TY  - CONF
AU  - Valentim, Carolina
AU  - Denecke, Jannis
AU  - Frerich, Simon
AU  - Malik, Rainer
AU  - Franzmeier, Nicolai
AU  - Ewers, Michael
TI  - Polygenic risk scores modify the association between amyloid and tau PET accumulation in patients with Alzheimer’s disease
JO  - Alzheimer's and dementia
VL  - 21
IS  - Suppl 8
SN  - 1552-5260
M1  - DZNE-2025-01501
SP  - e110860
PY  - 2025
AB  - Genome-wide association studies (GWAS) have identified a larger number of genetic variants that are associated with increased risk of AD dementia. The biological pathways that underlie the link between SNPs and the development of core AD pathologies remain however unclear. Here, we generated pathway-specific polygenic risk scores to test their modulating effect on the association between amyloid-beta (Aβ) chronicity and tau deposition in patients with AD.We analysed 295 amyloid-PET-positive participants from ADNI (mean age 76.5 ± 7.6; 165 CU, 85 MCI, 45 Dementia) with cross-sectional genetic, cognitive, and tau-PET (AV1451) and Aβ-PET (Florbetapir and Florbetaben) data. We identified in a meta-analysis of recent genome-wide association studies (GWAS) 388 independent SNPs associated with AD. We computed six pathway-specific PRS based on gene set enrichment analysis identifying the pathways implicating amyloid beta, immune activation, endocytosis/transport, clearance and signal transduction (Figure 1). Aβ-chronicity was estimated using the Sampled Iterative Local Approximation (SILA) technique (Betthauser et al., 2022), which infers the temporal trajectory and extent of amyloid accumulation by aligning PET-derived amyloid burden across longitudinal data points. Robust linear regression (Huber method) models assessed interactions between SILA-derived Aβ-chronicity and tau-PET uptake in Braak-stage ROIs (I, III-IV, and V-VI), controlling APOE-ε4 status, age, sex and education. Outliers were defined as three standard deviations from the mean.Significant interactions between Aβ-chronicity and pathway-PRS for amyloid beta and endocytosis/transport were observed, with higher genetic risk amplifying the association between longer amyloid exposure and tau accumulation in Braak-stage ROIs III-IV </td><td width="150">
AB  -  V-VI (p < 0.03). Effects remained significant after the removal of predefined outliers (p < 0.02).Our findings indicate that genetic variations, particularly within the amyloid-beta and endocytosis/transport pathways, strengthen the association between longer amyloid exposure and increased tau pathology. The significance of the amyloid-beta pathway suggests a direct genetic contribution to amyloid-driven tau accumulation, whereas the endocytosis/transport pathway findings support the hypothesis that amyloid-tau interactions at the synaptic level drive AD progression. These results align with prior evidence on mechanistic links between amyloid and tau pathology in AD.
T2  - Alzheimer’s Association International Conference
CY  - 27 Jul 2025 - 31 Jul 2025, Toronto (Canada)
Y2  - 27 Jul 2025 - 31 Jul 2025
M2  - Toronto, Canada
KW  - Humans
KW  - Alzheimer Disease: genetics
KW  - Alzheimer Disease: diagnostic imaging
KW  - Alzheimer Disease: metabolism
KW  - Male
KW  - Aged
KW  - Female
KW  - Genome-Wide Association Study
KW  - Positron-Emission Tomography
KW  - Amyloid beta-Peptides: metabolism
KW  - tau Proteins: metabolism
KW  - Aged, 80 and over
KW  - Cross-Sectional Studies
KW  - Polymorphism, Single Nucleotide
KW  - Brain: diagnostic imaging
KW  - Brain: metabolism
KW  - Aniline Compounds
KW  - Ethylene Glycols
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
KW  - Aniline Compounds (NLM Chemicals)
KW  - florbetapir (NLM Chemicals)
KW  - Ethylene Glycols (NLM Chemicals)
LB  - PUB:(DE-HGF)1 ; PUB:(DE-HGF)16
C6  - pmid:41433394
C2  - pmc:PMC12725496
DO  - DOI:10.1002/alz70862_110860
UR  - https://pub.dzne.de/record/283094
ER  -