The Role of ApoE4 in The Acceleration of Tau Aggregation.
Poster No:
231
Submission Type:
Abstract Submission
Authors:
Anna Steward1, Davina Biel1, Anna Dewenter1, Sebastian Niclas Roemer1, Zeyu Zhu1, Julia Pescoller1, Martin Dichgans2, Michael Ewers2,3, Amir Dehsarvi1, Matthias Brendel1, Nicolai Franzmeier1,4
Institutions:
1University Hospital LMU Munich, Munich, Bavaria, 2Institute for Stroke and Dementia Research, Munich, Bavaria, 3German Center for Neurodegenerative Diseases (DZNE), Munich, Germany, 4University of Gothenburg, Gothenburg, Sweden
First Author:
Co-Author(s):
Michael Ewers
Institute for Stroke and Dementia Research|German Center for Neurodegenerative Diseases (DZNE)
Munich, Bavaria|Munich, Germany
Institute for Stroke and Dementia Research|German Center for Neurodegenerative Diseases (DZNE)
Munich, Bavaria|Munich, Germany
Nicolai Franzmeier
University Hospital LMU Munich|University of Gothenburg
Munich, Bavaria|Gothenburg, Sweden
University Hospital LMU Munich|University of Gothenburg
Munich, Bavaria|Gothenburg, Sweden
Introduction:
Understanding the factors that affect the pathophysiological progression of Alzheimer's disease (AD) is crucial for determining the ideal timing and targets for treatment in each AD patient. One of these factors, the Apolipoprotein E ε4 allele (ApoE4), carried by 40-60% (Ward, Crean et al. 2012) of sporadic AD patients, has been associated with quicker spreading of amyloid beta (Aβ)-related tau at lower Aβ levels (Steward, Biel et al. 2023). However, the specific mechanisms driving this connection remain unclear. The major aim of this project was to understand how ApoE4 influences the pathological pathway of tau processes that lead to Aβ-related tau aggregation.
Methods The influence of ApoE4 on the connection between tau hyperphosphorylation and aggregation in relation to Aβ levels was examined through the cross-sectional analysis of CSF phosphorylated tau (P-tau/Aβ40) with tau- and Aβ-PET in 284 APOE genotyped cognitively normal and mildly cognitively impaired subjects from ADNI.
Methods The influence of ApoE4 on the connection between tau hyperphosphorylation and aggregation in relation to Aβ levels was examined through the cross-sectional analysis of CSF phosphorylated tau (P-tau/Aβ40) with tau- and Aβ-PET in 284 APOE genotyped cognitively normal and mildly cognitively impaired subjects from ADNI.
Methods:
The influence of ApoE4 on the connection between tau hyperphosphorylation and aggregation in relation to Aβ levels was examined through the cross-sectional analysis of CSF phosphorylated tau (P-tau/Aβ40) with tau- and Aβ-PET in 284 APOE genotyped cognitively normal and mildly cognitively impaired subjects from ADNI.
Results:
Findings demonstrated that ApoE4 did not moderate the relationship between Aβ-PET and P-tau/Aβ40 (Fig2.A, β=-0.03, p=0.69) but significantly moderated the relationship between P-tau/Aβ40 and Tau-PET (Fig2.B, β=0.72, p<0.001). Furthermore, we confirm the previously observed mediation effect of P-tau/Aβ40 on Aβ-related tau aggregation (Fig2.C, ACME: B=0.28; p<0.001; ADE: B=0.206; p=0.008) and found this to be moderated by ApoE4 (B=0.21, p=0.006).
Conclusions:
Results indicate that ApoE4 plays a role in the aggregation phase of tau but does not influence the level of Aβ-related tau phosphorylation and p-tau secretion. Furthermore, the moderated mediation analysis indicates that ApoE4 carriers experience faster tau spreading at lower Aβ levels due to ApoE4 enhancing Aβ-related aggregation of soluble tau into neurofibrillary tau tangles. These findings promote soluble tau as a potential therapeutic target in ApoE4 carriers to help prevent extensive tau aggregation across the cortex and therefore cognitive decline and dementia.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Novel Imaging Acquisition Methods:
PET 2
Keywords:
Data analysis
Degenerative Disease
Positron Emission Tomography (PET)
Other - Genetic Risk
1|2Indicates the priority used for review
Provide references using author date format
Ward, A., S. Crean, C. J. Mercaldi, J. M. Collins, D. Boyd, M. N. Cook and H. M. Arrighi (2012). "Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer’s disease: a systematic review and meta-analysis." Neuroepidemiology 38(1): 1-17.