ZonMw TOP grant for translational Alzheimer’s research

CNCR researcher Ronald van Kesteren receives a 675 k€ TOP grant from ZonMw to investigate alterations in brain activity that can provide new diagnostic markers or treatment targets for early-stage Alzheimer’s disease.

Project title: Interneuron networks in Alzheimer's disease: diagnostic and therapeutic implications

Alzheimer’s disease has a long prodromal stage and clinical signs become apparent only decades after onset of the disease. In-depth characterization of this prodromal disease stage holds the key to early diagnosis and early intervention. Recent studies show that excitation/inhibition imbalance in the brain and network hyperexcitability are early signs of Alzheimer’s disease. Such alterations can in principle be detected with non-invasive electro- or magneto-encephalography (M/EEG), but robust M/EEG markers for early Alzheimer’s disease are still not available.

Van Kesteren and his team have shown that interneuron hyperexcitability may be an early trigger of excitation/inhibition imbalance and network changes in Alzheimer’s disease. In this project they will characterize in detail the electrophysiological and molecular alterations in different interneuron subtypes that contribute to early network dysfunction in mice. In addition, they will collect longitudinal MEG data from prodromal Alzheimer’s disease patients, in particular PSEN1 mutation carriers that come to the clinic for genetic counselling long before they develop Alzheimer’s disease. By combining state-of the-art cell type-specific chemogenetic interventions, single-cell RNA sequencing and in vivo wireless electrophysiological recordings in mice with advanced in-house developed M/EEG analysis tools to measure excitation/inhibition ratios in patients, the team aims to find novel diagnostic or prognostic markers for Alzheimer’s disease, as well as relevant molecular targets for treatment of the disease in its earliest stage.

The project is in collaboration with CNCR neurophysiologist Klaus Linkenkaer-Hansen, VUmc Alzheimer Center neurologists Alida Gouw and Philip Scheltens and molecular neurobiologist Bart Eggen from Groningen University Medical Center.