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April 2007

Measuring the Risk of Alzheimer Disease

Arch Neurol. 2007;64(4):479-480. doi:10.1001/archneur.64.4.479

All is created and goes according to order,

yet o'er our lifetime rules an uncertain fate.

—Johann Wolfgang von Goethe1

In recent years, there have been hundreds of published reports citing or refuting a genetic association of specific susceptibility genes and the occurrence of Alzheimer disease (AD).2-6 It is clear that mutations in the amyloid precursor protein (APP) gene (chromosome 21), presenilin 1 gene (chromosome 14), and presenilin 2 gene (chromosome 1) are causal of AD.7 It is also well established that the ε4 allele of apolipoprotein E is a major susceptibility factor for AD.2,4,5,7 However, a clear consensus of other potential susceptibility genes for AD remains to be reached. Progress in this regard has been achieved by Bertram et al,2 who have collected systematic analyses of AD genetic association studies in the AlzGene database, a publicly available, updated database that catalogs all genetic association studies related to AD. They have identified at least 12 potential AD susceptibility genes with statistically significant allelic summary odds ratios (ranging from 1.11-1.38 for risk alleles and 0.92-0.67 for protective alleles).2 They do express caution in citing these association analyses by stating that “our results must be interpreted with caution and considered preliminary until the putative disease-modifying effects have been confirmed in sufficiently powered analyses and until plausible molecular mechanisms are elucidated for the observed statistical associations.”2

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