Of replications and refutations: The status of Alzheimer’s disease genetic research

Abstract

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date, mutations in three genes (APP, PSEN1, PSEN2) 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. However, 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 contribution to age of onset variation than the APOE epsilon 4-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 overview, we discuss the current status of genetic research in AD, including a brief summary of applicable analytic tools, and a summary of recent findings suggesting the existence of novel AD genes on chromosomes 10, 11, and 12.

Chromosome 21 BACE2 haplotype associates with Alzheimer's disease: A two-stage study

“…Association studies in AD have been prone to produce positive results, which cannot be replicated in other datasets [4]. Case-control design may produce false positive associations due to population heterogeneity, i.e.…”

“…As APOE q4 is neither sufficient nor necessary to cause the disease, it is likely that other genetic risk factors exist. Numerous AD loci have been suggested by previous studies, but only few of these findings have been replicated [4]. One of the most promising loci, on the basis of several linkage studies, is on chromosome 21q [5 -9].…”

The association between two single nucleotide polymorphisms within the insulin-degrading enzyme gene and Alzheimer’s disease in a Chinese Han population

“…To date, allele e4 of the apolipoprotein E (APOE) gene is the only consistently observed genetic risk factor for AD. [6][7][8] Therefore, the identification of other genetic risk factors is of importance in the elucidation of AD etiology.…”

Alzheimer’s Genetics in the GWAS Era: A Continuing Story of ‘Replications and Refutations’

“…Interestingly, the one overarching common finding emerging from all published AD GWAS to date is the highly significant association between increased AD risk and the presence of the apolipoprotein E (APOE) ε4 allele. Of course, the APOE association with AD resulted from conventional candidate gene analyses performed in the early 1990s [16], and was already the single most outstanding finding of our AD genetics review in this journal 10 years ago [1]. Of the more than 40 Table 2).…”

“…Ten years ago, I co-authored a review article in this journal on the status of Alzheimer's disease (AD) genetics research [1]. At the time, a "novel AD gene" was proclaimed almost by the month, but subsequent independent replication efforts essentially always failed to support the initial findings.…”