Plasma biomarkers and genetics in the diagnosis and prediction of Alzheimer’s disease

Author:

Stevenson-Hoare Joshua1ORCID,Heslegrave Amanda23,Leonenko Ganna1,Fathalla Dina1,Bellou Eftychia1,Luckcuck Lauren1,Marshall Rachel4,Sims Rebecca4,Morgan Bryan Paul1,Hardy John23,de Strooper Bart256,Williams Julie1,Zetterberg Henrik23789ORCID,Escott-Price Valentina14ORCID

Affiliation:

1. Dementia Research Institute, Cardiff University , Cardiff , UK

2. Dementia Research Institute, University College London , London , UK

3. Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square , London , UK

4. Division of Neuroscience and Mental Health, Cardiff University , Cardiff , UK

5. VIB Center for Brain and Disease Research , 3000 Leuven , Belgium

6. KU Leuven, Leuven Brain Institute , 3000 Leuven , Belgium

7. Hong Kong Center for Neurodegenerative Diseases , Hong Kong , China

8. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg , Mölndal , Sweden

9. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital , Mölndal , Sweden

Abstract

Abstract Plasma biomarkers for Alzheimer’s disease-related pathologies have undergone rapid developments during the past few years, and there are now well-validated blood tests for amyloid and tau pathology, as well as neurodegeneration and astrocytic activation. To define Alzheimer’s disease with biomarkers rather than clinical assessment, we assessed prediction of research-diagnosed disease status using these biomarkers and tested genetic variants associated with the biomarkers that may reflect more accurately the risk of biochemically defined Alzheimer’s disease instead of the risk of dementia. In a cohort of Alzheimer’s disease cases [n = 1439, mean age 68 years (standard deviation = 8.2)] and screened controls [n = 508, mean age 82 years (standard deviation = 6.8)], we measured plasma concentrations of the 40 and 42 amino acid-long amyloid-β (Aβ) fragments (Aβ40 and Aβ42, respectively), tau phosphorylated at amino acid 181 (P-tau181), neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) using state-of-the-art Single molecule array (Simoa) technology. We tested the relationships between the biomarkers and Alzheimer’s disease genetic risk, age at onset and disease duration. We also conducted a genome-wide association study for association of disease risk genes with these biomarkers. The prediction accuracy of Alzheimer’s disease clinical diagnosis by the combination of all biomarkers, APOE and polygenic risk score reached area under receiver operating characteristic curve (AUC) = 0.81, with the most significant contributors being ε4, Aβ40 or Aβ42, GFAP and NfL. All biomarkers were significantly associated with age in cases and controls (P < 4.3 × 10−5). Concentrations of the Aβ-related biomarkers in plasma were significantly lower in cases compared with controls, whereas other biomarker levels were significantly higher in cases. In the case-control genome-wide analyses, APOE-ε4 was associated with all biomarkers (P = 0.011−4.78 × 10−8), except NfL. No novel genome-wide significant single nucleotide polymorphisms were found in the case-control design; however, in a case-only analysis, we found two independent genome-wide significant associations between the Aβ42/Aβ40 ratio and WWOX and COPG2 genes. Disease prediction modelling by the combination of all biomarkers indicates that the variance attributed to P-tau181 is mostly captured by APOE-ε4, whereas Aβ40, Aβ42, GFAP and NfL biomarkers explain additional variation over and above APOE. We identified novel plausible genome wide-significant genes associated with Aβ42/Aβ40 ratio in a sample which is 50 times smaller than current genome-wide association studies in Alzheimer’s disease.

Funder

Medical Research Council

Alzheimer’s Research UK

Welsh Government

MRC Centre for Neuropsychiatric Genetics and Genomics

The Moondance Foundation

VIB and KU Leuven

European Union

Fonds voor Wetenschappelijk Onderzoek

Geneeskundige Stichting Koningin Elisabeth

Belgian Alzheimer Research Foundation

Swedish Research Council

European Research Council

Swedish State Support for Clinical Research

Alzheimer Drug Discovery Foundation

AD Strategic Fund and the Alzheimer's Association

Olav Thon Foundation

Erling-Persson Family Foundation

Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden

European Union Joint Program for Neurodegenerative Disorders

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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