Data from the PROTECT online platform, involving 19,000 healthy older adults (50-96), found that the more regularly older adults played puzzles such as crosswords and Sudoku, the better they performed on tasks assessing attention, reasoning and memory.
In some areas the improvement was quite dramatic, for example, on measures of problem-solving, people who regularly do these puzzles performed equivalent to an average of eight years younger compared to those who don't.
A meta-analysis of 32 randomized controlled trials with 3,624 older adults with or without cognitive impairment has concluded that mind-body exercises, especially tai chi and dance mind-body exercise, help improve global cognition, cognitive flexibility, working memory, verbal fluency, and learning in older adults.
Krell-Roesch, J., Syrjanen, J. A., Vassilaki, M., Machulda, M. M., Mielke, M. M., Knopman, D. S., … Geda, Y. E. (2019). Quantity and quality of mental activities and the risk of incident mild cognitive impairment. Neurology, 93(6), e548. https://doi.org/10.1212/WNL.0000000000007897
Brooker, H., Wesnes, K. A., Ballard, C., Hampshire, A., Aarsland, D., Khan, Z., … Corbett, A. (2019). The relationship between the frequency of number-puzzle use and baseline cognitive function in a large online sample of adults aged 50 and over. International Journal of Geriatric Psychiatry, 34(7), 932–940. https://doi.org/10.1002/gps.5085
Brooker, H., Wesnes, K. A., Ballard, C., Hampshire, A., Aarsland, D., Khan, Z., … Corbett, A. (2019). An online investigation of the relationship between the frequency of word puzzle use and cognitive function in a large sample of older adults. International Journal of Geriatric Psychiatry, 34(7), 921–931. https://doi.org/10.1002/gps.5033
Wu, C., Yi, Q., Zheng, X., Cui, S., Chen, B., Lu, L., & Tang, C. (2019). Effects of Mind-Body Exercises on Cognitive Function in Older Adults: A Meta-Analysis. Journal of the American Geriatrics Society, 67(4), 749–758. https://doi.org/10.1111/jgs.15714
Data from the large, long-running U.S. Health and Retirement Study found that healthy cognition characterized most of the people with at least a college education into their late 80s, while those who didn’t complete high school had good cognition up until their 70s.
The study found that those who had at least a college education lived a much shorter time with dementia than those with less than a high school education: an average of 10 months for men and 19 months for women, compared to 2.57 years (men) and 4.12 years (women).
The data suggests that those who graduated high school can expect to live (on average) at least 70% of their remaining life after 65 with good cogntion, compared to more than 80% for those with a college education, and less than 50% for those who didn't finish high school.
The analysis was based on a sample of 10,374 older adults (65+; average age 74) in 2000 and 9,995 in 2010.
https://academic.oup.com/psychsocgerontology/article/73/suppl_1/S20/4971564 (open access)
Data from around 196,000 subscribers to Lumosity online brain-training games found that higher levels of education were strong predictors of better cognitive performance across the 15- to 60-year-old age range of their study participants, and appear to boost performance more in areas such as reasoning than in terms of processing speed.
Differences in performance were small for test subjects with a bachelor's degree compared to those with a high school diploma, and moderate for those with doctorates compared to those with only some high school education.
But people from lower educational backgrounds learned novel tasks nearly as well as those from higher ones.
Data from more than 1,000 men participating in the Vietnam Era Twin Study of Aging revealed that their cognitive ability at age 20 was a stronger predictor of cognitive function later in life than other factors, such as higher education, occupational complexity or engaging in late-life intellectual activities.
All of the men, now in their mid-50s to mid-60s, took the Armed Forces Qualification Test at an average age of 20. The same test of general cognitive ability (GCA) was given in late midlife, plus assessments in seven cognitive domains.
GCA at age 20 accounted for 40% of the variance in the same measure at age 62, and approximately 10% of the variance in each of the seven cognitive domains. Lifetime education, complexity of job and engagement in intellectual activities each accounted for less than 1% of variance at average age 62.
The findings suggest that the impact of education, occupational complexity and engagement in cognitive activities on later life cognitive function simply reflects earlier cognitive ability.
The researchers speculated that the role of education in increasing GCA takes place primarily during childhood and adolescence when there is still substantial brain development.
 Crimmins, E. M., Saito Y., Kim J. Ki, Zhang Y. S., Sasson I., & Hayward M. D.
(2018). Educational Differences in the Prevalence of Dementia and Life Expectancy with Dementia: Changes from 2000 to 2010.
The Journals of Gerontology: Series B. 73(suppl_1), S20 - S28.
Guerra-Carrillo, B., Katovich, K., & Bunge, S. A. (2017). Does higher education hone cognitive functioning and learning efficacy? Findings from a large and diverse sample. PLOS ONE, 12(8), e0182276. https://doi.org/10.1371/journal.pone.0182276
 Kremen, W. S., Beck A., Elman J. A., Gustavson D. E., Reynolds C. A., Tu X. M., et al.
(2019). Influence of young adult cognitive ability and additional education on later-life cognition.
Proceedings of the National Academy of Sciences. 116(6), 2021.
Data from the Whitehall II study, tracking 10,228 participants for 30 years, found that increased social contact at age 60 is associated with a significantly lower risk of developing dementia later in life. Someone who saw friends almost daily at age 60 was 12% less likely to develop dementia than someone who only saw one or two friends every few months.
While previous studies have found a link between social contact and dementia risk, the long follow-up in the present study strengthens the evidence that social engagement could protect people from dementia (rather than precursors of dementia bringing about a decline in social engagement).
A three-year study of 217 healthy older adults (63-89) enrolled in the Harvard Aging Brain Study, has found that higher amyloid-beta levels in combination with lower social engagement was associated with greater cognitive decline over three years. Lower social engagement wasn’t associated with cognitive decline in those with a lower amyloid-beta burden.
Sommerlad, A., Sabia, S., Singh-Manoux, A., Lewis, G., & Livingston, G. (2019). Association of social contact with dementia and cognition: 28-year follow-up of the Whitehall II cohort study. PLOS Medicine, 16(8), e1002862. https://doi.org/10.1371/journal.pmed.1002862
Biddle, K et al, "Social Engagement and Amyloid-b-Related Cognitive Decline in Cognitively Normal Older Adults." American Journal of Geriatric Psychiatry. DOI: https://doi.org/10.1016/j.jagp.2019.05.005
A study involving 95 healthy older adults found that adults reporting a decline in sleep quality in their 40s and 50s had more amyloid-beta in their brains later in life, while those reporting poorer sleep in their 50s and 60s had more tau tangles. Those with high levels of tau protein were more likely to lack the synchronized brain waves during deep NREM sleep that are associated with a good night's sleep, and the more tau protein, the less synchronized these brain waves were.
Previous research has found that a dip in the amplitude of slow wave activity during deep NREM sleep was associated with higher amounts of beta-amyloid in the brain and memory impairment.
Studies of healthy animals and humans have reported higher levels of amyloid beta after a single night of sleep deprivation, and that disruption of slow-wave sleep causes amyloid beta levels to rise as much as 30%. Moreover, a single night’s sleep deprivation has been found to increase tau levels by as much as 50% in cerebrospinal fluid.
These findings suggest that quality sleep helps the body clear excess amyloid and tau proteins.
A preliminary study involving 20 healthy subjects aged 22 to 72 found beta-amyloid increases of about 5% after losing a night of sleep.
Many researchers believe the link between sleep disorders and Alzheimer's risk is "bidirectional," since elevated beta-amyloid may also lead to sleep disturbances.
A very small study involving eight people aged 30-60, who experienced (over time) two or three different sleep situations, found that amyloid beta levels were 25-30% higher when individuals had a a sleepless night — putting those amyloid beta levels on par with the levels seen in people genetically predisposed to develop Alzheimer’s at a young age.
A sleep study involving 17 healthy adults aged 35 to 65, found that those whose slow-wave sleep was disrupted (by a beeping sound that moved them into a shallower sleep) found a 10% increase in amyloid beta levels after a single night of interrupted sleep, but no corresponding increase in tau levels. However, participants whose activity monitors showed they had slept poorly at home for the week before showed a spike in levels of tau.
Data from 2,457 older adults (65+) in the Framingham study found that those who consistently slept more than nine hours every night had twice the risk of developing dementia and Alzheimer’s disease within the next 10 years, compared to those who slept less than nine hours a night.
Over the 10-year study period, 234 were diagnosed with dementia.
It’s suggested that one reason might be that those with depression tend to sleep longer. In any case, it’s thought that the longer sleep sessions reflect something else going on, rather than being a cause.
Education level also affected the degree of risk. Those without a high school degree who slept more than nine hours nightly had a 600% greater risk of later receiving a dementia diagnosis than people with a high school degree.
A ten-year Japanese study involving 1,517 older adults (60+) found that dementia rates were higher in those with daily sleep duration of less than 5 hours or more than 10 hours, compared with those with daily sleep duration of 5-6.9 hours. However, those with short sleep duration who had high physical activity did not have a greater risk of dementia.
294 participants (19%) developed dementia in the 10 year period.
A study involving 321 older adults (60+; average age 67), who participated in a sleep study between 1995 and 1998, found poorer REM sleep was associated with an increased risk of developing dementia over 12 years.
During that period, 32 people were diagnosed with some form of dementia (24 with Alzheimer’s)
Those who developed dementia spent an average of 17% of their sleep time in REM sleep, compared with 20% for those who didn’t develop dementia. For every percent that REM sleep was reduced, there was a 9% increase in dementia risk, and an 8% increase in Alzheimer’s risk specifically.
No such associations were found for other stages of sleep, although that shouldn’t be taken to mean that other sleep stages don’t affect key features of Alzheimer’s.
A study involving 288 cognitively healthy older adults (65+) found that those who had sleep apneas had on average 4.5% higher levels of tau in the entorhinal cortex than those who did not have apneas, after controlling for several other factors that could affect levels of tau in the brain, such as age, sex, education, cardiovascular risk factors and other sleep complaints.
15% (43 participants) were reported by their bed partners as having sleep apneas.
This preliminary study was presented at the American Academy of Neurology's 71st Annual Meeting in Philadelphia, May 4-10, 2019.
Data from 1,752 older adults found that sleep-disordered breathing was associated with poorer attention and processing speed. In particular, increased overnight hypoxemia (oxygen saturation below 90%) was linked with poorer attention and memory, and more daytime sleepiness associated with poorer attention and memory and slower cognitive processing speed.
These associations were strongest in APOE-ε4 carriers.
 Winer, J. R., Mander B. A., Helfrich R. F., Maass A., Harrison T. M., Baker S. L., et al.
(2019). Sleep as a Potential Biomarker of Tau and β-Amyloid Burden in the Human Brain.
Journal of Neuroscience. 39(32), 6315 - 6324.
 Ning, S., & Jorfi M.
(2019). Beyond the sleep-amyloid interactions in Alzheimer’s disease pathogenesis.
Journal of Neurophysiology. 122(1), 1 - 4.
 Shokri-Kojori, E., Wang G-J., Wiers C. E., Demiral S. B., Guo M., Kim S. Won, et al.
(2018). β-Amyloid accumulation in the human brain after one night of sleep deprivation.
Proceedings of the National Academy of Sciences. 115(17), 4483 - 4488.
 Lucey, B. P., Hicks T. J., McLeland J. S., Toedebusch C. D., Boyd J., Elbert D. L., et al.
(2018). Effect of sleep on overnight cerebrospinal fluid amyloid β kinetics.
Annals of Neurology. 83(1), 197 - 204.
 Ju, Y-E. S., Ooms S. J., Sutphen C., Macauley S. L., Zangrilli M. A., Jerome G., et al.
(2017). Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels.
Brain. 140(8), 2104 - 2111.
 Westwood, A. J., Beiser A., Jain N., Himali J. J., DeCarli C., Auerbach S. H., et al.
(2017). Prolonged sleep duration as a marker of early neurodegeneration predicting incident dementia.
Neurology. 88(12), 1172.
 Ohara, T., Honda T., Hata J., Yoshida D., Mukai N., Hirakawa Y., et al.
(2018). Association Between Daily Sleep Duration and Risk of Dementia and Mortality in a Japanese Community.
Journal of the American Geriatrics Society. 66(10), 1911 - 1918.
 Pase, M. P., Himali J. J., Grima N. A., Beiser A. S., Satizabal C. L., Aparicio H. J., et al.
(2017). Sleep architecture and the risk of incident dementia in the community.
Neurology. 89(12), 1244.
 Johnson, D. A., Lane J., Wang R., Reid M., Djonlagic I., Fitzpatrick A. L., et al.
(2017). Greater Cognitive Deficits with Sleep-disordered Breathing among Individuals with Genetic Susceptibility to Alzheimer Disease. The Multi-Ethnic Study of Atherosclerosis.
Annals of the American Thoracic Society. 14(11), 1697 - 1705.
A 10-year South Korean study using data from 262,349 older adults (50+) has found that those with chronic periodontitis had a 6% higher risk for dementia than did people without periodontitis. This connection was true despite behaviors such as smoking, consuming alcohol, and remaining physically active.
Gum disease has been linked to Alzheimer's as a risk factor, and now an animal study provides evidence that Porphyromonas gingivalis (Pg), the bacterium associated with chronic gum disease, colonizes the brain and increases production of amyloid beta.
Moreover, the bacterium's toxic enzymes (gingipains) have been found in the neurons of patients with Alzheimer’s. Gingipain levels were associated with two markers: tau, and ubiquitin (a protein tag that marks damaged proteins).
When molecule therapies targeting Pg gingipains were applied, there was reduced bacterial load of an established Pg brain infection, blocked amyloid-beta production, reduced neuroinflammation and protected neurons in the hippocampus.
Around half the population are said to have this bacteria in some form, and around 10% of those with the bacteria will develop serious gum disease, loose teeth, and have an increased risk of developing Alzheimer´s disease.
A mouse study found that long-term exposure to periodontal disease bacteria resulted in significantly higher amounts of amyloid beta plaque, more brain inflammation and fewer intact neurons. It’s important to note that the mice used in the study were not genetically engineered to develop Alzheimer's.
 Choi, S., Kim K., Chang J., Kim S. Min, Kim S. Jip, Cho H-J., et al.
(2019). Association of Chronic Periodontitis on Alzheimer's Disease or Vascular Dementia.
Journal of the American Geriatrics Society. 67(6), 1234 - 1239.
 Dominy, S. S., Lynch C., Ermini F., Benedyk M., Marczyk A., Konradi A., et al.
(2019). Porphyromonas gingivalis in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors.
Science Advances. 5(1), eaau3333.
 Ilievski, V., Zuchowska P. K., Green S. J., Toth P. T., Ragozzino M. E., Le K., et al.
(2018). Chronic oral application of a periodontal pathogen results in brain inflammation, neurodegeneration and amyloid beta production in wild type mice.
PLOS ONE. 13(10), e0204941.
Brain scans from over 4,000 people, across the age range (9 months to 94 years) and including 1,385 Alzheimer's patients, has revealed an early divergence between those who go on to develop Alzheimer’s and those who age normally. This divergence is seen in early atrophy of the hippocampus before age 40, and in the amygdala around age 40.
 Coupé, P., Manjón J. Vicente, Lanuza E., & Catheline G.
(2019). Lifespan Changes of the Human Brain In Alzheimer’s Disease.
Scientific Reports. 9(1), 1 - 12.
A fruitfly study suggests that losing neurons is not necessarily a bad thing. The study used fruitflies genetically engineered to express human amyloid-beta proteins in their brains. When neuronal death was blocked, the flies developed even worse memory problems, worse motor coordination problems, died earlier and their brain degenerated faster. However, when the normal process of cell competition was enhanced, the flies showed an impressive recovery.
Cell competition is a cell quality control mechanism, by which fitter cells trigger the suicide of less fit ones. Research has shown that cell competition is a normal, powerful anti-aging mechanism.
The findings suggest that neuron loss reflects the brain protecting itself from defective neurons, not something that should be prevented. (What we want, of course, is for the neurons not to be damaged.)
 Coelho, D. S., Schwartz S., Merino M. M., Hauert B., Topfel B., Tieche C., et al.
(2018). Culling Less Fit Neurons Protects against Amyloid-β-Induced Brain Damage and Cognitive and Motor Decline.
Cell Reports. 25(13), 3661 - 3673.e3.
A specially designed mobile phone game called Sea Hero Quest has found that gaming data can distinguish between those people who are genetically at risk of developing Alzheimer's disease ond those who are not. The game is designed to test spatial navigation skills — one of the first cognitive areas affected in Alzheimer's.
A standard memory and thinking test could not distinguish between the risk and non-risk groups.
Gaming data was taken from 27,108 UK players aged 50-75. This benchmark data was then compared with 60 people who had been genetically tested, of whom about half carried the APOE4 gene. The gene tested individuals were matched for age, gender, education and nationality with the benchmark cohort.
Previous findings from Sea Hero Quest data have shown that people in different countries and populations navigate differently, but this study shows that APOE4 carriers took less efficient (i.e., longer) routes to checkpoint goals. The difference in performance between carriers and non-carriers was particularly pronounced where the space to navigate was large and open.
Preliminary findings from a long-term UK study indicate that middle-aged adults (41-59) with close relatives with Alzheimer's did worse on a test that measured their ability to visualise their position. They also tended to have a small hippocampus.
The Four Mountains test involves showing people a picture of a mountain and asking them to identify it in a selection of four other landscapes.
A study involving 71 older adults found that increasing difficulties with building cognitive maps of new surroundings was associated with the development of Alzheimer's biomarkers. Difficulties in learning a new route were not evident at this stage, but appeared later, among those with early Alzheimer's.
The computer task involved navigating a virtual maze consisting of a series of interconnected hallways with four wallpaper patterns and 20 landmarks. Participants were tested on two navigation skills: how well they could learn and follow a pre-set route, and how well they could form and use a cognitive map of the environment. Participants were given 20 minutes to either learn a specified route, or to study and explore the maze with a navigation joystick. They were then tested on their ability to recreate the route or find their way to specific landmarks in the environment.
Humans generally find their way using two distinct forms of spatial representation and navigation: egocentric navigation, in which people rely on past knowledge to follow well-worn routes, moving from one landmark to another, and allocentric navigation, in which people become familiar with their big picture surroundings and create a mental map of existing landmarks, allowing them to plot best available routes and find shortcuts to new destinations. Allocentric navigation relies on the hippocampus, while egocentric navigation is more closely associated with a brain region called the caudate.
Those with cerebrospinal markers for Alzheimer’s but no symptoms, had significant difficulties only when they had to form a cognitive map (that is, with hippocampal allocentric navigation processes). However, additional training did enable them to eventually learn the cognitive map.
The researchers suggest that preclinical Alzheimer’s disease is characterized by hippocampal atrophy and associated cognitive mapping difficulties, and then, (if) the disease progresses, cognitive mapping deficits worsen, the caudate becomes involved, leading to route learning deficits.
Participants included 42 who were cognitively healthy and had no cerebrospinal fluid markers for Alzheimer’s, 13 cognitively normal individuals who had the biomarkers, and 16 with early Alzheimer’s.
 Coughlan, G., Coutrot A., Khondoker M., Minihane A-M., Spiers H., & Hornberger M.
(2019). Toward personalized cognitive diagnostics of at-genetic-risk Alzheimer’s disease.
Proceedings of the National Academy of Sciences. 116(19), 9285 - 9292.
 Ritchie, K., Carrière I., Su L., O'Brien J. T., Lovestone S., Wells K., et al.
(2017). The midlife cognitive profiles of adults at high risk of late-onset Alzheimer's disease: The PREVENT study.
Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 13(10), 1089 - 1097.
 Allison, S. L., Fagan A. M., Morris J. C., & Head D.
(2016). Spatial Navigation in Preclinical Alzheimer’s Disease.
Journal of Alzheimer's Disease. 52(1), 77 - 90.
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