Cross-sectional study of plasma phosphorylated Tau 217 in persons without dementia
Authors: Saari Toni T. , Palviainen Teemu , Hiltunen Mikko , Herukka Sanna-Kaisa , Kokkola Tarja , Kärkkäinen Sari , Urjansson Mia , Aaltonen Aino , Palotie Aarno , Runz Heiko , Kaprio Jaakko , Julkunen Valtteri , Vuoksimaa Eero ,   FinnGen
Published: May 2024

AbstractImportanceBlood levels of phosphorylated tau 217 (p-tau217) as measured by commercially available immunoassays are an emerging tool to assess Alzheimer’s disease (AD) pathology. Little is known about the performance of p-tau217 and contributors to its variability in aged individuals without AD.ObjectiveTo determine plasma p-tau217, its associations with age, sex, education and genetic risk, to estimate heritability, and to conduct a genome-wide association study (GWAS).DesignCross-sectional observational clinical biobank recall study called TWINGEN.SettingRecall of participants in the older Finnish Twin Cohort study without AD and other diagnoses affecting cognition based on health registry data. Sample collection in March 2023– December 2023 in six study sites across Finland. Biomarkers were determined in January 2024 and data were analyzed in March–April 2024.ParticipantsA population-based sample of 65-85 years old twins.ExposuresAge, sex, education,Apolipoprotein E(APOE) genotype and polygenic risk score of AD (ADPRS). Monozygosity (MZ) versus dizygosity (DZ) in heritability estimation.Main outcomes and measuresPlasma p-tau217 (ALZpath pTau217 assay): continuous and >0.42 pg/mL cut-off. Heritability. Single nucleotide polymorphisms (SNP’s) in the GWAS.ResultsThe study included 697 participants (mean [SD] age, 76.2 [4.6] years); 398 [57%] women and 299 [43%] men; 240 MZ [81 full pairs], 450 DZ [73 full pairs]; and 203 [29%]APOEε4-allele carriers. P-tau217 was higher as a function of age (means [SDs] from 0.32 [0.20] pg/mL in 65-69 year-olds to 0.53 [0.36] pg/mL in 80-85 year-olds). Twin-based heritability was 0.56 (95%CI 0.36-0.79).APOEε4-allele carriers (mean [SD]= 0.58 [0.35] pg/mL) had higher p-tau217 than non-carriers (mean [SD]= 0.39 [0.27] pg/ml,P<.001). Abnormal p-tau217 levels of >0.42 pg/mL were evident in 39% and predicted by higher age (OR=1.15 [95%CI, 1.10-1.20]) and havingAPOEε4-allele (OR=4.53 [95%CI, 3.10-6.62]). Sex, education and ADPRS were not related to p-tau217 levels or abnormality. GWAS indicated 45 SNPs associated with p-tau217 plasma levels (P<5x10−08) centered around theAPOElocus.Conclusions and relevanceOur results support the use of plasma p-tau217 as a biomarker in detecting preclinical or prodromal AD and in genome-wide association studies of biologically defined AD.Key pointsQuestionTo what extent are individual differences and abnormality in plasma p-tau217 associated with age, sex, and genetic factors in a population-based sample without a diagnosis of Alzheimer’s disease (AD)?FindingsIn this cross-sectional observational study of 697 twins (65-85-year-olds), older age and carrying anApolipoprotein E(APOE) ε4-allele were associated with higher plasma p-tau217; abnormal levels were evident in 39% of participants. The twin-based heritability estimate was 56% and genome-wide association study implicated genes aroundAPOEregion.MeaningResults support using blood-based plasma p-tau217 biomarker for preclinical or prodromal AD and explain parts of its variability in aging population.