Poor sleep has been associated with the development of Alzheimer's disease, and this has been thought to be in part because the protein amyloid beta increases with sleep deprivation. A new study explains more.

Experiments with mice show that sleep deprivation also rapidly increases levels of the other key Alzheimer’s disease protein, tau tangles.

The work built on findings that tau is high in older people who sleep poorly, and that, when people are kept awake all night, their tau levels rise by about 50%.

When mice had tau proteins seeded in the hippocampus of their brains, those who were kept awake for long periods each day (mice are nocturnal), showed significantly greater spread of tau tangles than those mice allowed to sleep normally. Moreover, the new tangles appeared in the same areas of the brain affected in people with Alzheimer’s.

Disrupted sleep also increased release of synuclein protein, a hallmark of Parkinson’s disease. People with Parkinson’s—like those with Alzheimer’s—often have sleep problems.

All of this supports the idea that sleep directly protects against the development of Alzheimer's.

https://www.futurity.org/alzheimers-disease-sleep-tau-1966962/

Survey data from 6,807 Danish older adults (average age 60) in the Copenhagen City Heart Study, has found that being distressed in late midlife is associated with a higher risk of dementia in later life.

The survey measured “vital exhaustion”, which is operationalized as feelings of unusual fatigue, increased irritability and demoralization and can be considered an indicator of psychological distress. Vital exhaustion is suggested to be a response to unsolvable problems in individuals' lives, in particular when being incapable of adapting to prolonged exposure to stressors.

The study found a dose-response relation between symptoms of vital exhaustion reported in late midlife and the risk of dementia later in life:

• for every additional symptom, dementia incidence increased by 2%
• those reporting 5 to 9 symptoms had a 25% higher risk of dementia compared to those with no symptoms
• those reporting 10 to 17 symptoms (the maximum) had a 40% higher risk of dementia compared with not having symptoms.

Results were adjusted for gender, marital status, lower educational level, lifestyle factors and comorbidities.

https://www.eurekalert.org/pub_releases/2019-01/ip-pdi011719.php

Full paper available at: https://content.iospress.com/articles/journal-of-alzheimers-disease/jad180478

The APOE gene, the strongest genetic risk factor for Alzheimer’s disease, is known to be involved in cholesterol and lipid metabolism. Now the largest ever genetic study of Alzheimer’s disease, using DNA from more than 1.5 million people, has identified 90 points across the genome that were associated with an increased risk of both cardiovascular disease and Alzheimer’s disease.

The study focused on specific risk factors for heart disease (e.g., high BMI, type 2 diabetes, high cholesterol) to see if any were genetically related to Alzheimer’s risk. It was found that only those genes involved in lipid metabolism also related to Alzheimer's risk.

Six of the 90 regions had very strong effects on Alzheimer’s and heightened blood lipid levels, including several points within the CELF1/MTCH2/SPI1 region on chromosome 11 that was previously linked to the immune system.

The same genetic risk factors were also more common in people with a family history of Alzheimer’s, even though they had not themselves developed dementia or MCI.

The findings suggest that cardiovascular and Alzheimer's risk co-occur because of a shared genetic basis.

They also suggest a therapeutic target — namely, pathways involved in lipid metabolism.

https://www.futurity.org/alzheimers-disease-heart-disease-cholesterol-1913312-2/

https://www.eurekalert.org/pub_releases/2018-11/wuso-cda111118.php

A review of nearly 2.8 million patient cases in Denmark found that the risk of dementia in individuals with a history of TBI was 24% higher than those without a history of TBI, after accounting for other risk factors.

Risk was greater when the TBI was characterized as "severe" — 35% compared to an increased risk of 17% for a single "mild" TBI or concussion.

Moreover, dementia risk increased 33% higher for two or three TBIs, 61% higher for four TBIs, and 183% higher for five or more TBIs.

Additionally, the study found that if you have a brain injury in your 20s, the risk of developing dementia in your 50s increased by 60%.

The findings suggest that those with a history of TBI (particularly multiple injuries) should make an effort to reduce other risk factors, such as limiting alcohol and tobacco use, engaging in regular exercise, preventing obesity, and treating hypertension, diabetes, and depression.

Among the nearly 2.8 million people observed, 4.7% had at least one TBI diagnosis. Among first TBI diagnoses, 85% were characterized as mild.

Among men and women with TBI histories, men had slightly higher rate of developing dementia (30% vs. 19%).

Note that an earlier study (much smaller) found no evidence of a link between TBI and Alzheimer's.

This study involved 706 older adults from the National Alzheimer's Coordinating Center database, of whom 274 had Alzheimer’s. It found that there was no significant difference in the rate of cognitive decline between demographically and clinically similar participants with and without a history of TBI. This held regardless of APOE4 status.

However, researchers added the caveat that the findings should be interpreted cautiously due to the crude and limited assessment of TBI history available through the database.

https://www.eurekalert.org/pub_releases/2018-04/uowh-scl041018.php

https://www.eurekalert.org/pub_releases/2017-07/bumc-snl070517.php

Data from the Women's Health Initiative Memory Study, involving 6,467 postmenopausal women (65+) who reported some level of caffeine consumption, has found that those who consumed above average amounts of coffee had a lower risk of developing dementia.

Caffeine intake was estimated from a questionnaire. The median intake was 172 mg per day (an 8-ounce cup of brewed coffee contains 95mg of caffeine, 8-ounces of brewed black tea contains 47mg, so slightly less than 2 cups of coffee or less than 4 cups of tea). The women were cognitively assessed annually.

Over ten years, 388 were diagnosed with probable dementia (209) or MCI (179). Those who consumed above the median amount of caffeine had a 36% reduction in risk. The average intake in this group was 261 mg (3 cups of coffee), while the average intake for those below the median was 64 mg per day (less than one cup).

Risk factors such as hormone therapy, age, race, education, body mass index, sleep quality, depression, hypertension, prior cardiovascular disease, diabetes, smoking, and alcohol consumption, were taken into account.

The findings are consistent with other research finding a benefit for older women. It should not be assumed that the findings apply to men. It also appears that there may be a difference depending on education level. This sample had a high proportion of college-educated women.

It should also be noted that there was no clear dose-response effect — we could put more weight on the results if there was a clear relationship between amount of caffeine and benefit. Part of the problem here, however, is that it’s difficult to accurately assess the amount of caffeine, given that it’s based on self-report intake of coffee and tea, and the amount of caffeine in different beverages varies significantly.

Moreover, we do have a couple of mechanisms for caffeine to help fight age-related cognitive decline.

A recent study using rats modified to have impaired receptors for the adenosine A2A produced rats showing typical characteristics of an aging brain. In humans, too, age-related cognitive decline has been associated with over-activation of these receptors and dysfunction in glucocorticoid receptors.

The rat study shows that over-activation of the adenosine A2A receptors reduces the levels of glucocorticoid receptors in the hippocampus, which in turn impairs synaptic plasticity and cognition. In other words, it is the over-activation of the adenosine receptors that triggers a process that ends with cognitive impairment.

The point of all this is that caffeine inhibits the adenosine A2A receptors, and when the rats were given a caffeine analogue, their memory deficits returned to normal.

Another more recent study has found that caffeine increases the production of an enzyme that helps prevent tau tangles.

Building on previous research finding that an enzyme called NMNAT2 not only protects neurons from stress, but also helps prevent misfolded tau proteins (linked to Alzheimer’s, and other neurodegenerative disorders), the study identified 24 compounds (out of 1,280 tested) as having potential to increase the production of NMNAT2. One of the most effective of these was caffeine.

When caffeine was given to mice modified to produce lower levels of NMNAT2, the mice began to produce the same levels of the enzyme as normal mice.

https://www.eurekalert.org/pub_releases/2016-10/oupu-fwc100316.php

https://www.eurekalert.org/pub_releases/2016-08/ind-cai083016.php

https://www.eurekalert.org/pub_releases/2017-03/iu-cbe030717.php