Unraveling the Nature of Resilience to Alzheimer’s and Age-related Neurodegenerative Diseases

Catherine Kaczorowski

Alzheimer’s disease (AD) is the leading cause of dementia in the United States and worldwide. An estimated 6 million Americans have AD and nearly 14 million are at risk of developing AD by 2050. The genetic causes of early onset familial AD (FAD) are known, but account for only a small minority of cases. By contrast, the vast majority of patients suffer from late-onset AD (LOAD) and AD-related dementias (ADRDs). The genetics and neuropathology of LOAD and ADRDs indicate a complex disease process involving neuron degeneration in brain regions responsible for cognition and executive function, driven by complex gene by environment interactions that are poorly understood.

In the case of AD, beta-amyloid plaques and tau tangles are canonical neuropathologies that form the basis for nearly 70% of drug development in AD for the past 30 years. However, efficacy trials for anti-amyloid and anti-tau therapies have failed, calling into question whether these pathologies are causes or consequences of disease and underscoring the urgent need for novel, disease-modifying therapeutic targets. Currently, there are no approved treatments.

Elevated beta-amyloid plaques and tau tangles are not the only factors associated with the onset and progression of AD dementia. In fact, many individuals who have high levels of these neuropathologies do not develop overt dementia. In rare instances, individuals carrying casual FAD mutations have been identified that exhibit normal cognition and executive function well past the estimated age at onset (AAO) of dementia symptoms. Taken together, these cases point towards the presence of genetic and environmental factors that promote cognitive resilience to AD pathology and to high genetic risk.

Discovery of genetic and environmental factors promoting cognitive resilience may thus provide key targets for treatment and prevention of dementia.

My lab develops and utilizes genetically diverse mice engineered to harbor causal human mutations for AD and other neurodegenerative dementias (i.e., Frontotemporal Lobe Dementia/FTD; Parkinson’s Disease dementia/PDD; and Huntington’s Disease dementia/HD) as a model system for studying resilience. We generate multi-scale data for characterization of the genes, pathways, cells and circuits that confer resilience to cognitive symptoms and protect neurons in disease-relevant brain regions from damage. By leveraging the random genomic perturbations that naturally segregate across our panel of mice, we exploit the most powerful experimental mammalian system available for conducting causal inference analyses. Through this work, we are developing an ever-more powerful computational model of brain resilience that tests links between genes, molecular networks, cells and circuits to best explain individual differences in age at onset and disease progression across a spectrum of dementias. Since each genotype in our mouse population is replicable, we can directly test and iteratively update our computational model by altering the genome and measuring the effect across an entire population at nearly all scales of biology. Moreover, this system allows us to quantify the extent to which multiple factors interact to explain the widest variation in resilience to neurodegeneration and relevant dementia traits. This will accelerate discovery of more robust therapeutics, as we will have the information needed prioritize targets and interventional strategies predicted to have the largest and earliest effects on neurodegeneration and dementia traits. Multiple preclinical trials can be conducted across the same set of mice expressing these human mutations, making them an ideal system to test the generality of brain resilience mechanisms. This approach offers a robust path towards experimental precision medicine.