Of Replications and Refutations: The Status of Alzheimer’s Disease Genetic Research Lars Bertram, MD, and Rudolph E. Tanzi, PhD Address Genetics and Aging Unit, D epartment of N eurology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA. E-mail: tanzi@ helix.mgh.har vard.edu Current N eurology and N euroscience Reports 2001, 1:442–450 Current Science Inc. ISSN 1528-4042 Copyright © 2001 by Current Science Inc. Introduction There is emerging consensus that Alzheimer’s Disease (AD) is a genetically complex and heterogeneous disorder: complex because there is no single (or simple) inheritance model that accounts for the heritability of all familial forms of the disease, and heterogeneous because muta- tions and polymorphisms in at least four genes contribute to the risk of developing this devastating disorder. Nearly three dozen additional genes have been proposed as putative AD loci in a literature that is encumbered with numerous refutations for every replication of a positive finding. Adding to the complexity and heterogeneity of AD genetics are effects owing to possible (and likely) gene- gene and gene-environment interactions. Nevertheless, great progress has been made in the past 15 years in the field of AD genetics and cell biology. This has laid the foundation for further elucidation of the neuropathologic and neurogenetic features that lead to AD. Eventually, this will enable the development of potent pharmacologic treatment or prevention strategies, and genetic risk profiling to allow for early-prediction/early-prevention procedures. In this overview, we discuss the current and future status of AD genetic research, including a brief summary of the analytic tools employed and recent data suggesting the existence of AD genes on three independent chromosomal regions. Strategies to Identify Novel Genes in a Complex Trait Usually, AD is divided into early- and late-onset forms, using arbitrary age cutoffs between 60 and 70 years of age, depending on study sample and research laboratory. The familial forms of early-onset AD often follow a typical autosomal-dominant inheritance pattern, with close to 100% penetrance, and typically half the offspring are affected. Genetic linkage analysis, which measures cosegregation of genetic markers and disease phenotype within individual families, is facilitated in this form of the disorder by the availability of large and multigenerational pedigrees, and has led to the identification of three early- onset AD genes. Linkage analysis is also widely employed as a method to pinpoint genes in late-onset AD. However, it is predominantly this form of the disease that is mostly influenced by the factors that constitute its genetic complexity and heterogeneity. Moreover, studies of highly prevalent late-onset disorders like AD are more often than not characterized by incomplete family data ( eg, relatives who died before the family-specific age of risk or the lack of genotypic information for parents). Another complica- tion is the unknown number of "phenocopies" ( ie, patients with a nongenetic form of the disease or patients suffering from other forms of age-related cognitive decline). In this case, linkage studies with reasonable sample sizes ( ie, 500 to 1000 families) may not be sufficiently powerful to identify genetic factors of small or modest effect [1]. It Alzheimer’s disease (AD ) is a genetically complex and heterogeneous disorder. To date, mutations in three genes (APP , PSEN 1 , PSEN 2 ) have been described to cause familial early-onset AD. In addition, a common polymorphism in the gene encoding apolipoprotein E ( APOE) has been associated with the more common late-onset form of the disease. H owever, many studies have shown that genetic factors other than APOE play an important role in late- onset AD. Along these lines, a recent report predicted the existence of at least four additional late-onset AD genes, one of which was estimated to have a much greater contri- bution to age of onset variation than the APOE ε4-allele. However, most of the nearly three dozen loci that have been proposed as putative AD genes to date have been followed by both replications and refutations, making consensus impossible. In this over view, we discuss the current status of genetic research in AD, including a brief summar y of applicable analytic tools, and a summar y of recent findings suggesting the existence of novel AD genes on chromosomes 10, 11, and 12.