Maintaining and regaining episodic memory in Alzheimer disease: a circuit-based perspective

Losing track of personal experiences is a defining feature of Alzheimer disease (AD), arising from the spread of AD pathology through the brain circuits that support episodic memory. In this Review, we explore strategies to improve the function of episodic memory circuits in AD by leveraging the optimized use of neural resources. We introduce the circuit utilization framework, which builds on evidence that synaptic dysfunction, maladaptive responses and deficient adaptive plasticity contribute to episodic memory impairment. The circuit utilization framework posits that by optimizing the utilization of circuit resources, episodic memory function can be partially regained. Our focus includes mitigation of hypoactive and hyperactive synaptic dysfunction, reduction of maladaptive processes and enhancement of brain and cognitive reserve. The circuit utilization framework is grounded in circuit-specific hypotheses that link the component processes of episodic memory to clinical symptoms of memory impairment and AD progression. Its overarching aim is to guide the development of interventions that support episodic memory in people with AD, complementing disease-modifying treatments such as anti-amyloid antibody therapies.