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J Alzheimers Dis. 2017;55(2):473-484.

Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer's Disease.

Darst BF1,2, Koscik RL1,3, Racine AM1,4, Oh JM1,4, Krause RA1,4, Carlsson CM1,3,4,5, Zetterberg H6,7, Blennow K6, Christian BT1,8, Bendlin BB1,3,4, Okonkwo OC1,3,4,5, Hogan KJ1,3,9, Hermann BP1,3,5,10, Sager MA1,3, Asthana S1,3,4,5, Johnson SC1,3,4,5, Engelman CD1,2,3,4.

Author information

1
University of Wisconsin, Madison, WI, USA.
2
Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
3
Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
4
Alzheimer's Diseases Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
5
Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial VA Hospital, Madison, WI, USA.
6
Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
7
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
8
Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
9
Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
10
Department of Neurology, University of Wisconsin School of Medicine and Public Health, WI, USA.

Abstract

Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer's disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer's Project's meta-analysis, we identified clusters of genes that grouped into pathways involved in amyloid-β (Aβ) deposition and neurodegeneration: Aβ clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral Aβ deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging in 168 individuals, and cerebrospinal fluid Aβ deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.

KEYWORDS:

APOE; Alzheimer’s disease; Pittsburgh compound B; WRAP; amyloid-beta; cerebrospinal fluid; cognitive function; genetic risk scores; genetics; polygenic risk scores

PMID:
27662287
PMCID:
PMC5123972
DOI:
10.3233/JAD-160195
[Indexed for MEDLINE]
Free PMC Article

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