Ludwig Maximilian University Munich
Institute for Stroke and Dementia Research
Dr. Michael Ewers received his PhD in Cognitive Psychology in 2003, following a Fulbright scholarship in 1998. Michael worked as a post-doc at the Ludwig Maximilian University, and subsequently as research scientist at institutions including Trinity College Dublin (Ireland) and University of California at San Francisco (USA). Since 2012 he is Associate Professor at the Ludwig-Maximilian-University Munich. Michael Ewers is head of the neuroimaging facility at the Institute of Stroke and Dementia Research at the University Hospital, LMU and is leading a research group on neuroimaging and biomarker research in Alzheimer’s disease. Michael Ewers’ lab combines functional connectomics, genetics and molecular PET markers to model the spatiotemporal evolution of fibrillar tau and beta-amyloid. The lab has developed connectome-based prediction models for the patient-tailored prediction of tau pathology (Franzmeier et al. Nature Comm 2020, Science Adv 2021). Another major research centers on the understanding of reserve and resilience in Alzheimer’s disease, which lead to the discovery of major hubs that support cognitive resilience in Alzheimer’s disease (Franzmeier et al. Brain, 2018, Ewers et al. Brain 2020). His lab also revealed the protective of a SNP in the longevity gene KLOTHO on the progression of tau pathology in Alzheimer’s (Neitzel et al Nature Comm 2021). Michael Ewers is senior editor of the Alzheimer Association’s journal Alzheimer’s & Dementia, and has published over 130 publications with > 10000 citations, and an H-index of 56 (Google scholar). Dr. Ewers received several awards, most recently the deLeon Senior Researcher Prize 2021 at the Alzheimer’s Association International Conference (AAIC).

Moderator of 1 Session

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
08:30 AM - 10:30 AM
Room
ONSITE: 113

Presenter of 1 Presentation

POLYGENIC SCORE ASSOCIATED WITH ACCELERATED INCREASES IN TAU PET ACCUMULATION IN ALZHEIMER’S DISEASE

Session Type
SYMPOSIUM
Date
Wed, 16.03.2022
Session Time
08:30 AM - 10:30 AM
Room
ONSITE: 113
Lecture Time
09:45 AM - 10:00 AM

Abstract

Aims

Polygenic scores (PGS) are a powerful tool to combine the predictive value of GWAS-identified genetic variants, but the value to predict the rate of progression in tau pathology underlying cognitive worsening is unclear.

To test whether:

higher PGS is associated with longitudinal rates of tau PET.

PGS effects on tau progression were cell-type specific.

risk stratification by PGS is of utility for saving sample size in clinical trials on tau.

Methods

We leveraged the yet largest number of lead SNPs (n = 85) from two recent GWAS including up to 1.1 million participants (Bellenguez et al., 2020; Wightman et al., 2020) to estimate the PGS in over 1800 participants assessed by longitudinal composite memory scores and global cognition (average FU-duration = 4 yrs) and tau-PET (N = 231, average FU-duration = 2 yrs) from ADNI. In linear mixed effects models, we tested PGS to predict the rate of tau-PET in major Braak-stage ROIs and on cognitive decline.

Results

Higher PGS was associated with faster rates of increases in tau-PET, which was pronounced in amyloid-PET positive participants independent of APOE genotype. Faster tau-PET increases mediated PGS effects on cognitive decline. Cell-type specific PGS analysis implicated microglia and oligodendrocytes alterations in faster tau-PET progression. Risk stratification (> median PGS) reduced by 15% the required sample size to detect a 20%-treatment effect on tau-PET progression in amyloid-positive participants.

Conclusions

PGS is associated with faster increases in tau-PET and provides utility for risk stratification in disease-modifying treatments on tau.

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