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Stephen C. Waring, DVM, PhD; Roger N. Rosenberg, MD

Arch Neurol. 2008;65(3):329-334.

The genetics of Alzheimer disease (AD) to date support an age-dependent dichotomous model whereby earlier age of disease onset (< 60 years) is explained by 3 fully penetrant genes (APP [NCBI Entrez gene 351], PSEN1 [NCBI Entrez gene 5663], and PSEN2 [NCBI Entrez gene 5664]), whereas later age of disease onset ( 65 years) representing most cases of AD has yet to be explained by a purely genetic model. The APOE gene (NCBI Entrez gene 348) is the strongest genetic risk factor for later onset, although it is neither sufficient nor necessary to explain all occurrences of disease. Numerous putative genetic risk alleles and genetic variants have been reported. Although all have relevance to biological mechanisms that may be associated with AD pathogenesis, they await replication in large representative populations. Genome-wide association studies have emerged as an increasingly effective tool for identifying genetic contributions to complex diseases and represent the next frontier for furthering our understanding of the underlying etiologic, biological, and pathologic mechanisms associated with chronic complex disorders. There have already been success stories for diseases such as macular degeneration and diabetes mellitus. Whether this will hold true for a genetically complex and heterogeneous disease such as AD is not known, although early reports are encouraging. This review considers recent publications from studies that have successfully applied genome-wide association methods to investigations of AD by taking advantage of the currently available high-throughput arrays, bioinformatics, and software advances. The inherent strengths, limitations, and challenges associated with study design issues in the context of AD are presented herein.

Author Affiliations: Department of Epidemiology, The University of Texas School of Public Health, The University of Texas Health Science Center at Houston (Dr Waring); Department of Neurology, The University of Texas Southwestern Medical Center at Dallas (Dr Rosenberg); and Texas Alzheimer's Research Consortium (University of Texas Southwestern Medical Center, Dallas; University of North Texas Health Science Center, Fort Worth; Texas Tech University Health Science Center, Lubbock; and Baylor College of Medicine, Houston) (Drs Waring and Rosenberg).

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