Anna Zettergren1, Jodie Lord2, Nicholas J Ashton3,4,5,6, Andrea L Benedet7, Thomas K Karikari3, Juan Lantero Rodriguez3, Anniina Snellman3,8, Marc Suárez-Calvet9,10,11,12, Petroula Proitsi2, Henrik Zetterberg3,13,14,15, Kaj Blennow3,13. 1. Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg, Sweden. anna.zettergren@neuro.gu.se. 2. Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK. 3. Department of Psychiatry and Neurochemistry, Institute of Neuroscience & Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. 4. Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden. 5. Department of Old Age Psychiatry, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, UK. 6. NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London, UK. 7. Translational Neuroimaging Laboratory, McGill Centre for Studies in Aging, McGill University, Montreal, QC, Canada. 8. Turku PET Centre, University of Turku, Turku, Finland. 9. Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain. 10. IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. 11. Servei de Neurologia, Hospital del Mar, Barcelona, Spain. 12. Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain. 13. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. 14. Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK. 15. UK Dementia Research Institute at UCL, London, UK.
Abstract
BACKGROUND: Recent studies suggest that plasma phosphorylated tau181 (p-tau181) is a highly specific biomarker for Alzheimer's disease (AD)-related tau pathology. It has great potential for the diagnostic and prognostic evaluation of AD, since it identifies AD with the same accuracy as tau PET and CSF p-tau181 and predicts the development of AD dementia in cognitively unimpaired (CU) individuals and in those with mild cognitive impairment (MCI). Plasma p-tau181 may also be used as a biomarker in studies exploring disease pathogenesis, such as genetic or environmental risk factors for AD-type tau pathology. The aim of the present study was to investigate the relation between polygenic risk scores (PRSs) for AD and plasma p-tau181. METHODS: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) was used to examine the relation between AD PRSs, constructed based on findings in recent genome-wide association studies, and plasma p-tau181, using linear regression models. Analyses were performed in the total sample (n = 818), after stratification on diagnostic status (CU (n = 236), MCI (n = 434), AD dementia (n = 148)), and after stratification on Aβ pathology status (Aβ positives (n = 322), Aβ negatives (n = 409)). RESULTS: Associations between plasma p-tau181 and APOE PRSs (p = 3e-18-7e-15) and non-APOE PRSs (p = 3e-4-0.03) were seen in the total sample. The APOE PRSs were associated with plasma p-tau181 in all diagnostic groups (CU, MCI, and AD dementia), while the non-APOE PRSs were associated only in the MCI group. The APOE PRSs showed similar results in amyloid-β (Aβ)-positive and negative individuals (p = 5e-5-1e-3), while the non-APOE PRSs were associated with plasma p-tau181 in Aβ positives only (p = 0.02). CONCLUSIONS: Polygenic risk for AD including APOE was found to associate with plasma p-tau181 independent of diagnostic and Aβ pathology status, while polygenic risk for AD beyond APOE was associated with plasma p-tau181 only in MCI and Aβ-positive individuals. These results extend the knowledge about the relation between genetic risk for AD and p-tau181, and further support the usefulness of plasma p-tau181 as a biomarker of AD.
BACKGROUND: Recent studies suggest that plasma phosphorylated tau181 (p-tau181) is a highly specific biomarker for Alzheimer's disease (AD)-related tau pathology. It has great potential for the diagnostic and prognostic evaluation of AD, since it identifies AD with the same accuracy as tau PET and CSF p-tau181 and predicts the development of AD dementia in cognitively unimpaired (CU) individuals and in those with mild cognitive impairment (MCI). Plasma p-tau181 may also be used as a biomarker in studies exploring disease pathogenesis, such as genetic or environmental risk factors for AD-type tau pathology. The aim of the present study was to investigate the relation between polygenic risk scores (PRSs) for AD and plasma p-tau181. METHODS: Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) was used to examine the relation between AD PRSs, constructed based on findings in recent genome-wide association studies, and plasma p-tau181, using linear regression models. Analyses were performed in the total sample (n = 818), after stratification on diagnostic status (CU (n = 236), MCI (n = 434), AD dementia (n = 148)), and after stratification on Aβ pathology status (Aβ positives (n = 322), Aβ negatives (n = 409)). RESULTS: Associations between plasma p-tau181 and APOE PRSs (p = 3e-18-7e-15) and non-APOE PRSs (p = 3e-4-0.03) were seen in the total sample. The APOE PRSs were associated with plasma p-tau181 in all diagnostic groups (CU, MCI, and AD dementia), while the non-APOE PRSs were associated only in the MCI group. The APOE PRSs showed similar results in amyloid-β (Aβ)-positive and negative individuals (p = 5e-5-1e-3), while the non-APOE PRSs were associated with plasma p-tau181 in Aβ positives only (p = 0.02). CONCLUSIONS: Polygenic risk for AD including APOE was found to associate with plasma p-tau181 independent of diagnostic and Aβ pathology status, while polygenic risk for AD beyond APOE was associated with plasma p-tau181 only in MCI and Aβ-positive individuals. These results extend the knowledge about the relation between genetic risk for AD and p-tau181, and further support the usefulness of plasma p-tau181 as a biomarker of AD.
Entities:
Keywords:
Alzheimer’s disease; Plasma phosphorylated tau 181; Polygenic risk score
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