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Nat Rev Neurol. 2016 Jul;12(7):413-27. doi: 10.1038/nrneurol.2016.84. Epub 2016 Jun 10.

Genetic variants in Alzheimer disease - molecular and brain network approaches.

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Rush Alzheimer's Disease Center, Rush University Medical Center, 600 S Paulina Street, Chicago, Illinois 60612, USA.
Department of Statistics, and Medical Genetics; Centre for Molecular and Medicine and Therapeutics, University of British Columbia, 950 West 28th Avenue, Vancouver, British Columbia V5Z 4H4, Canada.
Department of Psychology, University of Toronto, 100 St. George Street, 4th Floor Sidney Smith Hall, Toronto, Ontario M5S 3G3, Canada.
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, 75 Francis Street, Boston MA 02115, USA.


Genetic studies in late-onset Alzheimer disease (LOAD) are aimed at identifying core disease mechanisms and providing potential biomarkers and drug candidates to improve clinical care of AD. However, owing to the complexity of LOAD, including pathological heterogeneity and disease polygenicity, extraction of actionable guidance from LOAD genetics has been challenging. Past attempts to summarize the effects of LOAD-associated genetic variants have used pathway analysis and collections of small-scale experiments to hypothesize functional convergence across several variants. In this Review, we discuss how the study of molecular, cellular and brain networks provides additional information on the effects of LOAD-associated genetic variants. We then discuss emerging combinations of these omic data sets into multiscale models, which provide a more comprehensive representation of the effects of LOAD-associated genetic variants at multiple biophysical scales. Furthermore, we highlight the clinical potential of mechanistically coupling genetic variants and disease phenotypes with multiscale brain models.

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