In a tissue bank containing over 5,000 donated brains, researchers discovered 12 brains with Alzheimer’s disease pathology but no accompanying symptoms. Here, we delve into the biochemical variances found in these resilient brains, hoping to shed light on the condition and potential therapeutic strategies.
Some individuals display resilience to Alzheimer’s disease, exhibiting cognitive function despite neuropathological changes. The molecular basis for this resilience remains unclear. To better understand the molecular alterations linked to resilience, we examined gene expression in the brains of Alzheimer’s patients, resilient individuals, and controls.
Our analysis revealed significant gene expression differences between AD and controls, resilient individuals and controls, and resilient individuals and AD. Metallothionein (MT) and genes associated with mitochondrial processes were upregulated in resilient brains. Additionally, gene network analyses highlighted modules linked to the unfolded protein response, mitochondria, and synaptic signaling as contributors to resilience.
Further validation through immunohistochemistry confirmed elevated MT levels in astrocytes of resilient individuals, as well as differential mitochondrial gene expression and increased heat shock protein levels. Sex-specific alterations in resilience were also observed, particularly related to autophagy in females.
These findings suggest potential mechanisms involving MTs, mitochondria, and the unfolded protein response in maintaining cognitive function despite Alzheimer’s pathology. Understanding these mechanisms could lead to the development of effective therapeutic interventions.
