How Does a Rare APOE3 Variant Decrease Alzheimer’s Disease Risk?

Post by D. Chloe Chung

The takeaway

The protective APOE3-Jacksonville (APOE3-Jac) genetic variant can substantially lower the risk of Alzheimer’s disease (AD) by reducing protein aggregation and promoting lipid binding and transport.

What's the science?

Apolipoprotein E (APOE) is a lipid-binding protein that transports lipids and mediates fat metabolism. To date, the APOE4 variant is the biggest risk factor for late-onset Alzheimer’s disease (AD), while the APOE3 is the most common variant among populations. A few years ago, the rare variant termed APOE3-Jacksonville (APOE3-Jac) was found to be largely protective against AD, but it was unclear how it can reduce the risk of developing AD. This week in Science Translational Medicine, Liu and colleagues showed that this protective variant aggregates much less while promoting more lipid-binding.

How did they do it?

The authors surveyed three additional cohorts of brain tissues from healthy controls and dementia patients (with AD or Lewy body dementia) to confirm the association between the APOE3-Jac variant and protection against AD. From some of these brain tissues, the authors isolated APOE and amyloid-beta protein, one of the proteins that characteristically aggregates in AD brains, and examined changes in the degree of protein aggregation between people with or without the APOE3-Jac variant. They also used APOE proteins produced by the human cell line and tested whether the APOE3-Jac variant possesses different self-aggregation properties. To investigate whether this variant can have changes in its functional role (e.g., lipid-transporting capacity), the authors cultured astrocytes (the major cell type that produces APOE) isolated from the APOE-knockout mice and treated them with purified human APOE3 or APOE3-Jac proteins. Additionally, the authors injected virus expressing either APOE3 or APOE-Jac into the AD mouse model displaying the amyloid pathology to test how APOE-Jac can impact amyloid aggregation and associated pathological features.

What did they find?

From the additional sequencing of brain tissue, the authors found five no-disease cases with the APOE3-Jac variant but none in the dementia cases, confirming that the variant was strongly associated with the reduced risk of AD. Interestingly, both APOE and amyloid-beta proteins were found to be less aggregated in the brain tissues of the APOE3-Jac carrier compared to those without this variant. Purified APOE proteins also showed that APOE3-Jac forms much fewer oligomers than the normal APOE3, further suggesting that APOE3-Jac has a dramatically reduced tendency to self-aggregate. Additionally, experiments using cultured mouse astrocytes showed that APOE3-Jac was much more efficient in mediating lipid transport than the normal APOE3. The viral expression of APOE3-Jac in the AD mice significantly reduced the amount of amyloid-beta plaques, dying neuronal processes, and neuroinflammatory markers, demonstrating the protective role of the APOE3-Jac variant against AD.

What's the impact?

This study is the first to investigate the mechanisms of APOE3-Jac protection against AD. Also, the APOE3-Jac variant is the first mutation within the gene region critical for APOE’s self-oligomerization and lipid metabolism. It will be interesting to further investigate how this variant can impact pathological changes in the microtubue-associated protein tau, another key disease feature in AD. Findings from this study highlight the therapeutic potential of targeting APOE self-aggregation and APOE-mediated lipid metabolism in AD patients.

Liu et al. APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia. Science Translational Medicine (2021). Access the original scientific publication here.

“Visual Snow” and its Possible Origins

Post by Anastasia Sares

The takeaway

Visual snow syndrome is a condition where people continually see “static” or “snow” interfering with their vision, which may be accompanied by other visual problems. Visual neurons fire randomly all the time, but for people with visual snow, it seems that the brain is amplifying this random firing, bringing it to conscious awareness.

What's the science?

Visual snow is a newly-described condition that is currently estimated to affect around 2% of the population, and there are a few hypotheses as to why it occurs. One is that the neurons in the visual system could be producing an excessive amount of noise – random fluctuations that have nothing to do with the outside world – that are then interpreted as light signals. The second, slightly more nuanced theory is that the total amount of noise in visual neurons is the same for people with visual snow and people without it, but that the gain, or amplification of this noise is especially high for people with visual snow (think of someone turning up the volume on a bad-quality radio station). This week in Brain, Brooks and colleagues pitted these two possible causes of visual snow against each other and found a victor.

How did they do it?

The authors recruited people with and without visual snow to participate in some tasks. They also recruited people in both groups with and without migraines, because these people can also have visual snow as a symptom, though it may have a different cause. One task was designed to measure the total amount of noise (random activity) in the visual system. Participants were shown two squares and had to decide which one contained a lighter-colored circle inside it. The images were made increasingly “noisier” by adding a bunch of lighter and darker pixels (the authors called this “external noise” as opposed to the “internal noise” generated by the visual system itself). By doing the experiment three times with the same stimuli, they could get an idea of a person’s consistency in their responses, which should be related to the amount of internal noise in the visual system (low internal noise allows people to make more consistent responses).

The second task was designed to measure the gain of the visual system. Participants were shown four squares and asked which one’s brightness had been different from the others. The higher the contrast between the squares and the background, the more contrast is needed to identify the odd one out—this is called contrast gain, and the researchers suspected it would be especially strong in people with visual snow.

What did they find?

When comparing the different groups of participants, the authors found no difference in the total amount of noise in the visual system. On the other hand, contrast gain was increased only in people with visual snow, regardless of migraine status. Variations in the contrast gain experiment showed that the difference was specific to neurons in the parvocellular pathway—a pathway with slower-response neurons responsible for high-resolution color vision.

What's the impact?

By comparing different clinical groups (with/without migraine and with/without visual snow), the authors showed that abnormal contrast gain is specific to visual snow. Of course, these tasks are indirect measures of what’s actually going on in the brain; other studies are needed to examine the actual neural activity involved. The better we understand this syndrome, the more likely we will be to find a treatment.

Brooks et al. Visual contrast perception in visual snow syndrome reveals abnormal neural gain but not neural noise. Brain (2021). Access the original scientific publication here

The Association Between Post-Traumatic Stress Disorder (PTSD) and Heart Disease

Post by Leanna Kalinowski 

The takeaway

There is an increased risk of heart disease among individuals with PTSD. This risk strengthens following chronic PTSD and is attributable to impaired microvascular function.

What's the science?

The human body is designed to rapidly respond to threats and stressful situations by activating the sympathetic nervous system during the stress response. This leads to an increase in cardiovascular activity, helping one to fight or flee from a stressful stimulus. This is a normal physiological response; however, it can become dysregulated in disorders such as posttraumatic stress disorder (PTSD), which is a chronic psychiatric disorder that develops in some individuals who have experienced a traumatic event. When individuals with PTSD experience a reminder of their trauma, such as a loud noise, their sympathetic nervous system is activated despite the lack of an active threat. This repeated activation is believed to cause an increased risk of heart disease among individuals with PTSD, perhaps through repeated bouts of inflammation and vascular “wear and tear”. However, the exact mechanisms underlying this risk have not been demonstrated. This week in Biological Psychiatry, Vaccarino and colleagues conducted a longitudinal twin study with war veterans to determine the mechanisms underlying the association between PTSD and heart disease.

How did they do it?

A group of 275 twins was selected from the Vietnam Era Twin Registry, which is a large national sample of adult male twins who served on active duty during the Vietnam war era. Studying twins allows for the researchers to separate out factors that are often associated with both PTSD and heart disease but do not causally link the two disorders, including genetic and environmental factors that run in families and are shared among twins. Participants each underwent two examinations that were twelve years apart, each of which included a clinical assessment of PTSD. Participants were classified into one of three groups: no history of PTSD, late-onset PTSD (i.e., not diagnosed at visit 1 but diagnosed at visit 2), and longstanding PTSD (i.e., diagnosed at both visits).

Participants also underwent myocardial perfusion at both examinations, which is a positron emission tomography (PET) imaging test that shows how well blood flows through the heart muscle. PET scans of the heart were taken before and after administration of adenosine, which is a drug that increases the workload of the heart to uncover subclinical disease. From these scans, the researchers were first able to determine whether participants lacked blood flow to the heart because of obstructive coronary artery disease, which is when plaque accumulation leads to a narrowing or blockage of the large arteries that supply blood to the heart. They were also able to assess myocardial flow reserve, which is a measure of the health of the small coronary vessels that bring blood to the heart. Unlike obstructive coronary artery disease, coronary microvascular dysfunction is caused by damage to blood vessels rather than blockage by plaque. 

What did they find?

The researchers found that PTSD is associated with coronary microvascular dysfunction, indicated by lower myocardial flow reserve. This association was particularly noted among twins with longstanding PTSD. Twins with longstanding PTSD also experienced a lower myocardial flow reserve during their second visit compared to the first, suggesting a worsening of microvascular function following prolonged PTSD. These associations persisted even after comparing twin brothers with different PTSD trajectories, ruling out shared genetic and environmental factors, as well as when accounting for other psychiatric disorders, such as depression and substance abuse. Furthermore, there was no evidence that twins with PTSD had more obstructive coronary artery disease, suggesting that the association between PTSD and heart disease is due to damage to blood vessels rather than an increase in plaque accumulation.

What's the impact?

In summary, this unique study design allowed for the researchers to examine how heart disease progresses in relation to PTSD status and duration over a 12-year period. Their findings support a link between PTSD and heart disease and suggest that microvascular function is the mechanism underlying this association. Understanding this mechanism will help in long-term efforts for risk prediction, prevention, and treatment to reduce the burden of heart disease among individuals with PTSD. 

Vaccarino et al. Posttraumatic stress disorder, myocardial perfusion and myocardial blood flow: A longitudinal twin study. Biological Psychiatry (2021). Access the original scientific publication here.