Alzheimers

Alzheimer's & other dementias

Gender differences in Alzheimer's disease may be linked to tau spread

  • Brain scans suggest that tau proteins may spread more rapidly through women’s brains, increasing Alzheimer's risk and speeding its progression.

Accumulating evidence suggests that tau spreads through brain tissue like an infection, traveling from neuron to neuron and turning other proteins into abnormal tangles, subsequently killing brain cells.

A new study using brain scans of healthy individuals and patients with MCI has found that the architecture of tau networks is different in men and women, with women having a larger number of regions that connect various communities in the brain. This difference may allow tau to spread more easily between regions, boosting the speed at which it accumulates and putting women at greater risk for developing Alzheimer's disease.

https://www.eurekalert.org/pub_releases/2019-07/vumc-rap071619.php

https://www.theguardian.com/society/2019/jul/16/research-why-alzheimers-more-likely-women-than-men-tau-protein

Gender & APOE status affects tau accumulation

A study involving 131 cognitively healthy older adults (mean age 77) and 97 with MCI, found that women with MCI who were ApoE ε4 carriers were more susceptible than men to tau accumulation in the brain. However, no gender differences were found among the cognitively healthy adults.

https://www.eurekalert.org/pub_releases/2019-06/sonm-ads062419.php

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The findings of the first study were presented at the Alzheimer's Association International Conference July 14-18, 2019, in Los Angeles.

The second study was presented by Manish Paranjpe at the 2019 Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI), Abstract 253: "Sex Modulates the ApoE ε4 Effect on Tau 18F-AV-1451 PET Imaging in Individuals with Normal Aging and Mild Cognitive Impairment," Manish Paranjpe, Min Liu, Ishan Paranjpe, Rongfu Wang, Tammie Benzinger and Yun Zhou.

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Alzheimer's gene linked to worse cognition

  • Review found APOE4 carriers scored lower on IQ tests during childhood and adolescence.
  • A large internet-based study found that adults with a first-degree relative with Alzheimer's performed worse on a paired-learning task.

Alzheimer's gene affects IQ from childhood

Analysis of some old longitudinal studies has found that those carrying the APOE4 gene scored lower on IQ tests during childhood and adolescence. The effect was much stronger in girls than in boys, and affected reasoning most strongly.

IQ scores were lower by 1.91 points for each APOE4 allele carried. But boys scored only an average of 0.33 points lower, while girls scored almost 3 points lower for each APOE4 allele.

Almost all the participants (92%) were white.

https://www.eurekalert.org/pub_releases/2019-07/uoc--agm071819.php

Impaired learning linked to family history of Alzheimer's

A large internet-based study found that adults with a first-degree relative with Alzheimer's disease performed worse on a paired-learning task than adult without such a family history, and this impairment appears to be exacerbated by having diabetes or the APOE4 gene.

The online word-pair memory test (called MindCrowd) involved learning 12-word pairs and then completing the missing half of the pair when presented with one of the words. 59,571 individuals participated. Those with a family history of Alzheimer's were able to match about two and one-half fewer word pairs than individuals without a family history.

The family history effect was particularly pronounced among men, as well as those with lower educational attainment, diabetes, and carriers of APOE4.

The effect of family history was shown across every age group, up until age 65.

A subset of 742 participants who had a close relative with Alzheimer's were tested for the APOE gene.

https://www.eurekalert.org/pub_releases/2019-07/e-ill071019.php

Reference: 

Reynolds, C.A. et al. 2019. APOE effects on cogntion from childhood to adolescence. Neurobiology of Aging, Available online 18 April 2019.

[4418] Talboom, J. S., Håberg A., De Both M. D., Naymik M. A., Schrauwen I., Lewis C. R., et al.
(2019).  Family history of Alzheimer’s disease alters cognition and is modified by medical and genetic factors.
(Irish, M., & Franco E., Ed.).eLife. 8, e46179.

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Genes help explain why Alzheimer’s drugs have been so unsuccessful

  • A gene present in 75% of the human population may be a key reason why a class of drugs for Alzheimer’s disease seem promising in animal studies but fail in human studies.
  • Cell study finds APOE4 protein is slightly misshapen, causing it to break down into disease-causing fragments. But APOE4 doesn't affect amyloid-beta in mice.

Data from a ten-year study involving 345 Alzheimer's patients has found that cholinesterase inhibitors work better with those who don't have the gene CHRFAM7A. The gene is a fusion between a gene that codes for an Alpha 7 receptor for acetylcholine, and a kinase, a type of enzyme. It is not present in the animals genetically engineered to provide Alzheimer's models, but is present in 75% of humans.

Three of the four available Alzheimer’s drugs work by stimulating all receptors that respond to acetylcholine. More specific drugs for Alpha 7 have been in development for over 10 years but have yet to be successful.

The Alpha 7 receptor is one of the receptors binding amyloid beta.

More research is needed to confirm these preliminary findings.

https://www.eurekalert.org/pub_releases/2019-07/uab-sfc071719.php

https://www.futurity.org/alzheimers-disease-drugs-chrfam7a-2108902/

Scientists fix APOE4 gene in human brain cells

Research using human brain cells has found that the APOE4 protein is slightly misshapen and can’t function properly. It breaks down into disease-causing fragments, resulting in a number of problems, including the accumulation of the protein tau and of amyloid peptides.

The presence of APOE4 does not change the production of amyloid beta in mouse neurons, so this is a crucial species difference which shows why our animal models are of limited value.

Further research confirmed that it was specifically the presence of APOE4, and not the absence of the more common allele, APOE3, that promotes Alzheimer’s.

The human APOE4 neurons were treated with compounds developed to change the structure of the apoE4 protein so it resembles the APOE3 protein. This treatment eliminated the signs of Alzheimer's disease, restored normal function to the cells, and improved cell survival.

https://www.eurekalert.org/pub_releases/2018-04/gi-sfg040818.php

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The first study was presented at the annual Alzheimer's Association International Conference (AAIC) in Los Angeles, July 2019.

[4416] Wang, C., Najm R., Xu Q., Jeong D-eun., Walker D., Balestra M. E., et al.
(2018).  Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector.
Nature Medicine. 24(5), 647 - 657.

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Poor sleep drives Alzheimer’s progression

  • Getting a good night’s sleep is given greater importance with the discovery that sleep deprivation appears to rapidly increase the spread of tau tangles.

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/

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Exercise improves brain function in older adults with MCI

  • A short exercise program improved cognition and brain blood flow in older adults with mild cognitive impairment.

A small study has found that a 12-week exercise program significantly improved cognition in both older adults with MCI and those who were cognitively healthy, but that effect on blood flow in the brain was different in these two groups.

While the exercise increased cerebral blood flow in the frontal cortex of those in the healthy group, those with MCI experienced decreases in cerebral blood flow. It has been speculated that the brain responds to early difficulties by increasing cerebral blood flow. This suggests that exercise may have the potential to reduce this compensatory blood flow and improve cognitive efficiency in those who are in the very early stages of Alzheimer's Disease.

The exercise training program consisted of four 30-minute sessions of moderate-intensity treadmill walking per week.

Both working memory and verbal fluency were tested (using the Rey Auditory Verbal Learning Test, and the Controlled Oral Word Association Test).

Changes in cerebral blood flow were measured in specific brain regions that are known to be involved in the pathogenesis of Alzheimer's disease, including the insula, the anterior cingulate cortex, and the inferior frontal gyrus.

Among those with MCI, decreased blood flow in the left insula and anterior cingulate cortex was strongly associated with improved verbal fluency.

https://www.eurekalert.org/pub_releases/2019-01/uom-usf013119.php

Reference: 

Alfini, A. J. et al. 2019. Resting Cerebral Blood Flow After Exercise Training in Mild Cognitive Impairment. Journal of Alzheimer's Disease, 67 (2), 671-684.

 

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Gut microbiome a risk factor for dementia

  • Preliminary research suggests that microbes in the gut directly affects dementia risk.

A Japanese study looking at 128 patients' fecal samples, found that fecal concentrations of ammonia, indole, skatole and phenol were higher in dementia patients compared to those without dementia, while levels of beneficial Bacteroides were lower in dementia patients.

https://www.eurekalert.org/pub_releases/2019-01/aha-it012519.php

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The findings were presented at the American Stroke Association's annual conference.

 

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Intensive hypertension treatment reduces risk of cognitive impairment

  • A large clinical trial comparing the effects on cardiovascular disease of standard blood pressure control vs stricter control, has found that stricter control significantly reduced the risk of mild cognitive impairment.

A clinical trial involving 9361 older adults (50+) with hypertension but without diabetes or history of stroke has found that intensive control of blood pressure significantly reduced the risk of developing mild cognitive impairment.

While there was also a 15% reduction in dementia, this result did not reach statistical significance. This may have been due to the small number of new cases of dementia in the study groups.

Participants were randomly assigned to a systolic blood pressure goal of either less than 120 mm HG (intensive treatment) or less than 140 mm HG (standard treatment). They were then classified after five years as having no cognitive impairment, MCI or probable dementia.

The trial was stopped early due to its success in reducing cardiovascular disease. As a result, participants were on intensive blood pressure lowering treatment for a shorter period than originally planned. This impacted the number of cases of dementia occurring.

Hypertension affects more than half of Americans over age 50 and more than 75% of those older than 65.

https://www.eurekalert.org/pub_releases/2019-01/wfbm-lbp012419.php

Reference: 

The SPRINT MIND Investigators for the SPRINT Research Group. (2019). Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia: A Randomized Clinical Trial. JAMA, 321(6), 553–561.

 

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Psychological distress a risk factor for dementia

  • A large Danish study has found that the greater number of symptoms of distress in late midlife, the more likely the individual was to develop dementia later in life.

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

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Poor sleep in older adults may increase Alzheimer’s risk

  • Older people who spend less time in slow-wave sleep (deep sleep) have higher levels of the Alzheimer’s brain protein tau.

Poor sleep has been associated with Alzheimer's disease risk, but a new study suggests a specific aspect of sleep is important.

The study, involving 119 older adults (60+), of whom 80% were cognitively normal and the remainder very mildly impaired, found that decreased slow-wave sleep coincided with higher levels of tau in the brain and a higher tau-to-amyloid ratio in the cerebrospinal fluid.

Amyloid plaques and tau tangles develop for decades before cognitive symptoms of dementia emerge. Identifying the process at an early stage offers a possible window of opportunity for successful intervention.

Participants’ sleep at home was monitored over the course of a normal week, and participants also kept sleep logs of nighttime sleep and daytime napping. Thirty-eight people underwent PET brain scans for amyloid-beta and tau proteins, and 104 people underwent spinal taps to provide cerebrospinal fluid. Twenty-seven did both.

Those with increased tau pathology actually slept more, during both night and day, but their quality of sleep was poorer. In fact, daytime napping alone was significantly associated with high levels of tau, making it a useful indicator of risk.

https://www.futurity.org/alzheimers-disease-sleep-1954732/

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Cholesterol genes link risk of heart disease & Alzheimer’s

  • A very large genetic study provides evidence that cardiovascular disease risk and Alzheimer's risk are related because of one shared element: genes involved in cholesterol and lipid metabolism.

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

Reference: 

Broce I, Karch C, Desikan R, et al. Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease. Acta Neuropathologica, published online Nov. 9, 2018.

 

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