The key to discovering a therapeutic for Alzheimer’s disease is identifying resilience, according to the The Jackson Laboratory (JAX) researcher who created the first-ever Alzheimer’s disease mouse population.
As part of a virtual fireside chat moderated by JAX Chief Financial Officer Doug Abbott, M.B.A., C.P.A., Kaczorowski detailed her efforts to identify early causative events that underlie the cognitive deficits associated with normal aging and Alzheimer’s disease.
“One of the things that makes Alzheimer's so insidious is its impact not only on the patient, but the immediate and extended family members,” noted Abbott, whose grandmother had Alzheimer’s disease. “The impact is felt over many, many years.”
Kaczorowski’s program is focused on the genetic mechanisms that underlie cognitive deficits associated with ‘normal’ aging and AD, including the early causative events of AD and the genetic factors that protect individuals from the disease even when they are genetically predisposed toward it. Because it is very difficult to find the genes and mechanisms behind resistance to Alzheimer’s in humans, her team employs a strategy that uses sophisticated computational and statistical methods to merge knowledge from mouse experiments with human data.
Prime therapeutic targets
“My lab is really interested in identifying genes that travel across families and the pathways involved that regulate individual differences and the trajectory of cognitive decline,” said Kaczorowksi. “And we're really interested in the genes that are controlling this at a midlife critical time point. Because if we could identify those genes, we might be able to better understand the causes of age-related cognitive decline and dementia, and also identify potential therapeutic targets.”
Kaczorowski says that when examining the age of onset across an entire group of individuals that are carrying these mutations, there are some that show cognitive symptoms as early as 20 or 30 years of age, as well as several individuals that are 70 or even 80 years of age without showing any cognitive symptoms at all.
“These are what we call resilient individuals,” she explained. “This variation in the age at onset of cognitive symptoms isn't explained by simple clinical variables that you'll hear about like sex or APOE genotype. That suggests that there are other protective factors that exist in certain individuals that actually can delay their onset of cognitive decline by upwards of 30 or 40 decades.” Kaczorowski says that these yet-to-be identified genetic factors represent prime therapeutic targets that could be used to treat both susceptible familial mutation carriers, but more importantly, the largely sporadic Alzheimer's disease population.
Identifying resilient individuals
These resilient factors are difficult to identify in human populations, partly because the mutations are very rare and partly because the sheer complexity of humans, both at the genetic level – but also lifestyle choices and uncontrolled environments - makes it even harder to identify who those resilient individuals are, and to know how to study them.
A solution to this problem would be to build a better pre-clinical model of the disease that aligns with human disease. So the Kaczorowski lab created the first Alzheimer’s disease mouse population, with the goal being to identify and understand mechanisms underlying disease and to use this information to develop therapeutics.
“This is the first time anything like this has been done in a mouse population,” she said.
Important clues for preclinical testing
The team found that the variation across the panel of mice looks exactly like the variation in human individuals that are harboring these mutations.
“It’s the first time that we've been able to model the variation at the age of onset of cognitive symptoms using a mouse population,” she said. “But the other major breakthrough is that we identified resilient mouse strains that are able to maintain cognitive function for quite a bit longer.” Serendipitously, she explained, this ended up being the type of mouse strain in which many of the Alzheimer's disease early preclinical trials were analyzed.
“So in pursuing or trying to identify important genetic factors that promote resilience, we also identified a mouse strain that would be potentially the worst to be using for preclinical testing. We now can select much better mouse strains in order to test these drugs.”
Using data driven approaches, the researchers can prioritize those gene networks and hub genes that they hypothesize are controlling the ability to be resilient to Alzheimer's disease mutations.
“And with all this data structure, we can ask how well our discoveries in the mouse are overlapping with the humans, so that we're really prioritizing targets to pursue that are really human relevant and not necessarily mouse specific findings,” she explained.
Driving innovation at JAX
“If you want to look for a needle in the haystack, which is what these resiliency factors are, there's really no place else you could be than The Jackson Laboratory,” said Kaczorowski. She cited the collaborative nature of JAX researchers, strong female leadership and world-class expertise in mouse genetics as critical factors that makes the Laboratory unique.
Kaczorowski, who holds the Evnin Family Endowed Chair in Alzheimer’s Research, also says philanthropy is key to her success. “Philanthropy at the early stages of a scientist’s career is really important,” she said. “It allows people to conduct innovative and high-risk science. Philanthropy gives you that room to take risks and to ‘fail fast’ so that we can move things along.”
“I think that's really helping drive innovation at the lab - philanthropy and supporting new investigators,” she said.