Personalized prevention and halting of Alzheimer's Disease progression along the ATN axis: Targeting ApoE, neuroinflammation and lipid metabolism (R-12960)

Brains of AD patients are characterized by the progressive development of Amyloid (A), tau (T) and neurodegeneration (N) in the brains, or ATN axis, associated with a devastating disease, currently incurable. Interestingly, an initial phase of amyloid pathology precedes development of tau pathology and neurodegeneration, by more than a decade, providing a therapeutic window before symptoms develop. As AD is characterized by irreversible loss of neurons, (early) prevention is the best cure. Here, we aim to prevent AD using two different strategies. In the first, we will exploit a putative protective ApoE3chch mutation identified in human subjects capable of halting progression from amyloid to subsequent ATN stages, that are associated with symptoms. We here aim to exploit this preventive therapy offered by nature, to design innovative preventive therapies. In a second approach we aim to develop and exploit innovative insights in blood-based biomarkers as proxies for ADrelated process in the earliest pre-pathological phase to halt progression towards amyloid pathology. To these ends we will analyze preclinical models recapitulating different stages from A to ATN, and study the modifying potential in ApoE ko and ApoEchchKI mice, as well as designing and evaluating strategies modifying ApoE, lipids and neuroinflammation. We furthermore will use our ultra-sensitive technology platforms to detect Aß and tau forms as biomarkers in blood (BB-biomarkers) in the earliest pre-pathological stages in preclinical models and human subjects, and will analyze the modifying potential on Aß and tau BB-biomarkers by risk factors and prevention strategies in human cohorts. Taken together, we here aim to study 2 different prevention strategies aiming to prevent AD, by focusing on ApoE, Lipid metabolism and neuroinflammation and BB-biomarkers.

Keywords:Neuroinflammation

Disciplines:Neurological and neuromuscular diseases