Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-β Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer's Disease.
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.
University of Wisconsin, Madison, WI, USA.|Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Burcu F
BF
Darst
University of Wisconsin, Madison, WI, USA.|Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Rebecca L
RL
Koscik
University of Wisconsin, Madison, WI, USA.|Alzheimer's Diseases Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Annie M
AM
Racine
University of Wisconsin, Madison, WI, USA.|Alzheimer's Diseases Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Jennifer M
JM
Oh
University of Wisconsin, Madison, WI, USA.|Alzheimer's Diseases Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Rachel A
RA
Krause
University of Wisconsin, Madison, WI, USA.|Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Alzheimer's Diseases Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial VA Hospital, Madison, WI, USA.
Cynthia M
CM
Carlsson
Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.|Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
Henrik
H
Zetterberg
Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Sweden.
Kaj
K
Blennow
University of Wisconsin, Madison, WI, USA.|Department of Medical Physics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Bradley T
BT
Christian
University of Wisconsin, Madison, WI, USA.|Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Alzheimer's Diseases Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Barbara B
BB
Bendlin
University of Wisconsin, Madison, WI, USA.|Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Alzheimer's Diseases Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial VA Hospital, Madison, WI, USA.
Ozioma C
OC
Okonkwo
University of Wisconsin, Madison, WI, USA.|Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Kirk J
KJ
Hogan
University of Wisconsin, Madison, WI, USA.|Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial VA Hospital, Madison, WI, USA.|Department of Neurology, University of Wisconsin School of Medicine and Public Health, WI, USA.
Bruce P
BP
Hermann
University of Wisconsin, Madison, WI, USA.|Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Mark A
MA
Sager
University of Wisconsin, Madison, WI, USA.|Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Alzheimer's Diseases Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial VA Hospital, Madison, WI, USA.
Sanjay
S
Asthana
University of Wisconsin, Madison, WI, USA.|Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Alzheimer's Diseases Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Geriatric Research Education and Clinical Center, Wm. S. Middleton Memorial VA Hospital, Madison, WI, USA.
Sterling C
SC
Johnson
University of Wisconsin, Madison, WI, USA.|Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Wisconsin Alzheimer's Institute, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.|Alzheimer's Diseases Research Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Corinne D
CD
Engelman
D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000150:complications* / Q000000981:diagnostic imaging / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D000814:Aniline Compounds / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D003072:Cognition Disorders / Q000000981:diagnostic imaging / Q000209:etiology*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D049268:Positron-Emission Tomography; D012307:Risk Factors; D013844:Thiazoles / Q000378:metabolism; D016875:tau Proteins / Q000134:cerebrospinal fluid
C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D001057:Apolipoproteins E; D013844:Thiazoles; D016875:tau Proteins
APOE; Alzheimer’s disease; Pittsburgh compound B; WRAP; amyloid-beta; cerebrospinal fluid; cognitive function; genetic risk scores; genetics; polygenic risk scores
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