deletions | additions       diff --git a/section_Introduction_Alzheimer_s_disease__.tex b/section_Introduction_Alzheimer_s_disease__.tex  index 0ac1483..b23965d 100644  --- a/section_Introduction_Alzheimer_s_disease__.tex  +++ b/section_Introduction_Alzheimer_s_disease__.tex 
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Familial forms of AD classically present early (early-onset Alzheimer's disease or EOAD) and are rare. EOAD is the result of highly penetrant, autosomal dominant mutations within genes on the 'amyloid' pathway (\textit{APP}, \textit{PSEN1} and \textit{PSEN2}). However, approximately 95 percent of AD cases are of late onset (late onset Alzheimer's disease or LOAD). Typically presenting after the fifth decade, LOAD is aetiologically highly complex, involving multiple genetic and environmental risk factors. Although not a familial disease, it has been approximated that upwards of 60 percent of LOAD liability is genetic \cite{26312828}.  The first methodological approach to pay dividends was linkage analysis, which identifies genetic loci segregating with a disease phenotype between affected family members. In 1993 Corder et al identified a haplotype in the apolipoprotein-E gene (\textit{APOE}) on chromosome 19, which remains the strongest risk factor for LOAD to this day. day \cite{8346443}.  One and two copies of the $\epsilon$4 haplotype increases LOAD risk approximately fourfold and sixteenfold respectively. However, despite this early success, it would be another twenty years until the next genetic risk factor for LOAD was discovered. In hind sight APOE was the low hanging fruit; due to the atypically large effect it imparts on a complex phenotype, textit{APOE} was uniquely amenable to a family-based linkage approach in a modest sample size. A fundamental change in approach, and technology, would be required to identify smaller genetic effects in unrelated samples.