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Alzheimer’s Study Finds Potential Immune System Link, Mostly in Women

Research strengthens immune dysregulation connection, magnifies gender disparity

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Written by Debra Melani on February 5, 2024

When immune systems go awry, they can wreak havoc, triggering everything from diabetes to – scientists now believe – Alzheimer’s disease (AD). But immune systems are supposed to protect, not injure, the body. So what if scientists could pinpoint a window before things go amiss and harness the defense system in a way that curbs or prevents AD from taking hold?

Glossary of terms

Amyloid: Sticky protein aggregates that build up, becoming plaques in the brains of people with AD.

APOE ε4: The apolipoprotein E gene is involved in making a protein that helps carry cholesterol and other types of fat in the bloodstream. Problems in this process are thought to contribute to the development of AD. The APOE ε4 allele is associated with greater risk for Alzheimer’s disease.

Biomarker: A measurable marker in the body that indicates a disease, infection or environmental exposure.

Glia: Non-neuronal cells, including astrocytes, in the nervous system.

Neurons: Nerve cells in the brain and spinal cord.

Tau: A protein that forms insoluble filaments that accumulate as neurofibrillary tangles in AD.


It’s one possibility being targeted by a group of University of Colorado Anschutz Medical Campus researchers bent on halting the brain-destroying disease that affects 6.7 million Americans 65 or older.

In a recently published study, the group found an association between higher levels of an immune system-related biomarker and decreased microstructure in parts of the brain highly vulnerable to AD. The finding, which signals a greater risk of cognitive difficulties, was distinctly higher in women.

Finding mostly seen in women

“We were surprised at how strong the effect was,” said Brianne Bettcher, PhD, a clinical researcher at the University of Colorado Alzheimer's and Cognition Center (CUACC), who looked with colleagues at a biomarker called GFAP (glial fibrillary acidic protein), an important protein believed to be released with central nervous system (CNS) injuries, such as stroke or brain injuries.

“It was pretty notable, and it was mostly seen in women.”

Knowing that women are at almost twice the risk of AD as men, the scientists looked for the difference, but were still surprised by the wide sex gap as well as the findings overall, Bettcher said. “That means these helper cells (astrocytes that release GFAP) are really critical and probably impacting Alzheimer’s disease from an early, early stage.”

“I think another take-away from it is that we need to be focusing more on why

there are these sex differences in risk for Alzheimer’s disease. We should not accept

that women are at greater risk.” – Brianne Bettcher, PhD

The study sample of 109 (out of 114) participants included healthy older adults and adults with symptomatic AD identified from the CUACC Bio-AD study database. Participants were on average 70 years old, with 44% of individuals having at least one AD-related APOE E4 allele. Females comprised 63.3% of the sample.

Bettcher, an associate professor in the departments of Neurology and Neurosurgery at the CU School of Medicine, focuses largely on the neurobiology of aging and understanding the role of immune system dysfunction in aging and AD. The finding could help open the latch to that therapeutic window she seeks.

“My real passion is trying to understand before symptoms even begin what is putting someone down a path that could lead to Alzheimer’s disease and how we could potentially avoid that,” said Bettcher, who talks more about the study in the condensed Q&A below.

Q&A Header

Can you start with an overview of the association between immune dysregulation and AD?

We’re still learning so much about this, but we do know that immune dysregulation – so your immune system not functioning as it should – seems to be a contributor to Alzheimer’s disease. We know that as we get older, there are already changes in our immune system, that it’s not working quite as well as folks who are much younger. We’re trying to figure out how this really dovetails with the very early stages of Alzheimer’s disease, because we know that this dysregulation is magnified in people with Alzheimer’s and seems to predict worse outcomes.

Why did you target GFAP?

GFAP is associated with immune regulation and dysregulation and is specific to helper cells called astrocytes. Astrocytes help form your blood brain barrier and are important to the formation and maintenance of synapses, which are integral to memory and thinking.

We were very interested in this marker because it seems to be changing early in Alzheimer’s disease. There are a lot of models coming out now that say amyloid deposition, which we think is one of the earliest indicators of Alzheimer’s disease, is acting pretty early with this marker of astrocyte dysfunction, or GFAP.

So digging deeply into potential mechanisms, we were looking at tiny structures in the brain’s grey matter that are really important to synapse formation and maintenance called neurites (dendrites and axons) and how or if this biomarker of astrocyte dysregulation and immune dysregulation is related to this microstructure.

I understand an advanced form of imaging called neurite orientation dispersion and density imaging (NODDI) was key to the study. What is it?

It was key. It’s a very sophisticated approach to imaging. It helps us to look at these neurites that we know are important for memory and thinking, and we also know are impacted by aging. Even before you see a lot of shrinkage in the brain, these tiny structures called neurites are being affected. It helps us get that sort of granular level of insight.

What did you find?

The meta-result of this is that we found the higher the levels of GFAP were, the lower the microstructure in your brain was around these neurites, and that it was mostly seen in women. And this is after accounting for other Alzheimer’s risk factors, such as APOE allele status and plasma markers of amyloid and tau (see side box).

What do these results mean to your research?

We are still in the early stages of this. I think it’s always important to caution against overinterpreting things. But we’re certainly trying to find out: Is this pointing to early stages of immune dysregulation in our glia (non-neuronal cells, including astrocytes)? So are astrocytes playing a really big role? If they are, that could be such an important point of intervention – if it’s happening that early, and we can pinpoint it.

I think another take-away from it is that we need to be focusing more on why there are sex differences in risk for Alzheimer’s disease. We should not accept that women are at greater risk. It doesn’t seem to be strictly due to the fact that women live longer, either. So we really need to dig more deeply into the biological causes. Is it due to these differences in immune regulation, which we certainly were seeing something to that effect with this study.

What’s next?

There’s still a lot to learn. We need to do longitudinal studies, so look over time to see if there are these changes.

I think from that we are really interested in shifting some of our work to look more at some of these sex differences, particularly as they relate to your immune system and Alzheimer’s disease risk. And we are continuing to try to figure out what the earliest changes in the immune system are and if there’s any stage that could be good versus bad so that we can appropriately inform therapeutic interventions to do the right thing.

Topics: Research, Alzheimer's,

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Staff Mention

Brianne Bettcher, PhD