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@ARTICLE{Mourtzi:281521,
      author       = {Mourtzi, Niki and Charisis, Sokratis and Ntanasi, Eva and
                      Hatzimanolis, Alexandros and Ramirez, Alfredo and
                      Sampatakakis, Stefanos N and Yannakoulia, Mary and Kosmidis,
                      Mary H and Dardiotis, Efthimios and Hadjigeorgiou, George
                      and Sakka, Paraskevi and Mamalaki, Eirini and Papandreou,
                      Christopher and Georgakis, Marios K and Scarmeas, Nikolaos},
      title        = {{L}ongitudinal {A}ssociation of a {P}olygenic {R}isk
                      {S}core for {P}lasma {T}-{T}au {W}ith {I}ncident {A}lzheimer
                      {D}ementia and {M}ild {C}ognitive {I}mpairment.},
      journal      = {Neurology},
      volume       = {105},
      number       = {9},
      issn         = {0028-3878},
      address      = {Philadelphia, Pa.},
      publisher    = {Wolters Kluwer},
      reportid     = {DZNE-2025-01139},
      pages        = {e213904},
      year         = {2025},
      abstract     = {Elevated levels of total tau (t-tau) are a key biomarker of
                      neurodegeneration, often seen in Alzheimer disease (AD).
                      Identifying individuals at increased risk of AD using
                      minimally invasive biomarkers can enable early intervention.
                      We developed a polygenic risk score (PRS) for plasma t-tau
                      and examined its association with the risk for developing
                      clinical endophenotypes of AD pathology.This longitudinal
                      cohort study used data from the Hellenic Longitudinal
                      Investigation of Aging and Diet (HELIAD) study, involving
                      individuals aged 65 years or older, free of AD, or amnestic
                      mild cognitive impairment (aMCI-an AD prodrome) at baseline.
                      Our primary exposure was PRStau, a PRS based on common
                      genetic variants linked to plasma tau levels. The primary
                      outcome was aMCI or AD incidence. We assessed the
                      association between PRStau levels and aMCI/AD risk using Cox
                      regression models adjusted for age, sex, education, APOE ε4
                      allele carriership, and population structure. We sought
                      replication in a sample of UK Biobank (UKB) participants
                      aged 60 years or older without prevalent dementia.In the
                      HELIAD sample, among 618 cognitively healthy participants
                      (mean age 73.37 years, $58.4\%$ female), followed for 2.92
                      ± 0.80 years, 73 developed AD/aMCI. A 1 SD increase in
                      PRStau was linked to a $29\%$ higher AD/aMCI risk (hazard
                      ratio [HR] 1.290, $95\%$ CI 1.006-1.654). Stratified
                      analyses revealed greater effect estimates in women (HR
                      1.451, $95\%$ CI 1.023-2.058) and younger participants (HR
                      1.866, $95\%$ CI 1.175-2.962), whereas results in men and
                      older participants did not reach statistical significance.
                      In the UKB sample (n = 142,637, mean age 64.2 years, $52\%$
                      female), 2,737 participants developed AD over 12.9 ± 2.4
                      years of follow-up. Higher PRStau was also linked to
                      increased AD risk (HR 1.046, $95\%$ CI 1.007-1.086).These
                      results support the potential utility of PRS for plasma
                      t-tau in predicting AD/aMCI incidence. The relationship
                      between genetic predisposition for elevated plasma t-tau
                      levels and AD pathology might be influenced by sex and age,
                      suggesting that these factors should be considered in AD
                      genetic risk modeling. PRS could serve as an early indicator
                      of genetic propensity for tau pathology, enhancing existing
                      AD diagnostic and risk stratification algorithms.},
      keywords     = {Humans / Cognitive Dysfunction: blood / Cognitive
                      Dysfunction: genetics / Cognitive Dysfunction: epidemiology
                      / Aged / Female / Male / Alzheimer Disease: blood /
                      Alzheimer Disease: genetics / Alzheimer Disease:
                      epidemiology / tau Proteins: blood / tau Proteins: genetics
                      / Longitudinal Studies / Multifactorial Inheritance / Aged,
                      80 and over / Incidence / Biomarkers: blood / Risk Factors /
                      Middle Aged / Cohort Studies / Genetic Risk Score / tau
                      Proteins (NLM Chemicals) / Biomarkers (NLM Chemicals) / MAPT
                      protein, human (NLM Chemicals)},
      cin          = {Patient Studies (Bonn)},
      ddc          = {610},
      cid          = {I:(DE-2719)1011101},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41043097},
      doi          = {10.1212/WNL.0000000000213904},
      url          = {https://pub.dzne.de/record/281521},
}