Alzheimers

Alzheimer's & other dementias

Brain changes linked with Alzheimer's years before symptoms appear

  • A long-running study found subtle cognitive deficits evident 11-15 years before clear impairment, as were changes in tau protein.

A very long-running study involving 290 people at risk of Alzheimer's has found that, in those 81 people who developed MCI or dementia, subtle changes in cognitive test scores were evident 11 to 15 years before the onset of clear cognitive impairment. They also showed increases in the rate of change of tau protein in cerebrospinal fluid an average of 34.4 years (for t-tau, or total Tau) and 13 years (for a modified version called p-tau) before the beginning of cognitive impairment.

https://www.eurekalert.org/pub_releases/2019-05/jhm-bcl051419.php

Reference: 

Topics: 

tags problems: 

Difficulties identifying odors early sign of dementia

  • A large study found that most of those who were very poor at identifying common odors developed dementia within 5 years.
  • A study of older adults with a parent who had Alzheimer's found that those who were poorest at identifying odors showed the most Alzheimer's biomarkers.
  • A largish study found that poorer odor identification in older adults (average age 80) )was associated with a transition to dementia and with cognitive decline.
  • An animal study found olfactory dysfunction precedes cognitive problems, and relates amyloid-beta protein in the olfactory epithelium.
  • A large 13-year study found that a poor sense of smell was linked to a greater risk of death within 10 years, and of death from dementia and Parkinson’s disease in particular.

A long-term study of nearly 3,000 older adults (57-85) has found that those who couldn’t identify at least four out of five common odors were more than twice as likely as those with a normal sense of smell to develop dementia within five years.

Of the participants, some 14% could name just three out of five, 5% could identify only two scents, 2% just one, and 1% couldn’t identify a single smell.

Five years after the smell test, almost all of the study subjects who were unable to name a single scent had been diagnosed with dementia, and nearly 80% of those who provided only one or two correct answers.

The test involved a well-validated tool known as "Sniffin'Sticks." The five odors, in order of increasing difficulty, are peppermint, fish, orange, rose and leather.

https://www.eurekalert.org/pub_releases/2017-09/uocm-ewh092617.php

A study involving nearly 300 older adults (average age 63) who had a parent with Alzheimer’s has found that those with the most difficulty in identifying odors were those in whom Alzheimer's biomarkers were most evident.

Sense of smell was assessed using multiple choice scratch-and-sniff tests to identify scents as varied as bubble gum, gasoline or the smell of a lemon. A hundred of the participants had regular lumbar punctures to measure the Alzheimer's biomarkers in the cerebrospinal fluid.

https://www.eurekalert.org/pub_releases/2017-08/mu-col081617.php

A seven-year study involving a multi-ethnic (34% White, 30% African-American, 36% Hispanic) sample of 757 healthy older adults (average age 80.7) found that lower odor identification scores on UPSIT were significantly associated with both the transition to dementia and cognitive decline.

For each point lower that a person scored on the UPSIT, the risk of Alzheimer's increased by about 10%.

The report was reported at the Alzheimer's Association International Conference® 2014 in Copenhagen

http://www.eurekalert.org/pub_releases/2014-07/aa-sae071114.php

Loss of smell sense linked to amyloid-beta protein

An animal study has shown that olfactory dysfunction occurs much earlier than cognitive dysfunction, and that this is related to the amyloid-beta protein. Although it’s been thought that this protein is expressed only in the central nervous system, the study detected direct expression of the protein in the olfactory epithelium, part of the peripheral nervous system. Moreover, the amyloid-beta protein had a fatal effect on olfactory nerve cells in the olfactory epithelium and directly induced the failure of olfactory function.

A less alarming explanation for why our sense of smell tends to decline in old age comes from a mouse study that found that fewer stem cells become olfactory cells in old age as they tend to remain in the stem cell pool and become less active.

https://www.eurekalert.org/pub_releases/2017-09/dgi-oun092517.php

https://www.eurekalert.org/pub_releases/2018-12/hzm--bc-121918.php

Poor sense of smell linked to greater mortality risk

Following on from a previous study in which more than 2,200 older adults (71-82) undertook smell identification tests, investigation 13 years later found that a poor sense of smell was linked to a 46% greater risk of dying within 10 years compared with those ranked as having a good sense of smell. Poor sense of smell was particularly linked to death from dementia and Parkinson’s disease, with some signs that poor smell might also be linked to death from cardiovascular disease. There was no link between poor sense of smell and death from cancer or respiratory diseases. 22% of the overall increased risk of death among those with a poorer sense of smell was down to neurodegenerative diseases.

The link was only present among those who were in very good health at the start of the study.

https://www.theguardian.com/science/2019/apr/29/routine-sense-of-smell-tests-could-be-used-to-spot-signs-of-dementia

Reference: 

Source: 

Topics: 

tags memworks: 

tags problems: 

Blood-clotting protein implicated in cognitive decline and Alzheimer's

  • A blood-clotting protein called fibrinogen has been shown to provoke the brain's immune cells into destroying synapses. The process begins with fibrinogen leaking from the blood into the brain.
  • Another study has found that nearly half of all dementias begin with a breakdown of the gatekeeper cells (pericytes) that help keep fibrinogen out of the brain.

Alzheimer's disease is associated with abnormalities in the vast network of blood vessels in the brain, but it hasn’t been known how this affects cognition. A study has now shown that a blood-clotting protein called fibrinogen plays a part.

The study found that fibrinogen, after leaking from the blood into the brain, activates the brain's immune cells and triggers them to destroy synapses, which are critical for neuronal communication.

Loss of synapses is known to cause memory loss, and the study found that preventing fibrinogen from activating the brain's immune cells protected Alzheimer's mice from memory loss.

Moreover, fibrinogen had this effect even in brains that lack amyloid plaques.

The findings help explain how elderly people with vascular pathology could show similar rates of cognitive decline as age-matched people with amyloid pathology. The same human studies also found that those with both types of pathology had much worse and more rapid cognitive decline.

Another study suggests that nearly half of all dementias, including Alzheimer's, begins with the breakdown of the smallest blood vessels in the brain and the "gatekeeper cells" that surround and protect the capilleries.

The collapse of pericytes (the gatekeeper cells) reduces myelin and white matter structure in the brain. They do this via fibrinogen. Fibrinogen develops blood clots so wounds can heal but when the gatekeeper cells fail, too much fibrinogen enters the brain and causes white matter to die.

Mouse studies showed that controlling fibrinogen levels can reverse or slow white matter disease.

Postmortem study of human brains found that Alzheimer’s brains had about 50% fewer gatekeeper cells and three times more fibrinogen proteins in watershed white matter areas, compared to healthy brains.

The mouse study found that white matter changes in mice began as early as 12 to 16 weeks old, the equivalent of 40 years in humans.

When an enzyme known to reduce fibrinogen was introduced into the mice, white matter volume returned to 90% of their normal state, and white matter connections were back to 80% productivity.

https://www.eurekalert.org/pub_releases/2019-02/gi-anc020519.php

https://www.eurekalert.org/pub_releases/2018-02/uosc-hoa020218.php

Reference: 

Source: 

Topics: 

tags problems: 

Brain blood flow deficits in Alzheimer's explained

  • Blood flow deficits in the brain, seen early on in Alzheimer's, have now been linked to some capilleries being block by white blood cells.

It’s been known that decreased blood flow in the brain occurs in people with Alzheimer's, and recent studies suggest that brain blood flow deficits are one of the earliest detectable symptoms of dementia. A study has now shown why it occurs: a small percentage of capillaries, the smallest blood vessels in the brain, are blocked by white blood cells stuck to the inside of the capillaries.

Recent research has shown that capilleries are vital for monitoring and directing blood flow around the brain.

https://www.eurekalert.org/pub_releases/2019-02/cu-rct021119.php

https://www.nature.com/articles/s41593-018-0329-4

Reference: 

Topics: 

tags problems: 

New mechanism adds to understanding of Alzheimer's causes

  • Age-related changes in gene enhancers have been linked to faster cognitive decline in Alzheimer's brains.

New findings identify a mechanism that accelerates aging in the brain and gives rise to Alzheimer's disease.

The findings center on “enhancers”, which turn the activity of genes up or down based on influences like aging and environmental factors. Comparing enhancers in brain cells of people at varying stages of Alzheimer's and healthy people has revealed that in normal aging, there is a progressive loss of important epigenetic marks on enhancers. This loss is accelerated in the brains of people with Alzheimer's.

These enhancers also over-activate a suite of genes involved in Alzheimer's pathology, spurring the formation of plaques and tangles, and reactivating the cell cycle in fully formed cells — a highly toxic combination.

The study also links enhancer changes to the rate of cognitive decline in Alzheimer's patients.

https://www.eurekalert.org/pub_releases/2019-05/vari-rtc051719.php

Reference: 

Source: 

Topics: 

tags problems: 

Impaired waste management in the brain a cause of Alzheimer's?

  • A mouse study has shown that, as cells age, their ability to remove damaged proteins and structures (autophagy) declines, due to a decrease in the cell components (autophagosomes) that collect the damaged proteins.
  • A study found that the process of breaking down defective mitochondria and recycling the components (mitophagy) is impaired in those with Alzheimer's.
  • Microglia clear damage by engulfing the damaged matter then releasing it inside exosomes, which can be absorbed by other cells. Studies have now shown that these exosomes, designed to transmit information, can also spread harmful tau & amyloid-beta protein.
  • A mouse study has shown how amyloid plaques lead to tau tangles, and that weakened microglia facilitate this. It also links weak microglia to the risky variant of the TREM2 gene.
  • However, the common TREM2 variant is linked to faster plaque growth at later stages.
  • TREM2 appears to modify the way immune cells respond to tau tangles.
  • Another mouse study found that overactive microglia (achieved by turning off another gene) were linked to both better removal of amyloid-beta, and loss of synapses. This may help explain why reducing amyloid plaques often fails to improve cognition.

Aging linked to impaired garbage collection in the brain

A mouse study has shown that, as cells age, their ability to remove damaged proteins and structures declines.

The process of waste management, called autophagy, involves a component within the cell (an autophagosome) engulfing misfolded proteins or damaged structures (putting them in a garbage bag, essentially). The autophagosome then fuses with a second cellular structure, called a lysosome, that contains the enzymes needed to breakdown the garbage, allowing the components to be recycled and reused.

It’s thought that this decline in autophagy makes neurons more vulnerable to genetic or environmental risks.

The mouse study found that aging brought a significant decrease in the number of autophagosomes produced, along with pronounced defects in their structure.

However, activating the protein WIPI2B restored autophagosome formation.

https://www.eurekalert.org/pub_releases/2019-07/uops-tot071919.php

Breakdown in cleaning process in mitochondria linked to Alzheimer's

A cleaning process in brain cells called mitophagy breaks down defective mitochondria and reuses the proteins that they consist of. When the process breaks down, defective mitochondria accumulate in brain cells.

Research has now found that this is markedly present in cells from both humans and animals with Alzheimer's. Moreover, when active substances targeted at the cleaning process were tried in live animals, their Alzheimer's symptoms almost disappeared.

https://www.eurekalert.org/pub_releases/2019-02/uoct-oc021419.php

Microglia may spread toxic tau during early Alzheimer's

A 2015 study found how toxic tau fibrils spread during the early stages of Alzheimer's disease. Apparently the fibrils (accumulations of tau proteins) can be carried from one neuron to another by microglia.

Microglia act as the brain's immune cells, in which role they identify and clear damage and infection. They clear damage by first engulfing dead cells, debris, inactive synapses or even unhealthy neurons, then releasing nano-scale particles called exosomes, which can be absorbed by other cells.

It used to be thought that exosomes simply help the cell to get rid of waste products. It now appears that cells throughout the body use exosomes to transmit information. This requires them to contain both proteins and genetic material, which other cells can absorb. Hence their ability to spread tau protein, and hence, it now seems, their ability to also transport amyloid-beta.

http://www.eurekalert.org/pub_releases/2015-10/bumc-rdr100515.php

https://www.eurekalert.org/pub_releases/2018-06/lu-nmb061318.php

Microglia link Alzheimer’s amyloid and tau

Amyloid plaques and tau tangles are key biomarkers for Alzheimer’s, but research indicates that it is the tau tangles that are the real problem — the main problem with amyloid plaques is that they lead to tau tangles. A new study indicates how that happens.

A mouse study modified the TREM2 genes, which affect the health of microglia. So some mice carried the common variant of the gene, meaning that their microglia were fully functional, and some carried the risky variant, or no gene at all.

When seeded with tau protein from Alzheimer’s patients, those brains with weakened microglia produced more tau tangle-like structures near the amyloid plaques than in mice with functional microglia.

It was also revealed that microglia normally form a cap over amyloid plaques that limits their toxicity to nearby neurons. When the microglia failed to do that, neurons suffered more damage, creating an environment that fostered the formation of tau tangle-like lesions.

The findings were supported by the finding that humans with TREM2 mutations who died with Alzheimer’s had more tau tangle-like structures near their amyloid plaques than people who died with Alzheimer’s but didn’t have the risky gene.

https://www.futurity.org/alzheimers-disease-amyloid-plaques-tau-2095692/

https://www.eurekalert.org/pub_releases/2019-06/wuso-aml062319.php

However, it should be noted that in more advanced stages of Alzheimer’s, mice with the common TREM2 variant showed faster plaque growth. This appears to be linked to the gene inducing microglia to produce ApoE, which enhances aggregate formation.

The finding adds to evidence that Alzheimer's treatment has to take into account the stage at which the disease is at.

https://www.eurekalert.org/pub_releases/2019-01/d-gc-dic010819.php

Another study that modified the TREM2 gene in mice found that the difference between those with the gene and those without was not in the amount of tau tangles, but rather in the way their immune cells responded to the tau tangles. The microglia in mice with TREM2 were active, releasing compounds that in some circumstances help fight disease, but in this case primarily injured and killed nearby neurons. The microglia in mice without TREM2 were much less active, and their neurons were relatively spared.

https://www.eurekalert.org/pub_releases/2017-10/wuso-agp100617.php

http://www.futurity.org/trem2-alzheimers-disease-1573272/

Overactive microglia have multiple effects

A study found that, if the gene for the TDP-43 protein was turned off in microglia, its activity increased, and amyloid-beta was removed very efficiently. However, when TDP-43 was switched off in microglia in mice, it didn’t just get better at removing amyloid-beta, but also led to a significant loss of synapses.

Clearly, dysfunction of microglia is a complicated business, and it’s suggested that such dysfunction may be one reason why many Alzheimer's medications reduce amyloid plaques but fail to improve cognition.

https://www.eurekalert.org/pub_releases/2017-06/uoz-osc062917.php

Classifying brain microglia

Microglia come in many forms. A survey of brain microglia has classified microglia into at least nine distinct groups, including some types never detected in the past. Some types appeared almost exclusively in the embryonic or newborn stages, others only after injury.

One group tended to cluster near the brain's developing white matter. Another appears to be very inflammatory compared with other microglia, and has been found in people with MS.

Microglia were most diverse early in brain development, in the aged brain and in disease.

https://www.eurekalert.org/pub_releases/2018-12/bch-cbm120518.php

Reference: 

[4447] Stavoe, A. K. H., Gopal P. P., Gubas A., Tooze S. A., & Holzbaur E. L. F.
(2019).  Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons.
(Dikic, I., Marder E., & Hurley J. H., Ed.).eLife. 8, e44219.

[4448] Fang, E. F., Hou Y., Palikaras K., Adriaanse B. A., Kerr J. S., Yang B., et al.
(2019).  Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease.
Nature Neuroscience. 22(3), 401 - 412.

Maitrayee Sardar Sinha, Anna Ansell-Schultz, Livia Civitelli, Camilla Hildesjö, Max Larsson, Lars Lannfelt, Martin Ingelsson and Martin Hallbeck, Alzheimer disease pathology propagation by exosomes containing toxic amyloid-beta oligomers, Acta Neuropathologica, published online 13 June 2018, doi: 10.1007/s00401-018-1868-1 https://link.springer.com/article/10.1007/s00401-018-1868-1

[4451] Leyns, C. E. G., Gratuze M., Narasimhan S., Jain N., Koscal L. J., Jiang H., et al.
(2019).  TREM2 function impedes tau seeding in neuritic plaques.
Nature Neuroscience. 22(8), 1217 - 1222.

Parhizkar et al. (2019): "Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE", Nature Neuroscience, DOI: 10.1038/s41593-018-0296-9

Leyns C, Ulrich J, Finn M, Stewart F, Koscal L, Remolina Serrano J, Robinson G, Anderson E, Colonna M, Holtzman DM. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proceedings of the National Academy of Sciences. Week of Oct. 9, 2017.

[4452] Paolicelli, R. C., Jawaid A., Henstridge C. M., Valeri A., Merlini M., Robinson J. L., et al.
(2017).  TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss.
Neuron. 95(2), 297 - 308.e6.

[4464] Hammond, T. R., Dufort C., Dissing-Olesen L., Giera S., Young A., Wysoker A., et al.
(2019).  Single-Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell-State Changes.
Immunity. 50(1), 253 - 271.e6.

Topics: 

tags problems: 

Inflammation linked to brain health

  • Study indicates APOE4 carriers are only at greater Alzheimer's risk if they have chronic inflammation.
  • Large study finds increasing inflammation linked to more white matter damage.
  • Common causes of chronic inflammation include cardiovascular disease, heart failure, diabetes, high blood pressure and infections.

Link found between chronic inflammation and Alzheimer's gene risk

Data from the Framingham Heart Study has found carriers of the ApoE4 gene were much more likely to develop Alzheimer’s if they also had chronic low-grade inflammation. Indeed, the researchers suggest that, in the absence of inflammation, there might be no difference of Alzheimer's risk between ApoE4 and non-ApoE4 carriers.

https://www.eurekalert.org/pub_releases/2018-10/buso-lfb101818.php

Mid- to late-life increases in chronic inflammation age brain

Data from 1,532 participants in a long-running study, in which participants were tested five times every 3 years (on average), found that those who showed increasing inflammation had greater abnormalities in the brain's white matter structure.

90 people transitioned from low to persistently elevated C-reactive protein during midlife, indicating increasing inflammation. Their brains appear similar to that of a person 16 years older, researchers estimate.

Common causes of chronic inflammation include cardiovascular disease, heart failure, diabetes, high blood pressure and infections such as hepatitis C or HIV.

61% of participants were women, and 28% were African-American. At the final visit, participants were an average age of 76.

https://www.eurekalert.org/pub_releases/2018-07/jhm-mtl070218.php

Reference: 

Source: 

Topics: 

tags development: 

tags problems: 

Why APOE4 gene increases Alzheimer's risk

  • Synapses in Alzheimer's brains found to be clogged with clusterin and amyloid-beta proteins, and APOE4 carriers had more protein clumps than those without the gene variant.
  • APOE4 decreases activity in hippocampus that is critical for memory consolidation.
  • Study of Amazonian hunter-gatherers show APOE4 gene can provide benefits when exposure to parasites is high.

Alzheimer's gene linked to damage to brain connections

A study has found that synapses in people who had died with Alzheimer's contained clumps of clusterin and clumps of amyloid beta. These protein clumps may be damaging the links between neurons.

Those with the APOE4 gene had more clusterin and amyloid beta clumps than people with Alzheimer's without the risk gene. Those without dementia symptoms had less of the damaging proteins in their synapses.

https://www.eurekalert.org/pub_releases/2019-06/uoe-dsl062719.php

Alzheimer's gene impairs memory consolidation by disrupting brainwaves

A mouse study has found that the apoE4 protein decreases two types of brain activity in the hippocampus that are important for memory formation: sharp wave ripples (ripples) and coincident slow gamma activity. During the ripples, prior experiences are replayed numerous times to help preserve the memory of them, and the slow gamma activity that occurs during the ripples helps to ensure that the replay of those memories is accurate.

Mice with apoE4 had fewer ripples than mice with the normal apoE3 protein, and they had less slow gamma activity during the ripples. It appears that apoE4 expression disrupts slow gamma activity during ripples, and this in turn impairs memory consolidation.

The finding points to restoring slow gamma activity in the hippocampus as a therapeutic target.

http://www.eurekalert.org/pub_releases/2016-05/gi-glt050516.php

APOE4 gene benefits those with high parasite exposure

In response to those wondering why we have this gene variant if it's so damaging, a study looked at how the ApoE gene might function differently in the more infectious environment of our hunter-gatherer ancestors. It found that Amazonian forager-horticulturalists who carried ApoE4 and had a high parasitic burden displayed steadier or even improved cognitive function compared to non-carriers with a similar level of parasitic exposure.

For Tsimane ApoE4 carriers without high parasite burdens, the rates of cognitive decline were more similar to those seen in industrialized societies.

ApoE4 has previously been shown to eliminate some infections like giardia and hepatitis. Other studies have shown potential benefits of ApoE4 in early childhood development

https://www.eurekalert.org/pub_releases/2016-12/asu-adc122916.php

Reference: 

Source: 

Topics: 

tags problems: 

Researchers classify Alzheimer's patients in 6 subgroups

  • More evidence that Alzheimer's disease is not a single disease with a single cause and single pathway comes from a large study classifying patients into 6 groups, only two of which showed strong genetic association.
  • Another study using post-mortem brain tissue found that different genes were associated with different types of brain damage.

A study involving 4,050 people with late-onset Alzheimer's disease (mean age 80) has classified them into six groups based on their cognitive functioning at the time of diagnosis. A genetic study found two of the groups showed strong genetic associations.

The participants received cognitive scores in four domains: memory, executive functioning, language, and visuospatial functioning. The largest group (39%) had scores in all four domains that were fairly close to each other. The next largest group (27%) had memory scores substantially lower than their other scores. Smaller groups had language scores substantially lower than their other scores (13%), visuospatial functioning scores substantially lower than their other scores (12%), and executive functioning scores substantially lower than their other scores (3%). There were 6% who had two domains that were substantially lower than their other scores.

One group showed a very strong genetic association with 33 single nucleotide polymorphisms (SNPs) — this effect was stronger than the strongest effects found by an earlier and much larger international consortium study where Alzheimer's disease was treated as a single condition.

The memory group had a particularly strong relationship with the APOE e4 allele.

The participants were mostly white (92%) and 61% were female.

https://www.eurekalert.org/pub_releases/2018-12/uowh-rca120418.php

The finding is supported by another study using brain tissue from deceased patients with rare and common forms of Alzheimer’s, and from those who didn’t have the disease. The study showed that different genes are associated with different types of brain damage.

Those with the genes implicated in early-onset Alzheimer's (APP, PSEN1, and PSEN2) showed lower numbers of neurons and higher numbers of astrocytes than people who had Alzheimer’s but didn’t carry those mutations.

A similar pattern was found in patients with APOE4. However, carriers of TREM2 showed less neuronal loss and more damage to glial cells.

https://www.futurity.org/alzheimers-disease-genes-brain-cell-damage-1786192/

Reference: 

Source: 

Topics: 

tags problems: 

Genes linked to Alzheimer's

  • Very large study finds 5 new genes linked to increased Alzheimer's risk.
  • A rare gene variant that protects APOE4 gene carriers from getting Alzheimer's has been identified.
  • Two large surveys found that verbal recall score was significantly affected by TOMM40 genotype. TOMM40 is adjacent to APOE on their chromosome.
  • A study found that TOMM40's effect on Alzheimer's depends on parental history.
  • Data from three very large studies has produced a tool for assessing an individual's genetic risk for developing Alzheimer's, based on 31 genetic markers.
  • A small study found that, of the top 9 genes that affect Alzheimer's risk, excluding the APOE gene, only 2 affect brain atrophy.
  • A new gene variant that is associated with greater amyloid plaque than APOE4 has been identified.

Five new risk genes for Alzheimer's disease

Genetic data from more than 94,000 individuals has revealed five new risk genes for Alzheimer's disease, and confirmed 20 known others. The new genes are: IQCK, ACE, ADAM10, ADAMTS1 and WWOX.

The findings support developing evidence that groups of genes associated with specific biological processes, such as cell trafficking, lipid transport, inflammation and the immune response, are "genetic hubs" that are an important part of the disease process.

The study also suggests that variants affecting APP and amyloid beta protein processing are associated with both early-onset autosomal dominant Alzheimer's and with late onset Alzheimer's. In addition, for the first time, the study implicated a genetic link to tau binding proteins.

The findings follow on from a 2013 report.

https://www.eurekalert.org/pub_releases/2019-02/nioa-dsu022719.php

Gene variant found that protects against Alzheimer's

A large study involving families that had a large number of resilient individuals (those who carried the APOE4 gene but remained healthy into advanced age) has found that the resilient subjects shared a variant in the RAB10 gene while those who got the disease did not share that genetic variant.

https://www.eurekalert.org/pub_releases/2017-11/byu-rig112917.php

Gene linked to Alzheimer's gene affects age-related cognitive decline

TOMM40 and APOE genes are adjacent to each other on chromosome 19, and have sometimes been used as proxies for one another in genetic studies. TOMM40 has largely been thought of as a “sidekick” to ApoE4. But new research suggests it may have a stronger role.

Data from two large surveys — the U.S. Health and Retirement Study and the English Longitudinal Study of Ageing — found that verbal recall score was significantly affected by TOMM40 genotype.

The researchers examined 1.2 million gene variations across the human genome. TOMM40 was the only one with a strong link to declines in immediate recall and level of delayed recall. APOE4 also was linked but not as strongly.

To test immediate recall, an interviewer read a list of 10 nouns and then asked the participant to repeat the words back immediately. For delayed recall, the interviewer waited five minutes and then asked the participant to recall the list. Test scores ranged from 0 to 10. The average score for immediate recall was 5.7 words out of 10, and the delayed recall scoring average was 4.5 words out of 10. A large gap between the two sets of scores can signal the development of Alzheimer's or some other form of dementia.

Those who had received a likely diagnosis of dementia or a dementia-like condition were excluded from the study.

https://www.eurekalert.org/pub_releases/2017-09/uosc-it091417.php

Family history of Alzheimer's may alter gene that increases risk

There have been conflicting findings about whether the gene, TOMM40 (Translocase of Outer Mitochondrial Membrane-40kD) increases the risk for Alzheimer's. A new study, however, has found that its impact on memory and dementia risk depends on two other factors: parental history of Alzheimer's, and the length of a specific section of the gene.

In the study, late middle-aged people with a family history (parent with Alzheimer’s) and longer version of the gene had twice as much memory loss up to 10 years later as someone with a family history and a short version of the gene. A similar but stronger finding was seen in a group of older adults.

https://www.eurekalert.org/pub_releases/2017-05/isu-fho051917.php

Multiple genetic markers combine to estimate Alzheimer's risk

Genotype data from three very large studies has enabled researchers to construct a test that can be used to calculate any individual’s yearly risk for onset of Alzheimer's. The polygenic hazard score (PHS) is based on 31 genetic markers.

Those with the highest PHS (top 10%) were more than three times more likely to develop Alzheimer's than those with the lowest PHS, and to do so more than 10 years earlier.

In people with the high-risk version of ApoE, those ranked in the top 10% of risk on the new test got Alzheimer’s at an average age of 84 years, compared with 95 years for those ranked in the lowest 10%.

The study also demonstrates that, aside from ApoE, there are thousands of background genetic variations that each have a tiny influence on Alzheimer’s risk, but whose cumulative influence is substantial.

But note that this doesn’t tell us that it’s all about genes! Lifestyle factors are still very important in determining whether you actually get Alzheimer's.

https://www.eurekalert.org/pub_releases/2017-03/p-mgm031317.php

https://www.theguardian.com/society/2017/mar/22/new-alzheimers-test-can-predict-age-when-disease-will-appear

Two Alzheimer's risk genes linked to brain atrophy

A study involving 50 older adults (50+) with no cognitive difficulties and 90 who had been diagnosed with MCI has examined the top nine genetic variants associated with Alzheimer's risk, excluding the APOe4 gene, to find which of them was associated with atrophy in the cortex and hippocampus.

Only ABCA7 and MA4A6A were associated with brain atrophy.

http://www.eurekalert.org/pub_releases/2015-12/iu-tar122315.php

New gene linked to amyloid beta plaque buildup

A study involving nearly 500 individuals has found that a variant of the IL1RAP gene was associated with higher rates of amyloid plaque buildup in the brains of Alzheimer's patients and older adults at risk for the disease, and its effect on amyloid buildup was stronger than that of APOE4.

IL1RAP codes for the key immune signaling factor Interleukin-1 Receptor Accessory Protein, which plays a central role in the activity of microglia, the immune system cells that clear up waste products such as plaques and tangles.

Additionally, the IL1RAP variant was associated with:

  • a lower level of microglial activity
  • greater atrophy of the temporal cortex
  • faster cognitive decline
  • greater likelihood of progression from MCI to Alzheimer's.

http://www.eurekalert.org/pub_releases/2015-10/iu-rin100515.php

Reference: 

[4419] Kunkle, B. W., & et al
(Submitted).  Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing | Nature Genetics.

[3586] Lambert, J-C., Ibrahim-Verbaas C. A., Harold D., Naj A. C., Sims R., Bellenguez C., et al.
(2013).  Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.
Nature Genetics. 45(12), 1452 - 1458.

[4420] Ridge, P. G., Karch C. M., Hsu S., Arano I., Teerlink C. C., Ebbert M. T. W., et al.
(2017).  Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience.
Genome Medicine. 9(1), 100.

[4422] Arpawong, T. E., Pendleton N., Mekli K., McArdle J. J., Gatz M., Armoskus C., et al.
(2017).  Genetic variants specific to aging-related verbal memory: Insights from GWASs in a population-based cohort.
PLOS ONE. 12(8), e0182448.

[4423] Willette, A. A., Webb J. L., Lutz M. W., Bendlin B. B., Wennberg A. M. V., Oh J. M., et al.
(2017).  AD FAMILY HISTORY MODULATES EFFECTS OF TOMM40 ‘523’ POLY-T ON MTL ATROPHY AND HYPOMETABOLISM IN PRECLINICAL AND AD COHORTS.
Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 13(7), P54 - P55.

[4424] Desikan, R. S., Fan C. Chieh, Wang Y., Schork A. J., Cabral H. J., L. Cupples A., et al.
(2017).  Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score.
PLOS Medicine. 14(3), e1002258.

[4412] Ramirez, L. M., Goukasian N., Porat S., Hwang K. S., Eastman J. A., Hurtz S., et al.
(2016).  Common variants in ABCA7 and MS4A6A are associated with cortical and hippocampal atrophy.
Neurobiology of Aging. 39, 82 - 89.

[4425] Ramanan, V. K., Risacher S. L., Nho K., Kim S., Shen L., McDonald B. C., et al.
(2015).  GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer’s disease implicates microglial activation gene IL1RAP.
Brain. 138(10), 3076 - 3088.

Topics: 

tags problems: 

Pages

Subscribe to RSS - Alzheimers
Error | About memory

Error

The website encountered an unexpected error. Please try again later.