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

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Credit: gettyimages/Creatista

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


Blast Off! Sending Human Tissue Chips into Space

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Tissue Chips in Space

Credit: Josh Valcarcel, NASA

A big challenge in unlocking the mysteries of aging is how long you need to study humans, or even human cells, to get answers. But, in partnership with NASA, NIH is hoping that space will help facilitate this important area of research.

It’s already known, from what’s been seen in astronauts, that the weightless conditions found in space can speed various processes associated with aging. So, might it be possible to use the space station as a lab to conduct aging experiments?


Can Childhood Stress Affect the Immune System?

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Katie Ehrlich

Katie Ehrlich
Credit: Alan Flurry, University of Georgia, Athens

Whether it’s growing up in gut-wrenching poverty, dealing with dysfunctional family dynamics, or coping with persistent bullying in school, extreme adversity can shatter a child’s sense of emotional well-being. But does it also place kids at higher of developing heart disease, diabetes, and other chronic health conditions as adults?

Katherine Ehrlich, a researcher at University of Georgia, Athens, wants to take a closer look at this question. She recently received a 2018 NIH Director’s New Innovator Award to study whether acute or chronic psychosocial stress during childhood might sensitize the body’s immune system to behave in ways that damage health, possibly over the course of a lifetime.


Creative Minds: Exploring the Role of Immunity in Hypertension

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Meena Madhur

Meena Madhur / Credit: John Russell

If Meena Madhur is correct, people with hypertension will one day pay as much attention to their immune cell profiles as their blood pressure readings. A physician-researcher at Vanderbilt University School of Medicine, Nashville, Madhur is one of a growing number of scientists who thinks the immune system contributes to—or perhaps even triggers—hypertension, which increases the risk of stroke, heart disease, kidney disease, and other serious health problems.

About one of every three adult Americans currently have hypertension, yet a surprising number don’t know they have it and less than half have their high blood pressure under control—leading many health experts to refer to the condition as a “silent killer”[1,2]. For many folks, blood pressure control can be achieved through lifestyle changes, such as losing weight, exercising, limiting salt intake, and taking blood pressure medicines prescribed by their health-care provider. Unfortunately, such measures don’t work for everyone, and some people continue to suffer damage to their kidneys and blood vessels from poorly controlled hypertension.

Madhur wants to know whether the immune system might be playing a role, and whether this might hold some clues for developing new, more targeted ways of treating high blood pressure. To get such answers, this practicing cardiologist will use her 2016 NIH Director’s New Innovator Award to conduct sophisticated, single-cell analyses of the immune systems of people with and without hypertension. Her goal is to produce the most comprehensive catalog to date of which human immune cells might be involved in hypertension.


Precision Oncology: Gene Changes Predict Immunotherapy Response

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Cancer Immunotherapy

Caption: Adapted from scanning electron micrograph of cytotoxic T cells (red) attacking a cancer cell (white).
Credits: Rita Elena Serda, Baylor College of Medicine; Jill George, NIH

There’s been tremendous excitement in the cancer community recently about the life-saving potential of immunotherapy. In this treatment strategy, a patient’s own immune system is enlisted to control and, in some cases, even cure the cancer. But despite many dramatic stories of response, immunotherapy doesn’t work for everyone. A major challenge has been figuring out how to identify with greater precision which patients are most likely to benefit from this new approach, and how to use that information to develop strategies to expand immunotherapy’s potential.

A couple of years ago, I wrote about early progress on this front, highlighting a small study in which NIH-funded researchers were able to predict which people with colorectal and other types of cancer would benefit from an immunotherapy drug called pembrolizumab (Keytruda®). The key seemed to be that tumors with defects affecting the “mismatch repair” pathway were more likely to benefit. Mismatch repair is involved in fixing small glitches that occur when DNA is copied during cell division. If a tumor is deficient in mismatch repair, it contains many more DNA mutations than other tumors—and, as it turns out, immunotherapy appears to be most effective against tumors with many mutations.

Now, I’m pleased to report more promising news from that clinical trial of pembrolizumab, which was expanded to include 86 adults with 12 different types of mismatch repair-deficient cancers that had been previously treated with at least one type of standard therapy [1]. After a year of biweekly infusions, more than half of the patients had their tumors shrink by at least 30 percent—and, even better, 18 had their tumors completely disappear!


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