Neurology Central

From risk to resilience: understanding the role of genetics in Alzheimer’s disease


Catherine Kaczorowski is an Associate Professor and the Evnin Family Endowed Chair in Alzheimer’s Research at the Jackson Laboratory (JAX; ME, USA) – a research institution specializing in genetics and genomics in order to discover solutions for disease. Find out more about Dr Kacszorowski and her work at JAX here.

In this interview, Dr Kacszorowski speaks to us about the innovative work that JAX is doing to accelerate drug discovery in Alzheimer’s disease (AD), including how this can impact patients and what the next steps of her research involve. She also provides her outlook on where she thinks the field will be in 5–10 years’ time.

What are your current research focuses and what inspired you to work in this area?

The biggest research focus right now is understanding the resilience to normal cognitive aging and AD. What really inspired my current research is the observation that there are individual differences in the onset and severity of cognitive symptoms, even in those who carry causal familial AD (FAD) mutations. Some of these individuals will display cognitive decline in their 20’s and 30’s, while others remain symptom free until their 70’s and 80’s. We refer to these individuals as ‘escapees’ because even though they carry causative FAD mutations and exhibit abnormal brain pathology, they can live out to 70 or 80 years of their life without showing cognitive deficits. This observation suggested to me that there are certain genetic factors that can protect against harmful mutations, and if identified, these genetic factors could represent ideal therapeutic targets.

However, the identification of specific genes and variants underlying resilience to AD is difficult in human populations. There are many barriers the field still has to overcome, including difficulties in identifying large numbers of ‘escapees’, incredibly complex human genomes, uncontrollable environmental factors and limitations to collecting disease-relevant brain tissue at early stages in disease progression. I believe mouse models present an incredible opportunity to overcome some of these barriers, and I work in parallel with researchers to identify new drug targets to treat disease. The one thing that was lacking in available mouse models when I started my research was the ability to incorporate genetic diversity, which we know contributes significantly to the disease, into mouse models. This observation inspired me to create a new genetically diverse mouse population, which we call the AD-BXDs, that incorporates both genetic diversity and causal human AD mutations in order to identify, for the first time, how individual genetic variation can modify the penetrance of these mutations and confer resilience in certain individuals.

Initial attempts to get funding for our studies were unsuccessful because the mouse has been recently criticized as a poor model system for human AD. In the process of evaluating these concerns systematically, we discovered that the genetic background of most current AD models (C57BL/6J) is a very resilient strain – it appears to possess genetic factors that protect it against developing cognitive symptoms (despite having brain pathology and amyloid plaques) that likely confounded prior preclinical studies. The lesson here is that, although it may not be an ideal preclinical model to screen analogs to treat AD, the 5xFAD transgenic on the C57BL/6J background may hold the key to new therapeutics. This is what I’m currently interested in, as I think this approach is really going to help us get at new drug targets and mechanisms.

Could you tell us more about the innovative work that JAX is doing to accelerate drug discovery in AD?

We are searching for new drug targets and strategies by leveraging the AD-BXD mouse population I described earlier in order to identify specific genes and pathways that promote resilience. As we identify genes we hypothesize to be important in promoting resilience, we reach out to our collaborators, including researchers Tim Hohman (Vanderbilt University, TN, USA), David Bennett (Rush University, IL, USA) and Matt Huentelman (Translational Genomics Research Institute, AZ, USA), to then ask whether or not these specific genes and pathways may promote resilience in humans as well as in mice.

We have a couple of really exciting new candidates that we have been able to regulate using gene therapy in the mouse, which reduce amyloid and improve cognitive function, but are also possible modifiers of cognition and resilience in humans. This is something that I believe is very unique to JAX, as we have several unique resources that allow us to perform large-scale mouse studies that would be difficult at other institutions, as well as cutting-edge genomic resources that enable gene therapy as well as precision genome editing.

What are the current priorities for Alzheimer’s drug discovery and how has this progressed in recent years?

Recently, results from clinical trials have suggested clearing amyloid alone might not be sufficient to maintain high cognitive function in human populations. As a result, I think in recent years the biggest shift has come from moving our focus away from amyloid as a causative agent in AD toward identifying alternative pathways that may drive disease. In particular, there has been increasing focus towards understanding which neural networks are responsible for encoding, storing and recalling information, and how we may promote and preserve these networks through therapeutic intervention. In addition, recent GWAS results have highlighted that neuroimmune pathways might be involved in cognitive decline and resilience to AD, so a number of groups (including ours) have prioritized understanding the role of the immune system in AD. There is also a major shift toward data-driven hypothesis-generating approaches that have been empowered by advances in computational analyses, including artificial intelligence.

What impact could this research have for patients in the future?

If we are able to identify genes and molecules that promote resilience against age-associated neurodegenerative disorders, then this will have a tremendous impact because it could potentially delay the onset of AD. In some of the pathways, enhancing resilience may also be protective against Huntington’s disease, Parkinson’s disease, frontotemporal dementia and amyotrophic lateral sclerosis. Imagine identifying molecules that really just promote brain health in the context of aging and neurodegenerative stimuli, such as genetic or environmental risk factors – this would be a game changer.

With the recent advances in genomic technologies, I think we can now better align what pathways we want to target on an individual basis and design personalized intervention strategies – and we can start to do this in the mouse. Just like in the human population, certain individual mouse strains may benefit by intervening at the level of the neuroimmune system, while others would require something like enhancing neuronal excitability, or even by dampening down hyperexcitability. It is likely that different subtypes of AD exist, driven by unique pathways and mechanisms, and now we can begin to use genetics to both understand and treat underlying causes of disease, not just modify symptoms.

This is the exciting thing at JAX – we are creating the models that will allow us to do experimental precision medicine. A great example of cutting-edge approaches to creating new research models for AD is MODEL-AD, which is led by Bruce Lamb (Indiana University, IN, USA), and JAX researchers Gareth Howell and Greg Carter. If we are going to get a precision medicine to work in humans then we need to get the building blocks and technology for this right. We want to create a guide on how to do it in a much more complex population like humans, and I think an important step towards precision medicine is going to require large-scale studies in diverse mouse populations – experimental precision medicine.

In your opinion, what are the key challenges to be overcome in this field?

A huge advancement is in sequencing abilities, and whole-genome sequencing being affordable is definitely a game changer. However, I think right now we really need biomarkers. Not only to differentiate between AD and normality, but what we really want is for someone to be able to go in and see their primary care physician and have a biomarker that would differentiate between AD, amyotrophic lateral sclerosis, frontotemporal vascular dementia and so on. I’m not working in this field but I am really excited about it as it’s tremendously important.

What are the next steps of your research?

For the last 5 years, we have been working toward developing more efficient, more predictive and more powerful mouse models to bridge the preclinical-to-clinical gap that has been plagued by the poor reproducibility and translatability of efficacy studies using ‘classical’ genetic engineered mouse models. Now that we have developed these mouse resources and analytical tools, we are leveraging these to identify resilience factors and new drug targets. We then cross-check our candidates against data from several human cohorts in order to select candidates with human resilience. Having this data freely available through the AMP-AD Consortium that is committed to open science in order to rapidly move towards a cure for AD has been tremendously helpful to us. Currently, we have several drug targets in the pipeline. Thus, our next step includes preclinical studies to test their efficacy in new models of human AD. We have around two or three that I would consider really strong candidates that are brand new targets, which no one else in the field has investigated. This work is enhanced by the In Vivo Pharmacology Services at JAX, which is directed by Cat Lutz, and the MODEL-AD Preclinical Testing Core led by Stacey Rizzo.

We’re also really trying to understand how many different subtypes of AD there are – is there a neuroimmune-deficient subtype? Is there a hyperexcitability type, a hypoexcitability type or even a metabolic type?

A huge advantage of using mouse genetic reference panels under well-controlled environmental settings in the lab is that you can identify genes and variants that impact how an individual will respond to various environmental factors (e.g., high-fat diet), or even respond to a particular treatment. A lot of the work that we are conducting now is focused on understanding the genetics behind our population that drives baseline AD risk or resilience. Next steps in the lab are expanding on these baseline conditions and identifying how the environment or other variables influence AD susceptibility. I’m particularly excited by this work, as we know AD rarely occurs alone and is often co-morbid with a host of other conditions. In particular, we are investigating how a high-fat diet, elevated risk for diabetes, stress, traumatic brain injuries and other environmental insults differentially affect cognition based on your genetics. These interactions are critically important but difficult to observe in the human population, as you can’t control these factors the same way you could in the lab mouse.

An area that we are really focusing on right now is defining the nature of resilience. Does resilience to developing cognitive symptoms depend on the remodeling of neurons in typical memory networks that are affected by disease? Or does resilience depend on remodeling of neurons from other brain regions that normally wouldn’t participate in encoding, storing and recalling information that are somehow endowed with the ability to get allocated into doing that job? Might individuals who have exceptional cardiovascular fitness or really exquisite immune function be resilient to AD?

As a neuroscientist, I am biased to think that mechanisms underlying resilience to AD are mediated through direct effects on memory networks in the brain. However, as a geneticist and biologist, I can imagine where resilience could manifest itself in cells and tissues outside of the brain, perhaps through individual differences in the content of circulating exosomes or even in the gut microbiome. The biology of resilience is so new and that’s where the most extraordinary things that we’re doing in the lab are coming from right now.

Where do you anticipate that the field will be in 5–10 years’ time?

Hopefully we’ll have an anti-amyloid treatment that is, at least for some set of patients, disease modifying. I am really hopeful that these trials end up having a beneficial impact on people with dementia that are driven by amyloid toxicity. I don’t think this will be a one-size-fits-all therapy for everyone because the causes of cognitive symptoms in AD appear to be very complex. That said, even an anti-amyloid therapeutic that was disease modifying in a subset of cases would be remarkable.

Another thing I am excited about is the design and application of algorithms that can use gene expression information from small molecular screens (e.g., CMAP) to identify US FDA-approved drugs that might be effective in off-label treatment of AD based on their ability to upregulate resilience genes. Although we are working with chemists to make new compounds capable of altering the expression or function of some of our hits, it would be even better if we could identify a compound that has already gone through safety trials for another disease that we could repurpose.

Therefore, in the next 5–10 years, I really see a lot of gains in repurposing FDA-approved drugs to target some of these new hits that we are finding through a combination of mouse and human research, both in my lab and throughout the AMP-AD consortium, as well as the NIA resilience consortium.

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Extended biography

Aging and genetics are the largest risk factors for developing AD, but genetic diversity has historically remained unaccounted for in preclinical animal studies aimed at understanding the disease. To address the critical need to understand how genetic diversity impacts disease susceptibility, Dr Kaczorowski and her graduate student, Sarah Neuner (JAX), developed the first genetically diverse population of mice that harbor human mutations previously identified as causative for familial AD. The lab is now studying these unique mice as they age in order to identify genetic factors that protect individuals from this devastating disease, even when they carry a genetic predisposition (e.g., familial AD) or are exposed to high-risk environmental factors (e.g., poor diet).

During her graduate studies at Northwestern University (IL, USA), Dr Kaczorowski studied behavioral neuroscience and neurophysiology. Many studies have linked cognitive symptoms in AD to alterations in how well specific neurons in the brain are able to communicate with one other. At Northwestern, she became interested in how differences between individual mice (and humans) can change either the function or expression of individual proteins that control these neuronal functions, known as ion channels and receptors, with aging and disease. This central question is carried forward in her lab today through the use of genetically diverse aging and AD mice.

Dr Kaczorowski’s research is made possible through funding from the National Institute on Aging Resilience Consortium (5R01AG057914-02) and generous support from Tony and Judith Evnin.

The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Neuro Central or Future Science Group.