In people with early-stage Alzheimer’s, brain cells become hyperexcitable during the day, and the normal calming process that should happen during sleep fails—this project will test whether boosting that sleep-related brain activity can slow or reverse cognitive decline. Dementia affects 55 million people worldwide, with Alzheimer’s disease causing 60–70% of cases. Current treatments do not stop or reverse cognitive decline. The researchers hypothesise that toxic protein aggregates trigger neural hyperexcitability, and that a deficit in homeostatic plasticity—the brain’s nightly reset mechanism—makes this worse. They will measure neural activity during sleep, neural excitability, and cognitive performance in a cohort of people with early-stage Alzheimer’s, then use non-invasive brain stimulation to augment the homeostatic plasticity effect, first acutely and then repeatedly over days. If successful, this project would establish a clear mechanism for cognitive decline in early Alzheimer’s and demonstrate a neuromodulation therapy that could be developed into a clinically meaningful treatment. That would directly affect the daily lives of millions of patients and their families by potentially preserving memory and independence for years longer than current care allows.
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Dementia is a global health challenge, with an estimated 55 million individuals globally, projected to increase to 152 million by 2050. The leading cause of dementia is Alzheimer’s disease (AD), a neurodegenerative disease accounting for 60–70% of all dementia cases. There is an urgent need for a therapeutic breakthrough that stops and even reverses the cognitive decline in a broad range of AD patients. Since cognitive functions arise from the interactions between many neurons organised in circuits, the central question of this project is how AD-induced abnormalities in individual neurons eventually impair the function of the embedding circuits. We hypothesise that neural hyperexcitability contributes to the pathogenesis of cognitive impairments in early-stage AD. Toxin aggregates trigger neural hyperexcitability but escalate by a deficit in homeostatic plasticity during sleep. This project aims to establish the scientific evidence of the neural plasticity mechanism in people with early AD and then demonstrate a neuromodulation strategy to ameliorate it. It involves a stepwise experiment that includes two studies with repeated measurements of neural activity during sleep, neural excitability, and cognitive performance before and after in a cohort of people with early-stage AD. We will also use novel non-invasive brain stimulation technology to augment the neural activity during sleep that is known to have a homeostatic plasticity effect, first acutely and then repeatedly over days. If successful, the project will elucidate a pathogenesis mechanism in the early stages of AD that is critical for developing clinically meaningful therapies and demonstrate the feasibility of a neuromodulation therapeutic strategy.
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