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New Study Points to Targetable Protective Factor in Alzheimer’s Disease

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If you’ve spent time with individuals affected with Alzheimer’s disease (AD), you might have noticed that some people lose their memory and other cognitive skills more slowly than others. Why is that? New findings indicate that at least part of the answer may lie in differences in their immune responses.

Researchers have now found that slower loss of cognitive skills in people with AD correlates with higher levels of a protein that helps immune cells clear plaque-like cellular debris from the brain [1]. The efficiency of this clean-up process in the brain can be measured via fragments of the protein that shed into the cerebrospinal fluid (CSF). This suggests that the protein, called TREM2, and the immune system as a whole, may be promising targets to help fight Alzheimer’s disease.

The findings come from an international research team led by Michael Ewers, Institute for Stroke and Dementia Research, Ludwig-Maximilians-Universität München, Germany, and Christian Haass, Ludwig-Maximilians-Universität München, Germany and German Center for Neurodegenerative Diseases. The researchers got interested in TREM2 following the discovery several years ago that people carrying rare genetic variants for the protein were two to three times more likely to develop AD late in life.

Not much was previously known about TREM2, so this finding from a genome wide association study (GWAS) was a surprise. In the brain, it turns out that TREM2 proteins are primarily made by microglia. These scavenging immune cells help to keep the brain healthy, acting as a clean-up crew that clears cellular debris, including the plaque-like amyloid-beta that is a hallmark of AD.

In subsequent studies, Haass and colleagues showed in mouse models of AD that TREM2 helps to shift microglia into high gear for clearing amyloid plaques [2]. This animal work and that of others helped to strengthen the case that TREM2 may play an important role in AD. But what did these data mean for people with this devastating condition?

There had been some hints of a connection between TREM2 and the progression of AD in humans. In the study published in Science Translational Medicine, the researchers took a deeper look by taking advantage of the NIH-funded Alzheimer’s Disease Neuroimaging Initiative (ADNI).

ADNI began more than a decade ago to develop methods for early AD detection, intervention, and treatment. The initiative makes all its data freely available to AD researchers all around the world. That allowed Ewers, Haass, and colleagues to focus their attention on 385 older ADNI participants, both with and without AD, who had been followed for an average of four years.

Their primary hypothesis was that individuals with AD and evidence of higher TREM2 levels at the outset of the study would show over the years less change in their cognitive abilities and in the volume of their hippocampus, a portion of the brain important for learning and memory. And, indeed, that’s exactly what they found.

In individuals with comparable AD, whether mild cognitive impairment or dementia, those having higher levels of a TREM2 fragment in their CSF showed a slower decline in memory. Those with evidence of a higher ratio of TREM2 relative to the tau protein in their CSF also progressed more slowly from normal cognition to early signs of AD or from mild cognitive impairment to full-blown dementia.

While it’s important to note that correlation isn’t causation, the findings suggest that treatments designed to boost TREM2 and the activation of microglia in the brain might hold promise for slowing the progression of AD in people. The challenge will be to determine when and how to target TREM2, and a great deal of research is now underway to make these discoveries.

Since its launch more than a decade ago, ADNI has made many important contributions to AD research. This new study is yet another fine example that should come as encouraging news to people with AD and their families.

References:

[1] Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease. Ewers M, Franzmeier N, Suárez-Calvet M, Morenas-Rodriguez E, Caballero MAA, Kleinberger G, Piccio L, Cruchaga C, Deming Y, Dichgans M, Trojanowski JQ, Shaw LM, Weiner MW, Haass C; Alzheimer’s Disease Neuroimaging Initiative. Sci Transl Med. 2019 Aug 28;11(507).

[2] Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M, Focke C, Nuscher B, Xiong M, Ghasemigharagoz A, Katzmarski N, Krasemann S, Lichtenthaler SF, Müller SA, Colombo A, Monasor LS, Tahirovic S, Herms J, Willem M, Pettkus N, Butovsky O, Bartenstein P, Edbauer D, Rominger A, Ertürk A, Grathwohl SA, Neher JJ, Holtzman DM, Meyer-Luehmann M, Haass C. Nat Neurosci. 2019 Feb;22(2):191-204.

Links:

Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)

Alzheimer’s Disease Neuroimaging Initiative (University of Southern California, Los Angeles)

Ewers Lab (University Hospital Munich, Germany)

Haass Lab (Ludwig-Maximilians-Universität München, Germany)

German Center for Neurodegenerative Diseases (Bonn)

Institute for Stroke and Dementia Research (Munich, Germany)

NIH Support: National Institute on Aging


Largest-Ever Alzheimer’s Gene Study Brings New Answers

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Alzheimer's Risk Genes

Predicting whether someone will get Alzheimer’s disease (AD) late in life, and how to use that information for prevention, has been an intense focus of biomedical research. The goal of this work is to learn not only about the genes involved in AD, but how they work together and with other complex biological, environmental, and lifestyle factors to drive this devastating neurological disease.

It’s good news to be able to report that an international team of researchers, partly funded by NIH, has made more progress in explaining the genetic component of AD. Their analysis, involving data from more than 35,000 individuals with late-onset AD, has identified variants in five new genes that put people at greater risk of AD [1]. It also points to molecular pathways involved in AD as possible avenues for prevention, and offers further confirmation of 20 other genes that had been implicated previously in AD.

The results of this largest-ever genomic study of AD suggests key roles for genes involved in the processing of beta-amyloid peptides, which form plaques in the brain recognized as an important early indicator of AD. They also offer the first evidence for a genetic link to proteins that bind tau, the protein responsible for telltale tangles in the AD brain that track closely with a person’s cognitive decline.

The new findings are the latest from the International Genomics of Alzheimer’s Project (IGAP) consortium, led by a large, collaborative team including Brian Kunkle and Margaret Pericak-Vance, University of Miami Miller School of Medicine, Miami, FL. The effort, spanning four consortia focused on AD in the United States and Europe, was launched in 2011 with the aim of discovering and mapping all the genes that contribute to AD.

An earlier IGAP study including about 25,500 people with late-onset AD identified 20 common gene variants that influence a person’s risk for developing AD late in life [2]. While that was terrific progress to be sure, the analysis also showed that those gene variants could explain only a third of the genetic component of AD. It was clear more genes with ties to AD were yet to be found.

So, in the study reported in Nature Genetics, the researchers expanded the search. While so-called genome-wide association studies (GWAS) are generally useful in identifying gene variants that turn up often in association with particular diseases or other traits, the ones that arise more rarely require much larger sample sizes to find.

To increase their odds of finding additional variants, the researchers analyzed genomic data for more than 94,000 individuals, including more than 35,000 with a diagnosis of late-onset AD and another 60,000 older people without AD. Their search led them to variants in five additional genes, named IQCK, ACE, ADAM10, ADAMTS1, and WWOX, associated with late-onset AD that hadn’t turned up in the previous study.

Further analysis of those genes supports a view of AD in which groups of genes work together to influence risk and disease progression. In addition to some genes influencing the processing of beta-amyloid peptides and accumulation of tau proteins, others appear to contribute to AD via certain aspects of the immune system and lipid metabolism.

Each of these newly discovered variants contributes only a small amount of increased risk, and therefore probably have limited value in predicting an average person’s risk of developing AD later in life. But they are invaluable when it comes to advancing our understanding of AD’s biological underpinnings and pointing the way to potentially new treatment approaches. For instance, these new data highlight intriguing similarities between early-onset and late-onset AD, suggesting that treatments developed for people with the early-onset form also might prove beneficial for people with the more common late-onset disease.

It’s worth noting that the new findings continue to suggest that the search is not yet over—many more as-yet undiscovered rare variants likely play a role in AD. The search for answers to AD and so many other complex health conditions—assisted through collaborative data sharing efforts such as this one—continues at an accelerating pace.

References:

[1] Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Kunkle BW, Grenier-Boley B, Sims R, Bis JC, et. al. Nat Genet. 2019 Mar;51(3):414-430.

[2] Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, et al. Nat Genet. 2013 Dec;45(12):1452-8.

Links:

Alzheimer’s Disease Genetics Fact Sheet (National Institute on Aging/NIH)

Genome-Wide Association Studies (NIH)

Margaret Pericak-Vance (University of Miami Health System, FL)

NIH Support: National Institute on Aging; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute of Diabetes and Digestive and Kidney Disease; National Institute of Neurological Disorders and Stroke


Sleep Loss Encourages Spread of Toxic Alzheimer’s Protein

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In addition to memory loss and confusion, many people with Alzheimer’s disease have trouble sleeping. Now an NIH-funded team of researchers has evidence that the reverse is also true: a chronic lack of sleep may worsen the disease and its associated memory loss.

The new findings center on a protein called tau, which accumulates in abnormal tangles in the brains of people with Alzheimer’s disease. In the healthy brain, active neurons naturally release some tau during waking hours, but it normally gets cleared away during sleep. Essentially, your brain has a system for taking the garbage out while you’re off in dreamland.

The latest findings in studies of mice and people further suggest that sleep deprivation upsets this balance, allowing more tau to be released, accumulate, and spread in toxic tangles within brain areas important for memory. While more study is needed, the findings suggest that regular and substantial sleep may play an unexpectedly important role in helping to delay or slow down Alzheimer’s disease.

It’s long been recognized that Alzheimer’s disease is associated with the gradual accumulation of beta-amyloid peptides and tau proteins, which form plaques and tangles that are considered hallmarks of the disease. It has only more recently become clear that, while beta-amyloid is an early sign of the disease, tau deposits track more closely with disease progression and a person’s cognitive decline.

Such findings have raised hopes among researchers including David Holtzman, Washington University School of Medicine, St. Louis, that tau-targeting treatments might slow this devastating disease. Though much of the hope has focused on developing the right drugs, some has also focused on sleep and its nightly ability to reset the brain’s metabolic harmony.

In the new study published in Science, Holtzman’s team set out to explore whether tau levels in the brain naturally are tied to the sleep-wake cycle [1]. Earlier studies had shown that tau is released in small amounts by active neurons. But when neurons are chronically activated, more tau gets released. So, do tau levels rise when we’re awake and fall during slumber?

The Holtzman team found that they do. The researchers measured tau levels in brain fluid collected from mice during their normal waking and sleeping hours. (Since mice are nocturnal, they sleep primarily during the day.) The researchers found that tau levels in brain fluid nearly double when the animals are awake. They also found that sleep deprivation caused tau levels in brain fluid to double yet again.

These findings were especially interesting because Holtzman’s team had already made a related finding in people. The team found that healthy adults forced to pull an all-nighter had a 30 percent increase on average in levels of unhealthy beta-amyloid in their cerebrospinal fluid (CSF).

The researchers went back and reanalyzed those same human samples for tau. Sure enough, the tau levels were elevated on average by about 50 percent.

Once tau begins to accumulate in brain tissue, the protein can spread from one brain area to the next along neural connections. So, Holtzman’s team wondered whether a lack of sleep over longer periods also might encourage tau to spread.

To find out, mice engineered to produce human tau fibrils in their brains were made to stay up longer than usual and get less quality sleep over several weeks. Those studies showed that, while less sleep didn’t change the original deposition of tau in the brain, it did lead to a significant increase in tau’s spread. Intriguingly, tau tangles in the animals appeared in the same brain areas affected in people with Alzheimer’s disease.

Another report by Holtzman’s team appearing early last month in Science Translational Medicine found yet another link between tau and poor sleep. That study showed that older people who had more tau tangles in their brains by PET scanning had less slow-wave, deep sleep [2].

Together, these new findings suggest that Alzheimer’s disease and sleep loss are even more intimately intertwined than had been realized. The findings suggest that good sleep habits and/or treatments designed to encourage plenty of high quality Zzzz’s might play an important role in slowing Alzheimer’s disease. On the other hand, poor sleep also might worsen the condition and serve as an early warning sign of Alzheimer’s.

For now, the findings come as an important reminder that all of us should do our best to get a good night’s rest on a regular basis. Sleep deprivation really isn’t a good way to deal with overly busy lives (I’m talking to myself here). It isn’t yet clear if better sleep habits will prevent or delay Alzheimer’s disease, but it surely can’t hurt.

References:

[1] The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, Finn MB, Manis M, Geerling JC, Fuller PM, Lucey BP, Holtzman DM. Science. 2019 Jan 24.

[2] Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer’s disease. Lucey BP, McCullough A, Landsness EC, Toedebusch CD, McLeland JS, Zaza AM, Fagan AM, McCue L, Xiong C, Morris JC, Benzinger TLS, Holtzman DM. Sci Transl Med. 2019 Jan 9;11(474).

Links:

Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)

Accelerating Medicines Partnership: Alzheimer’s Disease (NIH)

Holtzman Lab (Washington University School of Medicine, St. Louis)

NIH Support: National Institute on Aging; National Institute of Neurological Disorders and Stroke; National Center for Advancing Translational Sciences; National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering


A New Piece of the Alzheimer’s Puzzle

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A couple enjoying a hot drink

Credit: National Institute on Aging, NIH

For the past few decades, researchers have been busy uncovering genetic variants associated with an increased risk of Alzheimer’s disease (AD) [1]. But there’s still a lot to learn about the many biological mechanisms that underlie this devastating neurological condition that affects as many as 5 million Americans [2].

As an example, an NIH-funded research team recently found that AD susceptibility may hinge not only upon which gene variants are present in a person’s DNA, but also how RNA messages encoded by the affected genes are altered to produce proteins [3]. After studying brain tissue from more than 450 deceased older people, the researchers found that samples from those with AD contained many more unusual RNA messages than those without AD.


An Aspirin a Day for Older People Doesn’t Prolong Healthy Lifespan

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Credit: iStock/thodonal

Many older people who’ve survived a heart attack or stroke take low-dose aspirin every day to help prevent further cardiovascular problems [1]. There is compelling evidence that this works. But should perfectly healthy older folks follow suit?

Most of us would have guessed “yes”—but the answer appears to be “no” when you consider the latest scientific evidence.  Recently, a large, international study of older people without a history of cardiovascular disease found that those who took a low-dose aspirin daily over more than 4 years weren’t any healthier than those who didn’t. What’s more, there were some unexpected indications that low-dose aspirin might even boost the risk of death.


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