Open AccessPhenotype‐informed polygenic risk scores are associated with worse outcome in individuals at risk of Alzheimer's disease
Author(s) -
Nordengen Kaja,
Pålhaugen Lene,
Bettella Francesco,
Bahrami Shahram,
Selnes Per,
Jarholm Jonas,
Athanasiu Lavinia,
Shadrin Alexey,
Andreassen Ole A.,
Fladby Tormod
Publication year - 2022
Publication title -
alzheimer's and dementia: diagnosis, assessment and disease monitoring
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.497
H-Index - 37
ISSN - 2352-8729
DOI - 10.1002/dad2.12350
Subject(s) - disease , medicine , dementia , pathological , atrophy , hazard ratio , alzheimer's disease , prospective cohort study , cohort , oncology , pathology , bioinformatics , biology , confidence interval
Patients with predementia Alzheimer's disease (AD) and at‐risk subjects are targets for promising disease‐modifying treatments, and improved polygenic risk scores (PRSs) could improve early‐stage case selection. Methods Phenotype‐informed PRSs were developed by selecting AD‐associated variants conditional on relevant inflammatory or cardiovascular traits. The primary outcome was longitudinal changes in measures of AD pathology, namely development of pathological amyloid deposition, medial temporal lobe atrophy, and cognitive decline in a prospective cohort study including 394 adults without AD dementia. Results High‐risk groups defined by phenotype‐informed AD PRSs had significantly steeper volume decline in medial temporal cortices, and the high‐risk group defined by the cardiovascular‐informed AD PRS had significantly increased hazard ratio of pathological amyloid deposition, compared to low‐risk groups. Discussion AD PRSs informed by inflammatory disorders or cardiovascular risk factors and diseases are associated with development of AD pathology markers and may improve identification of subjects at risk for progression of AD.