In contrast to the plethora of potential disease mechanisms detected in humans with LOAD, the search for LOAD-modifying interventions has focused primarily on compounds targeting the amyloid-β pathway. Both biological risk factors, often related to vascular health and psychosocial factors (Cechetto et al., 2008; Qiu et al., 2010), as well as genetic susceptibility play a critical role in the underlying pathophysiology of LOAD (Bertram et al., 2010). APOE is still the best validated suceptibility gene accounting for at least 30% of the genetic variance in LOAD (Corder et al., 1993). Several additional genetic risk loci for LOAD have been identified via genome-wide association studies (GWAS) that seem to cluster in patterns suggesting immunity (CLU, CR1, CD33, EPHA1, MS4A4A/MS4A6A), lipid processing (APOE, ABCA7) and endocytosis (PICALM, BIN1, CD2AP) as important causal biological processes (Bettens et al., 2013). More recently, low-frequency missense variants in APP and TREM2 were found to confer strong protection or elevated risk of LOAD (Guerreiro et al., 2013; Jonsson et al., 2012; Jonsson et al., 2013). However, the overall contribution of these new common and low-frequency variants to
