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000281521 1001_ $$00000-0002-8650-4239$$aMourtzi, Niki$$b0
000281521 245__ $$aLongitudinal Association of a Polygenic Risk Score for Plasma T-Tau With Incident Alzheimer Dementia and Mild Cognitive Impairment.
000281521 260__ $$aPhiladelphia, Pa.$$bWolters Kluwer$$c2025
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000281521 520__ $$aElevated 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.
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000281521 650_7 $$2NLM Chemicals$$atau Proteins
000281521 650_7 $$2NLM Chemicals$$aBiomarkers
000281521 650_7 $$2NLM Chemicals$$aMAPT protein, human
000281521 650_2 $$2MeSH$$aHumans
000281521 650_2 $$2MeSH$$aCognitive Dysfunction: blood
000281521 650_2 $$2MeSH$$aCognitive Dysfunction: genetics
000281521 650_2 $$2MeSH$$aCognitive Dysfunction: epidemiology
000281521 650_2 $$2MeSH$$aAged
000281521 650_2 $$2MeSH$$aFemale
000281521 650_2 $$2MeSH$$aMale
000281521 650_2 $$2MeSH$$aAlzheimer Disease: blood
000281521 650_2 $$2MeSH$$aAlzheimer Disease: genetics
000281521 650_2 $$2MeSH$$aAlzheimer Disease: epidemiology
000281521 650_2 $$2MeSH$$atau Proteins: blood
000281521 650_2 $$2MeSH$$atau Proteins: genetics
000281521 650_2 $$2MeSH$$aLongitudinal Studies
000281521 650_2 $$2MeSH$$aMultifactorial Inheritance
000281521 650_2 $$2MeSH$$aAged, 80 and over
000281521 650_2 $$2MeSH$$aIncidence
000281521 650_2 $$2MeSH$$aBiomarkers: blood
000281521 650_2 $$2MeSH$$aRisk Factors
000281521 650_2 $$2MeSH$$aMiddle Aged
000281521 650_2 $$2MeSH$$aCohort Studies
000281521 650_2 $$2MeSH$$aGenetic Risk Score
000281521 7001_ $$00000-0001-6578-393X$$aCharisis, Sokratis$$b1
000281521 7001_ $$aNtanasi, Eva$$b2
000281521 7001_ $$aHatzimanolis, Alexandros$$b3
000281521 7001_ $$0P:(DE-2719)2812825$$aRamirez, Alfredo$$b4
000281521 7001_ $$aSampatakakis, Stefanos N$$b5
000281521 7001_ $$00000-0003-2171-7337$$aYannakoulia, Mary$$b6
000281521 7001_ $$aKosmidis, Mary H$$b7
000281521 7001_ $$00000-0003-2957-641X$$aDardiotis, Efthimios$$b8
000281521 7001_ $$00000-0001-5386-4273$$aHadjigeorgiou, George$$b9
000281521 7001_ $$aSakka, Paraskevi$$b10
000281521 7001_ $$aMamalaki, Eirini$$b11
000281521 7001_ $$aPapandreou, Christopher$$b12
000281521 7001_ $$00000-0003-3507-3659$$aGeorgakis, Marios K$$b13
000281521 7001_ $$00000-0001-6453-8908$$aScarmeas, Nikolaos$$b14
000281521 773__ $$0PERI:(DE-600)1491874-2$$a10.1212/WNL.0000000000213904$$gVol. 105, no. 9, p. e213904$$n9$$pe213904$$tNeurology$$v105$$x0028-3878$$y2025
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