New grant to study early brain signals of Alzheimer’s disease

We are grateful to receive a grant from the Alzheimer’s Association “New to the Field” research program and the Brain Canada Foundation to transfer our expertise in time resolved brain imaging to Alzheimer’s research.

We will study new electrophysiological measures of proteinopathy in asymptomatic older adults. This work is in collaboration with Prof Sylvia Villeneuve, Dr. Alex Wiesman, Jonathan Gallego and the PREVENT-AD cohort.

The accumulation of amyloid-beta (Aβ) and tau are hallmarks of Alzheimer’s disease (AD) pathophysiology. Current tests for AD proteinopathy involve costly radiotracers and imaging procedures (PET), or are invasive and anatomically non-specific (e.g., lumbar puncture), which hinders mechanistic insight. In addition, and to date, their predictive value of conversion to AD is uncertain in asymptomatic individuals. We propose to develop an entirely non-invasive brain mapping procedure of AD proteinopathy in asymptomatic older adults. We will transfer to AD research our recent advances with magnetoencephalography (MEG) where we showed that i) neurophysiological oscillations play a causal role in complex behaviour and cognition, and that ii) they can robustly differentiate between individuals over weeks, months, and years.

We will establish whether such neurophysiological brain fingerprints are sensitive to the Aβ/tau concentrations that start accumulating early in pre-symptomatic brains. Our main premise is that AD proteinopathy, even at its earliest stages, develops alongside subtle perturbations of neural dynamics in local circuits, and gradually affects brain networks as the disease progresses and cognitive symptoms start to manifest. 

Previous work has established that pathological and clinical features of AD covary with alterations of neurophysiological activity measured by electroencephalography (EEG) or MEG. So far, studies have reported changes of brain rhythmic patterns in prodromal and symptomatic stages, leading to a hypothesis of neural “slowing” in AD. How these observations relate to AD proteinopathy remains an unresolved issue, with significant potential impact on our ability to detect and track individual progression and the outcome of present and future interventions. 

AD disease models suggest that early Aβ deposition leads to neuronal hyperexcitability, whereas later additive effects of aggregated Aβ plaques and tau neurofibrillary tangles may cause synapses loss and induce a shift towards suppression of neuronal activity. The present absence of similar evidence in humans represents a major knowledge gap in the field, both at the fundamental level, and considering emerging therapeutics for reversing neural hypoexcitability. 

We specifically aim to (1) produce proxy maps of Aβ and tau concentrations from fast and non-invasive MEG imaging in a large, existing cohort of participants, and (2) relate longitudinal neurophysiological changes to progressive cognitive and clinical declines. 

Overall, our project will address a key question that so far has hindered the clinical implementation of a safe, quick, and repeatable assessment of AD progression. If our proposition of short, minutes-long recordings of task-free brain activity yields a reliable proxy map of proteinopathy in asymptomatic individuals, the impact on earlier diagnosis, tracking of disease stages and assessment of pharmacotherapy efficacy would be of major significance.

We also foresee transfers to widely accessible, routine clinical EEG and possible new targets for clinical intervention via e.g., non-invasive neurostimulation6. Fundamentally, the new link established between AD proteinopathy and changing patterns of neuronal activity in asymptomatic individuals will advance the mechanistic understanding of the cascade of biological events leading to AD-type dementia. Finally, we are resolute to openly share all data and software tools to encourage replicability and catalyze future AD research.