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Whilst an early-onset, mendelian form of the disease exists (Early-onset Alzheimer's disease or EOAD), typically the results of highly penetrant autosomal dominant mutations in genes on the amyloid pathway (\textit{APP}, \textit{PSEN1} and \textit{PSEN2}), the late-onset form of the disease (Late-onset Alzheimer's disease or LOAD) is more common accounting for ~95\% of AD cases. LOAD typically manifests after the sixth decade of life and in understood to be genetically complex - the result of multiple genetic and environmental risk factors. However, twin and family based studies have estimated that the genetic component is considerable, accounting for approximatly 60-80\% of the heritability of LOAD. However, unearthing the genes involved in LOAD was going to be tricky.   In the early 1990's family-based linkage analysis identified the first genetic risk factor for LOAD, the apolipoprotein-E gene (\textit{APOE}) on Chromosome 19 (Figure 1). This remains the strongest risk factor to date; one and copies of the $\epsilon$4 allele increases the risk of LOAD fourfold and sixteen fold respectively. A second missense mutation in the same exon ($\epsilon$2 allele) has a dose-dependent protection again LOAD. Despite this early success, it would be another twenty years until the next genetic risk factor for LOAD is discovered. APOE, due to the size of its effect, was amenable to established family-based linkage approaches. A new approach would be required to identify small genetic effects in outbread populations.  \section{The era of the genome-wide association study}  The completion of the Human Geneome Project ushered in a new era of genomics, and with it the expection that complex human diseases would