FIGURE 2.

A functional snapshot of AD genetics and cellular processes implicated by genes involved in early onset, familial AD, as well genes implicated by GWAS analysis of late onset AD (Scheltens et al., 2021; Bellenguez et al., 2022). Genes in black print have been identified by either sequencing of rare variants or GWAS analysis. APP and PSEN1/2 are shown in red print to highlight both their high penetrance in affecting AD and their association with early onset AD in families. Some of the genes with variants showing significant association with AD from GWAS are listed, representing functional categories. This is not intended to be a comprehensive list, but simply providing illustrative examples of genes within these groupings. Red arrows represent the important functional relationships between cellular processes and genes affecting them, with mitochondrial activity. The graphic overlay of groups represents that these are functionally connected groups and genes can participate in more than one of these processes. All these processes are known to be affected by HSPGs, denoted by the red circle labelled, “HS” within each functional group. References providing evidence for HSPG involvement in these processes include the following: APP processing and deposition (Snow et al., 1988; Jendresen et al., 2015; Liu et al., 2016), lipid/cholesterol metabolism (Yamashita et al., 2018), mitochondrial morphology and function (Reynolds-Peterson et al., 2017; Yamashita et al., 2018; Schultheis et al., 2021), membrane trafficking (Shteingauz et al., 2015; Reynolds-Peterson et al., 2017; Sanderson et al., 2017; Nadanaka and Kitagawa, 2018; Reynolds-Peterson et al., 2020) and Tau aggregation and spread.