In recent years, genome-wide association studies have linked PLCG2 polymorphisms with Alzheimer’s disease (AD), AD related dementias (ADRD), and longevity. Phospholipase C-gama-2 (PLCγ2) regulates lipid metabolism and intracellular calcium, controlling multiple cellular signaling pathways.

We use humanized MAPT, hAPP, and APOE mouse models that remain largely pathology‑free unless challenged by major environmental stressors, allowing us to isolate how “life events” unlock Alzheimer’s pathologies. By combining these next‑generation models with molecular, imaging, and behavioral readouts, we define when and how gene–environment interactions push the aging brain toward neurodegeneration, with a specific focus on circadian rhythm disruption and stroke.

We are testing the effects of ceramide‑lowering drugs (myriocin) and the TZD mitoglitazone on long-term metabolic and brain health and healthy aging in genetically diverse UM‑HET3 mice, building directly on findings from the NIA Interventions Testing Program. Using detailed metabolic and cognitive phenotyping, body composition, and tissue analyses, we ask how targeting ceramide synthesis and mitochondrial metabolism reshapes healthspan in late life.