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Tau Pathology in Alzheimer’s disease: Spreading and Resilience

Objective

Alzheimer’s disease (AD) poses a major challenge, as 40 million people worldwide are diagnosed with AD and there is currently no cure. AD is characterized by Aβ plaques and tau neurofibrillary tangles. Recently, several phase III clinical trials targeting the Aβ pathway have failed to reach their primary endpoints. This stresses the need for diversification of the drug portfolio. Tau pathology is a promising drug target due to its strong associations with synaptic density, atrophy and cognition. I envision two treatment options to be potentially effective in halting or slowing AD: 1) preventing the spreading of pathological tau, and 2) boosting resilience against tau pathology. Both processes are currently insufficiently understood, especially in living humans. Since a few years, AD-specific tau pathology can be measured in vivo using PET. TAU-NOW uniquely utilizes longitudinal tau PET in conjunction with functional and structural MRI, biofluid and cognitive data, to investigate mechanisms of tau spread and resilience in humans. In WP1, I will test the hypothesis that tau predominantly spreads through functionally connected regions, by relating tau PET changes over time to the functional architecture of the brain. Next, molecular (CSF) and genetic (GWAS) drivers of tau spread will be identified. On top of that, I will assess whether functional disconnection in subjects who underwent epileptic surgery (i.e. unilateral medial temporal lobe resection or corpus callosotomy) leads to an asymmetric tau PET pattern decades later. In WP2, I will investigate the functional (fMRI), molecular and genetic modifiers that render individuals resilient to tau pathology. In WP3, I will examine the consequences of tau spreading and resilience for important clinical trial outcomes like cognitive and volumetric changes over time. Altogether, TAU-NOW will enhance our understanding of tau spreading and resilience and may ultimately identify novel leads for drug discovery against AD.

Call for proposal

ERC-2020-STG
See other projects for this call

Funding Scheme

ERC-STG - Starting Grant

Host institution

LUNDS UNIVERSITET
Address
Paradisgatan 5C
22100 Lund
Sweden
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 860 192,50

Beneficiaries (2)

LUNDS UNIVERSITET
Sweden
EU contribution
€ 860 192,50
Address
Paradisgatan 5C
22100 Lund
Activity type
Higher or Secondary Education Establishments
STICHTING VUMC
Netherlands
EU contribution
€ 639 807,50
Address
De Boelelaan 1117
1081 HV Amsterdam
Activity type
Research Organisations