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000283094 0247_ $$2ISSN$$a1552-5279
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000283094 041__ $$aEnglish
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000283094 1001_ $$aValentim, Carolina$$b0
000283094 1112_ $$aAlzheimer’s Association International Conference$$cToronto$$d2025-07-27 - 2025-07-31$$gAAIC 25$$wCanada
000283094 245__ $$aPolygenic risk scores modify the association between amyloid and tau PET accumulation in patients with Alzheimer’s disease
000283094 260__ $$c2025
000283094 3367_ $$0PUB:(DE-HGF)1$$2PUB:(DE-HGF)$$aAbstract$$babstract$$mabstract$$s1767099035_6287
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000283094 520__ $$aGenome-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 & 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.
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000283094 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000283094 650_7 $$2NLM Chemicals$$atau Proteins
000283094 650_7 $$2NLM Chemicals$$aAniline Compounds
000283094 650_7 $$06867Q6IKOD$$2NLM Chemicals$$aflorbetapir
000283094 650_7 $$2NLM Chemicals$$aEthylene Glycols
000283094 650_2 $$2MeSH$$aHumans
000283094 650_2 $$2MeSH$$aAlzheimer Disease: genetics
000283094 650_2 $$2MeSH$$aAlzheimer Disease: diagnostic imaging
000283094 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000283094 650_2 $$2MeSH$$aMale
000283094 650_2 $$2MeSH$$aAged
000283094 650_2 $$2MeSH$$aFemale
000283094 650_2 $$2MeSH$$aGenome-Wide Association Study
000283094 650_2 $$2MeSH$$aPositron-Emission Tomography
000283094 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000283094 650_2 $$2MeSH$$atau Proteins: metabolism
000283094 650_2 $$2MeSH$$aAged, 80 and over
000283094 650_2 $$2MeSH$$aCross-Sectional Studies
000283094 650_2 $$2MeSH$$aPolymorphism, Single Nucleotide
000283094 650_2 $$2MeSH$$aBrain: diagnostic imaging
000283094 650_2 $$2MeSH$$aBrain: metabolism
000283094 650_2 $$2MeSH$$aAniline Compounds
000283094 650_2 $$2MeSH$$aEthylene Glycols
000283094 7001_ $$aDenecke, Jannis$$b1
000283094 7001_ $$aFrerich, Simon$$b2
000283094 7001_ $$aMalik, Rainer$$b3
000283094 7001_ $$aFranzmeier, Nicolai$$b4
000283094 7001_ $$0P:(DE-2719)9000543$$aEwers, Michael$$b5$$eLast author
000283094 773__ $$0PERI:(DE-600)2201940-6$$a10.1002/alz70862_110860$$gVol. 21 Suppl 8, no. Suppl 8, p. e110860$$nSuppl 8$$pe110860$$tAlzheimer's and dementia$$v21$$x1552-5260$$y2025
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