Abstract
Importance Blood 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.
Objective To 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).
Design Cross-sectional observational clinical biobank recall study called TWINGEN.
Setting Recall 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.
Participants A population-based sample of 65-85 years old twins.
Exposures Age, sex, education, Apolipoprotein E (APOE) genotype and polygenic risk score of AD (ADPRS). Monozygosity (MZ) versus dizygosity (DZ) in heritability estimation.
Main outcomes and measures Plasma p-tau217 (ALZpath pTau217 assay): continuous and >0.42 pg/mL cut-off. Heritability. Single nucleotide polymorphisms (SNP’s) in the GWAS.
Results The 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%] APOE ε4-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). APOE ε4-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 having APOE ε4-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 the APOE locus.
Conclusions and relevance Our 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.
Question To 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)?
Findings In this cross-sectional observational study of 697 twins (65-85-year-olds), older age and carrying an Apolipoprotein 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 around APOE region.
Meaning Results support using blood-based plasma p-tau217 biomarker for preclinical or prodromal AD and explain parts of its variability in aging population.
Competing Interest Statement
AP is the scientific director of the FinnGen project that is in part funded by 13 pharmaceutical companies (finngen.fi). HR is a former employee of Biogen and holds stocks at Merck & Co and Biogen.
Funding Statement
TWINGEN study was funded by the FinnGen project that is funded by two grants from Business Finland (HUS 4685/31/2016 and UH 4386/31/2016) and the following industry partners: AbbVie, AstraZeneca UK, Biogen, Bristol Myers Squibb (and Celgene Corporation & Celgene International II), Genentech, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Pfizer, GlaxoSmithKline Intellectual Property Development, Sanofi US Services, Maze Therapeutics, Janssen Biotech, Novartis, and Boehringer Ingelheim. Eero Vuoksimaa was supported by the Sigrid Juselius senior researcher funding and the Research Council of Finland (grants 314639 and 345988). Jaakko Kaprio has been supported by the Research Council of Finland Centre of Excellence in Complex Disease Genetics (grant 352792). Data collection in the twin cohort has been supported by ENGAGE - European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, the Academy of Finland Center of Excellence in Complex Disease Genetics (grant numbers: 213506, 129680), and the Academy of Finland (grants 265240, 263278 and 264146 to Kaprio). Mikko Hiltunen was supported by the Research Council of Finland (grant numbers 338182 and 353053); Sigrid Juselius Foundation; the Strategic Neuroscience Funding of the University of Eastern Finland.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
Ethical approvals for TWINGEN protocol were obtained from the Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa (HUS) (number 16831/2022) and THL Biobank approved the research plan with the permission no: THLBB2022_83.
I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
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Yes
Footnotes
↵* see Supplementary Material for FinnGen author list
Data Availability
TWINGEN data is stored at the THL Biobank for those participants who gave consent for transferring their data to the biobank. Data is available to qualified applicants from academia and companies, for details see https://thl.fi/en/research-and-development/thl-biobank/for-researchers/application-process.