Gregory W. Carter

Laboratory mice and marmosets provide potential models of aging and Alzheimer’s disease with the capacity to track the initiation and progress of pathology across compressed lifespans. We have performed genetic, genomics, and proteomic analyses of plasma and postmortem tissues to map multi-modal aspects of disease development and progression in these model species. We have drawn from human genetic studies to engineer multiple mouse strains carrying candidate genetic factors for late-onset Alzheimer's disease. In the marmoset, we are combining genetic engineering of select loci with outbred genetic variability to analyze biomarkers of aging and dementia. We assembled a new telomere-to-telomere reference genome for the common marmoset (Callithrix jacchus) and performed whole-genome Illumina sequencing on over 230 marmosets. For both model systems, we have used high-coverage proteomics, Alamar NULISA, and transcriptomics to assess the disease-relevant consequences of genetic factors. We have identified a broad range of disease-associated signatures in knock-in mouse and marmoset models, including immune, metabolic, and synaptic alterations. These outcomes frequently correlate with clinically relevant biomarkers and behavioral outcomes. We have also used multi-omic signatures to understand the molecular pharmacodynamics of candidate drugs. Our findings constitute a data and model resource for identifying the appropriate animal model for understanding genetic liability in Alzheimer's and preclinical testing of targeted therapeutics.

The Jackson Laboratory, Bar Harbor, ME, USA