Ellen M. Wijsman

Research Program:

Alzheimer's disease (AD) is a common neurodegenerative disease for which no treatment or preventative measures exist. Affected individuals eventually require institutional care and invariably die from disease-related conditions. Although onset can occur as early as the third decade of life, AD is a disease of the elderly; 11% of those over 65 yrs. and 32% of those over 85 yrs. have AD.

While, in some families, AD develops as a result of a mutation in a specific gene (APP on chromosome 21, or the presenillin loci, PSEN1 and PSEN2 on chromosomes 1 and 14), the majority of early-onset families and some late-onset families do not develop AD in this way. Early on we mapped early-onset AD loci to chromosomes 1 and 14, and subsequently identified the locus on chromosome 1. We continue to pursue studies of the genetic basis of Alzheimer's disease, with a greater focus on gene-mapping and gene identification of later-onset disease. We showed that the defect in some families with non-specific dementia maps to chromosome 17, and that there are mutations in tau that appear to be responsible for some cases of progressive supranuclear palsy, a related neurological disorder. We also showed that not all highly-penetrant mutations are easily identified with standard bioinformatics prediction tools.

We have reported evidence for loci that contribute to or modify age-at-onset in both late onset and early onset AD, and showed that population heterogeneity is an important confounder in association studies of AD in North American populations of European descent. We are now working with whole-genome sequence data, together with the rich existing marker and phenotype data in our sample and in collaboration with other groups, to identify additional genes contributing to both age-at-onset and risk of AD. These studies are uncovering extensive heterogeneity in the genetic basis of AD, and multiple different possible mechanisms.

The focus of our laboratory in defining the genetic basis of AD is on development and application of statistical methods for characterizing the inheritance patterns of AD, for localizing the associated genes, and for using epidemiological data to aid in developing and interpreting genetic models.

Supported by NIH AG 066509 "Alzheimer's Disease Research Center" (T. Grabowski, center PI; E. Wijsman data and biostatistics core), Metropolitan Life Foundation Award (E. Wijsman, PI), NIH R00 AG040184 "Identifying Alzheimer's disease genes using genomic and family data" (E. Blue, PI), NIH R01 AG059737 "Identification of genetic modifiers of Alzheimer's disease in multiethnic cohorts" (E. Blue, PI), NIH U01 AG049507 "Sequence-based discovery of AD risk & protective alleles, family-based study" (E. Wijsman, PI), NIH U01 AG052409 Follow-up in multi-ethnic cohorts via endophenotypes, omics, & model systems (PI: S Seshadri, E Wijsman site PI), and NIH U01 AG058589 Therapeutic target discovery in ADSP data via comprehensive whole-genome analysis incorporating ethnic diversity and systems approaches (Co-PIs A DeStefano, S Seshadri, P de Jager, E Wijsman, M Fornage, E Boerwinkle).

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