Affiliations: Genetics and Aging Research Unit, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Correspondence:
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Correspondence to: Rudolph E. Tanzi, PhD, Genetics and Aging Research Unit, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA. Tel.: +1 617 726 6845; Fax: +1 617 724 1949; E-mail: tanzi@helix.mgh.harvard.edu.
Abstract: The rich and colorful history of gene discovery in Alzheimer's disease (AD) over the past three decades is as complex and heterogeneous as the disease, itself. Twin and family studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations in APP, PSEN1, and PSEN2 are fully penetrant for early-onset (<60 years) familial AD, which represents <5% of AD. On the other hand, common gene polymorphisms, such as the ε4 and ε2 variants of the APOE gene, influence susceptibility for common (>95%) late-onset AD. These four genes account for 30–50% of the inheritability of AD. Genome-wide association studies have recently led to the identification of additional highly confirmed AD candidate genes. Here, I review the past, present, and future of attempts to elucidate the complex and heterogeneous genetic underpinnings of AD along with some of the unique events that made these discoveries possible.
Keywords: Amyloid-β, amyloid-β protein precursor, APOE, CD33, chromosome 21, down syndrome, genome-wide association study, presenilin
