Tuberous sclerosis complex (TSC) is a genetic condition due to mutations in TSC1 or TSC2 commonly diagnosed in the first few years of life. Advances in TSC research have allowed TSC patients to live well beyond the age of 50. Subsequently, many TSC patients note brain function changes such as memory difficulties or problems learning new computer programs beginning in their mid-to-late 40s. Dr. Andy Liu began characterizing these brain function changes in 2018. His team at Duke University is conducting a two-year study called “Tuberous Sclerosis Complex as a novel Alzheimer’s Disease-related Tauopathy (TSART).” This study will determine if brain function changes in TSC participants represents the early stages of a neurodegenerative condition called Alzheimer’s Disease (AD).
The following conversation has been edited for length and clarity.
How did you begin studying this very specialized field?
AL: As a fellow starting in 2018, I initiated a clinical trial at UCSF trying to recruit adult TSC patients to see if they were developing a clinical syndrome that’s very similar to frontotemporal dementia. I recruited about 25 patients, and we completed formal neuropsychological testing. What it showed was that there were a lot of memory difficulties, executive dysfunction and poor attention. Some people had language difficulties as well, but the finding that stood out to me was with the cerebral spinal fluid that was sent for testing of Alzheimer’s Disease biomarkers. There are two proteins associated with Alzheimer’s disease. One is amyloid beta — that was normal. The other protein is phosphorylated tau (p-tau). That was very abnormal. We also did PET imaging with tau, and we found focal uptake in specific brain regions. What didn’t make sense to me was that there were a lot of memory problems with these TSC patients. That’s not very common in frontotemporal dementia. The very high phosphorylated tau levels and focal uptake of this tau radiotracer is supposed to be very specific to Alzheimer’s disease— which leads to my current thinking that TAND symptoms may represent early stages of Alzheimer’s disease
You continued studying along this line when you went to Duke.
AL: I started looking in TSC brains, and we found that they are accumulating the same phosphorylated tau protein as that found in Alzheimer’s disease. TSC is likely causing the accumulation of phosphorylated tau leading to an Alzheimer’s disease phenotype — more than a frontal temporal dementia. With the TSC Alliance Seed Grant, I’m looking at a whole bunch of blood samples and seeing if there is elevated phosphorylated tau. This really has a lot of implications. It means this mTOR pathway is a cause of phosphorylated tau, because we see normal levels of amyloid, but abnormal levels of tau. This unlinks the hypothesis with Alzheimer’s disease that amyloid causes tau. It will lead to a whole host of new biomarker therapies not just for Alzheimer’s disease, but for TSC, because I believe the accumulation of this tau protein is causing a lot of TAND symptoms in TSC.
From these studies, could you determine whether TSC patients are more likely to suffer symptoms very similar to Alzheimer’s as they age?
AL: That’s what I see right now in terms of the symptoms. They significantly overlap in the symptoms that Alzheimer’s disease patients have, but at a much earlier age. Patients are saying in their mid to late 40s to early 50s is when they’re seeing the memory problems, the executive function problems, and the concentration problems. I’m trying to link a neurodevelopmental disorder, TSC, with a neurodegenerative condition, to see what we can learn from both sides and go from there.
You’ve been researching TSC for seven years. What are the new developments in the field, compared to when you started out?
AL: There’s a disconnect. What I see is that the AD camp is not aware of the TSC camp. There is a lot of AD literature that says the mTOR pathway is involved in the development of Alzheimer’s disease, but they don’t connect TSC clinically with that description. Same thing with the TSC group. In our 2022 paper, we were the first to describe that tau – the Alzheimer’s disease related tau – is the one that is seen in TSC brains. Making that connection and really allowing us to bring both camps together will be very impactful.
Do you think there may be people who have Alzheimer’s walking around today who might have had undiagnosed TSC?
AL: It’s possible. What has been eye-opening for me in seeing TSC patients is the clinical symptoms is so variable. I have a woman in my study right now who still doesn’t know definitively if she has TSC. She has some characteristics. She’s probably a mosaic mutation, with very mild symptoms, but she doesn’t know for certain. I want to establish more biomarkers for the mTOR pathway and test Alzheimer’s disease patients to see how many of those patients have abnormalities in the mTOR pathway, possibly suggesting TSC1 or TSC2 mutations.
Would it be fair to say that your greatest hope is that your work will not only improve treatment for TSC and TAND – but also impact treatment for Alzheimer’s disease?
AL: That’s exactly right. I think 60 or 70% of the TAND symptoms are seen in neurodegenerative conditions. It’s such a huge overlap that I’m really trying to push and get that message out. If we can repurpose an FDA-approved drug for Alzheimer’s disease, that would be huge. It’s an oral medication. A lot of these medications we have for Alzheimer’s disease are through the IV or through intrathecal, so you need a spinal tap every time. Having an oral medication that can help modify the disease course would be a game-changer for that population, too.
What are your research priorities, both in the near and long term?
AL: My short-term goal is to establish that phosphorylated-tau is causing TAND. My long-term goal is to really start honing in on what biomarkers we can use and how early are they abnormal to tell and correlate with the symptoms of TAND. A lot of people have anxiety and depression very early on, late teens, early twenties. In the Alzheimer’s disease field, that’s usually one of the first symptoms of the disease – anxiety and depression in someone who’s never had a psychiatric history. In the AD literature, the proteins are there a few decades before symptom onset. That makes sense if people are in their early twenties, late teens, and they’re starting to build this protein up already. Number one is trying to map out how soon this protein starts accumulating. Number two is, what can we do along this pathway to help stop those TAND symptoms. It’s a lifetime of work, which I’m really excited about.
Help the TSC Alliance accelerate TSC research by donating to the 50 Forward Fund!
