Prof. Dr. Bart De Strooper

Director of the UK Dementia Research institute, Professor at Faculty of Brain Sciences, UCL, Professor at Department for Neurosciences, KU Leuven, Head VIB Laboratory for the Research of Neurodegenerative Diseases

Title: The cellular phase of Alzheimer’s Disease and how that affects the effectivity of anti-amyloid therapies

Abstract:The recent success of the Lecanemab antibody trial for the treatment of Alzheimer’s Disease has validated the hard core findings of basic research performed in the field over many years and reinforced the hypothesis that amyloid-beta peptides are triggers of the disease process (Karran et al, Nature drug discovery, 2011). However amyloid peptide is only the trigger of the disease which is then followed by a long preclinical cellular phase (De Strooper, Karran, Cell 2016). This cellular phase might encompass processes that become independent of the trigger (Tau pathology, inflammation), and are even irreversible (neuronal loss). Thus when the clinical trials measure effects on cognition and behaviour, it should be taken into account that quite some serious damage to the brain has already occurred. Until a few weeks ago we did not know whether reversing amyloid pathology at such late stage (considering MCI a late stage of the disease) would have still clinical effects. The moderate effects of Lecanemab at the clinical level suggest strongly that treating amyloid beta pathology early (eg biomarker positive, clinical normal) will give more benefit to the patient (Karran and De Strooper, Nature reviews drug discovery, 2022). I will review the cellular processes triggered by amyloid pathology and argue that treatments of the cellular phase are needed to complement the anti-amyloid treatments currently under development. We use spatial transcriptomics and novel human-mouse chimeric models to understand how genetic risk of Alzheimer’s disease not only drives amyloid peptide generation but also the cellular response in a protective or damaging way.