Neurocognitive Aging Following Acute Illness: Pathobiology and a Framework for Developing Neurotherapeutic Agents

The purpose of this paper is to synthesize current mechanistic insights and translational progress on neurocognitive aging after critical illness and to outline a framework for developing neurotherapeutic drugs for clinical application.

The method includes a narrative, focused review of clinical studies in patients' neurocognitive symptoms after critical illness, such as sepsis, trauma, and burns, reported up to December 2025. Evidence was organized across domains, including acute systemic inflammation (ASI), communication channels to the central nervous system (CNS), neuroinflammation and neural integrity, autoimmunity in critically ill patients, and potential therapeutic targets and strategies.

Acute illness and inflammatory states, including sepsis, trauma, and burns, can lead to accelerated neurocognitive aging, early-onset cognitive impairment, and memory loss. In acute and critical illness, this is attributed to neuroinflammation, microvascular damage, blood-brain barrier (BBB) disruption, and microglial activation resulting from ASI and immune dysregulation. Current research suggests that it also induces cellular senescence, triggering immune dysregulation and subsequent autoimmunity and autoantibody production, contributing to the progression of neurocognitive aging amid chronic low-grade inflammation and inflammaging. These processes affect the function and integrity of the CNS, leading to neurocognitive decline.

This review examined the scientific basis for the development of neurocognitive aging after acute illness and how this information may be used to develop potential targets to modulate inflammatory and immune responses and treat this debilitating condition. Such interventions may reduce the burden of senescent cells, mitigate BBB breakdown, restore immune balance, and enhance the brain's neuroplasticity and resilience.