UCSF

Alzheimer’s disease is the most common cause of progressive, age-associated memory loss and neuronal death. Despite recent advances in slowing disease progression, the underlying factors that confer cognitive resilience or accelerated decline remain poorly understood. Here, two potential determinants of resilience are investigated: the intrinsic energetic and metabolic profile of neurons, and the genetic context that governs the brain’s response to injury. To characterize the intrinsic metabolic landscape, we began with metabolomic profiling of iPSC-derived human neurons, which revealed a substantial contribution of the physiologic ketone β-hydroxybutyrate to energetic pathways. Subsequent studies revealed that neurons are capable of rapidly rewiring their metabolism under ketogenic conditions and preferentially oxidize the ketone acetoacetate in place of glucose. Physiologic ketone metabolism was, in fact, essential for maximum mitochondrial respiration and neuronal function. In adult-inducible, neuron-specific Bdh1 knockout mice, loss of neuronal ketone oxidation in early adulthood accelerated mortality and produced memory deficits under normal dietary conditions—phenotypes that became markedly worse on an Alzheimer’s disease background. Together, these findings establish an obligate requirement for neuronal ketone oxidation in meeting the energetic demands of the brain, with direct implications for protecting against neurodegeneration. To probe the genetic foundations of cognitive resilience, we then asked whether inherited Alzheimer’s risk factors modify cognitive change following brain irradiation, a common cancer therapy. Using mice homozygous for humanized APOE3 or APOE4, with or without knock-in mutant amyloid precursor protein (mutAPP), we demonstrated that APOE genotype shapes the cognitive outcome of irradiation in opposing directions: APOE3 mice develop worsened memory, whereas APOE4 mice maintained or improved memory, most notably in females. Introducing a mutAPP background abolished this protective effect in APOE4 mice, leaving memory deficits comparable with or without radiation. Together, these results suggest that radiation converges on a pathway shared with APOE4 and mutAPP to influence memory, and that genotype and sex jointly determine its cognitive consequences. Taken together, these studies identify metabolic and genetic factors that shape the resilience of memory during aging and Alzheimer’s disease, and in response to brain injury. They also chart a hopeful path forward: enhancing neuronal ketone metabolism offers a promising, nontraditional strategy to help preserve cognition, and APOE genotype and sex may serve as predictors for tailoring cancer therapy to protect the brain. More broadly, this work reframes cognitive decline as a process shaped by both intrinsic and extrinsic factors, revealing new avenues toward keeping neurons—and memory—intact.