New Frontiers in Alzheimer's Disease Genetics Rudolph E. Tanzi, Lars Bertram  Neuron  Volume 32, Issue 2, Pages 181-184 (October 2001) DOI: 10.1016/S0896-6273(01)00476-7

Figure 1 Possible Pathogenetic Routes of Aβ Production, Clearance, and Degradation Early-onset AD genes APP, PSEN1, and PSEN2 along with BACE (β-secretase) are involved in the production of Aβ. The late-onset AD gene APOE and the putative AD gene α-1-antichymotrypsin (ACT) have been proposed to play roles in the aggregation and fibrillogenesis of Aβ. APOE and putative AD genes LRP and A2M may play roles in the clearance of Aβ as follows. Once α2M-Aβ or apoE-Aβ complexes are internalized by LRP, they may be targeted for endosomal recycling, lysosomal degradation, or undergo trancytosis across the blood-brain barrier to the plasma. Membrane APP containing an alternatively spliced Kunitz protease inhibitor (KPI) domain may also undergo internalization by LRP and generate Aβ (dotted arrows) via the endocytic pathway. (Note: APP has also been shown to undergo LRP-independent endocytosis.) Extracellular degradation of Aβ can occur via binding of the peptide to α2M followed by degradation by an active protease (e.g., trypsin) bound to the bait region of α2M. Alternatively, Aβ may be degraded by “free” proteases, such as the insulin-degrading enzyme (IDE) or neprilysin (MME). Asterisk (*) denotes established AD genes Neuron 2001 32, 181-184DOI: (10.1016/S0896-6273(01)00476-7)

Figure 2 Strategy for Identifying Novel AD Genes Candidate genes are chosen as either “positional candidates” from chromosomal regions implicated by genetic linkage studies and/or as “biological candidates” implicated by pathobiological studies of AD. DNA variants (e.g., SNPs) in these candidate genes are tested for association using either case control or family-based studies. For those yielding positive association, independent samples are tested for confirmation. If confirmatory studies are consistently positive, the variant is likely to be pathogenic. If the association cannot be replicated, the initial results most likely represent a false positive finding. If confirmation is inconsistent, the possibility of linkage disequilibrium, a minor gene effect (or a false positive finding) must be considered Neuron 2001 32, 181-184DOI: (10.1016/S0896-6273(01)00476-7)