Targeting the Gene that Produces Tau to Fight Alzheimer’s Disease

Post by Christopher Chen

The takeaway

MAPT is a gene in the body that codes for tau, one of the key pathological markers of Alzheimer’s disease (AD). By using a new therapeutic designed to disrupt MAPT, researchers found that treated patients saw more than a 50% reduction in tau levels.

What's the science?

Affecting over 50 million people worldwide, AD is a neurodegenerative disease resulting in severe cognitive decline and decreases in quality of life. A critical pathological marker in AD is tau, a protein in neurons that at certain levels will prevent a neuron’s ability to “talk” with other neurons, a process called neurotransmission. Animal models that express AD-like phenotypes show marked increases in tau accumulation as well as decreased overall brain function. Conversely, researchers have found that lowering tau production in animal models leads to enhancements in memory and overall brain functioning.

In humans, the gene MAPT codes for tau production. Thus, strategies aimed at reducing MAPT activity may lead to reductions in tau levels and improvement in symptoms of AD. Synthetic molecules called antisense-nucleotide oligonucleotides (ASO) can hijack a gene’s ability to make new proteins (like tau), thus making them good potential therapeutic agents to use in the fight against AD. In a recent article in Nature Medicine, researchers conducted a clinical trial where they injected patients with AD with an ASO called MAPTRx to see if doing so would lead to a reduction in tau levels. 

How did they do it?

The randomized, double-blind, placebo-controlled clinical trial was conducted over a 36-week period (13-week treatment period + 23-week post-treatment period) across multiple research centers and focused on 46 total patients (34 experimental, 12 placebo) with mild AD. In short, patients were given a spinal injection of either MAPTRx or placebo at fixed intervals throughout a 13-week period with tau levels in the cerebrospinal fluid (CSF) taken at specific timepoints during the 36-week period.  

One of the trial’s primary goals was the overall safety of MAPTRx so researchers employed a diverse set of techniques to measure physiological and cognitive health throughout the trial. Specifically, researchers recorded any adverse events patients experienced, gave neurological and physical exams, took bloodwork, and measured readouts from MRI and electrocardiograms (EEG).

There were also therapeutic goals that focused on how well patients metabolized the drug and whether it lowered overall tau levels. To understand MAPTRx’s pharmacokinetics (PK), or how the drug was metabolized in the body, researchers used a variety of specialized measurement techniques to quantify whether increasing dosages of MAPTRx resulted in higher baseline levels in the body. As for quantifying the amount of tau, researchers used similar measurement techniques to compare the concentration of tau in the CSF from experimental and control cohorts.  

What did they find?

Considering the trial was early phase, researchers were primarily focused on the safety of MAPTRx. First, injection of MAPTRx did not lead to any adverse events deemed severe or serious, with all symptoms being recorded as either mild (88%) or moderate (12%). The most common symptom was a post-lumbar puncture headache, which was a mild headache following the spinal injection. As for the drug’s metabolic profile, MAPTRx concentrations were found in dose-dependent concentrations, showing that the body did not eliminate it immediately and suggesting that the drug remains in the body long enough to exert its therapeutic effects.

In terms of lowering overall tau concentration, MAPTRx-treated patients expressed on average ~50% reduction in CSF tau concentration compared to controls. However, no significant therapeutic effects of these reductions were seen on cognitive assessments in post-treatment analysis. It should be noted that this study was not powered to show a cognitive benefit; such a trial would require larger numbers of participants. The authors are exploring this in a phase 2 trial that is ongoing. The value of the exploratory cognitive measures is in how they will inform future clinical trials more focused on the effects of MAPTRx on AD-related health outcomes.

What's the impact?

This clinical trial was the first of its kind using ASO-mediated treatment of AD. It showed that the drug was relatively well-tolerated in the body and that such treatment did not lead to any severe side effects in patients. Perhaps most significantly, it showed target engagement: treated patients saw on average a 50% reduction in tau levels in the body. While the drug’s overall ability to slow the cognitive decline associated with AD is still unclear, researchers acknowledged that more comprehensive trials are needed to determine the full therapeutic potential of MAPTRx.

Access the original scientific publication here.

Decoding “Zoom Fatigue”

Post by Anastasia Sares

The takeaway

During the COVID pandemic, the term “Zoom fatigue” was coined as people participated in more virtual meetings than ever before. Now, since virtual work is here to stay, scientists are trying to dissect this phenomenon to better understand what it is about virtual conferences that is so draining. It turns out there are many factors that may be at play, and not all of them have to do with the technology itself.

What’s different about video-conferencing?

Through conceptual analysis, it is possible to collect theories from different areas of psychological research about how virtual communication can cause fatigue. One important area of difference is eye contact: this is a crucial element of human nonverbal communication, and it works very differently in virtual meetings. In in-person meetings, we use eye contact sparingly, taking turns looking at different speakers, whereas, during an on-screen meeting, everyone can look at everyone else during the entire meeting—the experience of being stared at by 8-10 people for an hour straight can change our body’s arousal and stress responses. At the same time, full and mutual eye contact is impossible, because for one person to experience full eye contact, the other person has to look into their camera. Being in different spaces and unable to focus on the same things in the environment or experience the three-dimensional movement of another person further hampers nonverbal communication.

The lag in video calls is another important factor that can hamper behavioral and brain synchrony. People are very sensitive to conversational timing, and while spontaneous coordination can arise in person, it can often be disrupted in virtual environments. In-person, eye contact can also synchronize brain waves between individuals, but this effect is attenuated in virtual situations (as covered in a previous BrainPost).

Call quality can also increase the amount of effort needed for communication. Noisy audio can increase listening effort, which in turn reduces the neural resources left over for memory. In addition, poor video quality can increase visual fatigue. People on virtual calls may also feel the need to exaggerate their voice or expressive gestures in order to be understood, leading to heightened social monitoring and more fatigue.

Figure from Döring et al.

But wait, what if it’s not the technology?

As research into Zoom fatigue continues, it will be important to account for factors that are less related to the technology itself, and more related to the situations people might use it in. For example, when scheduling virtual meetings, the number and length of meetings might differ, as well as the number of breaks afforded, and the reason for needing a virtual meeting in the first place (home obligations, financial issues precluding travel, a global pandemic) might create a situation of stress before the meeting even starts. In addition, an individual’s technological ability and personality, including their opinion of virtual meetings, may impact their experience.

What's the impact?

As researchers continue to explore the underlying factors of "Zoom fatigue," a better understanding of the multifaceted reasons behind the exhaustion experienced in virtual meetings can be achieved. This knowledge can then be used to develop improved strategies and tools for virtual communication, ultimately enhancing the well-being and productivity of remote workers. With virtual work becoming an integral part of modern society, addressing the issue of Zoom fatigue is vital for fostering healthier, more effective communication in the digital era.

References +

1. Döring, N., Moor, K. D., Fiedler, M., Schoenenberg, K., & Raake, A. (2022). Videoconference Fatigue: A Conceptual Analysis. International Journal of Environmental Research and Public Health, 19(4), 2061. https://doi.org/10.3390/ijerph19042061
2. Troje, N. F. (2023). Zoom disrupts eye contact behaviour: Problems and solutions. Trends in Cognitive Sciences, 27(5), 417–419. https://doi.org/10.1016/j.tics.2023.02.004
3. Bailenson, J. N. (2021). Nonverbal overload: A theoretical argument for the causes of Zoom fatigue. Technology, Mind, and Behavior, 2(1). https://doi.org/10.1037/tmb0000030
4. Zamm, A., Debener, S., & Sebanz, N. (2023). The spontaneous emergence of rhythmic coordination in turn taking. Scientific Reports, 2023(13), 3259. https://doi.org/10.1038/s41598-022-18480-6
5. Schwartz, L., Levy, J., Endevelt-Shapira, Y., Djalovski, A., Hayut, O., Dumas, G., & Feldman, R. (2022). Technologically-assisted communication attenuates inter-brain synchrony. NeuroImage, 264, 119677. https://doi.org/10.1016/j.neuroimage.2022.119677

How the Brain Creates False Memories Based on Misinformation

Post by Kulpreet Cheema

The takeaway

Hippocampal activity and connectivity with prefrontal and parietal cortices in the brain are responsible for creating misinformation-induced false memories.

What's the science?

The misinformation effect is when a memory of an event changes after exposure to misleading information. False memories can occur as a result of the misinformation effect. The classic three-stage misinformation paradigm involves someone witnessing an event, exposure to the misinformation, and finally performing a memory test about the original event. The hippocampus is a brain structure involved in these three stages of memory, however, how hippocampal representations change across these stages is not well known. This week in Nature Communications, Shao and colleagues investigated the role of the hippocampal-cortical network involved in creating misinformation-induced false memories.

How did they do it?

The authors performed behavioral and functional magnetic resonance imaging (fMRI) studies to investigate the misinformation effect. In study one, 122 participants were randomly assigned to the misinformation, neutral or consistent group. The misinformation group had the highest number of false memories, confirming that the misinformation paradigm did lead to increased false memories. In study two, another 57 participants completed a memory test in an fMRI scanner. The study had three stages: during the original-event stage, participants were shown photos of eight events and later heard narratives about the photos (during the post-event phase). Nineteen hours after the post-event stage, the memory of the original event was tested in a memory test. In the misinformation condition, the descriptions of the critical elements of the original photos given in the narratives were inaccurate.  

The activity of hippocampal and prefrontal brain regions during the three stages was analyzed to investigate their involvement in true and false memories. This was followed by a whole-brain ‘searchlight’ analysis to see whether other brain regions were involved in false memory and the misinformation effect.

What did they find?

The hippocampal activity pattern during the original-event and post-event stages were similar, suggesting the original information was reactivated in the hippocampus during the misinformation (i.e., post-event) stage. Prefrontal brain activity was more positively correlated with hippocampus reactivation of post-event information during false memory than original-event information representation. This means the prefrontal cortex works with the hippocampus to monitor memory traces and resolves conflict when false memories occur. In addition to the hippocampus, the participant-specific representations stored in the lateral parietal cortex predicted true memory. On the other hand, misinformation during the false memory was supported by the hippocampus and medial-parietal cortex activity. This suggests that lateral and medial parietal cortices were distinctly connected to the hippocampus to carry original-event and post-event information to create true and false memories, respectively.

What's the impact?

This study shows that dynamic changes in the activity and connectivity of the hippocampus, prefrontal and parietal cortices create the misinformation effect. The representations of original information in the hippocampus become weak when a memory is retrieved, and the misinformed memory representations compete with these original representations. The results also support the multiple-trace memory theory and confirm human memory's fragile and reconstructive nature. 

Access the original scientific publication here.