Multiple combinations of co-factors produce variants of age-related cognitive decline: A theory

Canadian Journal of Experimental Psychology, Sep 2002 by Robert J McDonald

The APP gene codes for the precursor of the amyloid protein, which is a major component of the beta-amyloid peptide found in senile plaques, is an extracellular neuropathological feature typical of Alzheimer's disease brain pathology. Abnormal processing of amyloid precursor protein seems to be the main cause of senile plaque formation in the brain. APP is found in cell membranes and is eventually broken down by a cleavage process at various sites into smaller pieces. Cleavage at certain sites produces pieces that are harmless to neuronal processes while cleavage of the protein at other sites releases the products into the extracellular space which then produce the dangerous betaamyloid peptide found in neuritic plaques (Schellenberg, 1995).

The role of the presenilin genes is still unknown but they are predominantly expressed in neurons (Kovacs et al., 1996) and may play a fundamental role in the recycling of proteins or intracellular trafficking (Tanzi et al., 1997). This hypothesized role of the presenilin genes is interesting because disrupting the normal function of these genes may affect production and trafficking of APP, as well as hamper the recycling of abnormal accumulations of beta-amyloid peptide (Scheuner, Eckman, Jensen, Song, Citron, Suzuki, Bird, Hardy, Hutton, Kukull, Larson, Levy-Lahad, Viitanen, Peskind, Poorkaj, Schellenberg, Tanzi, Wasco, Lannfelt, Selkoe, & Younkin, 1996). These gene defects (APP, PSi, PS2) show 100% penetrance which means that an individual possessing the gene mutation would develop early-onset Alzheimer's disease.

The apolipoprotein E (APOE) gene, which is found on chromosome 19, is the only genetic factor linked to the much more common late-onset Alzheimer's disease (Saunders, Strittmatter, Schmechel, George-Hyslop, Pericak-Vance, Joo, Rosi, Gusella., Crapper-Maclachlan, Alberts, 1993; Strittmatter & Roses, 1996). Unlike the causative mutations associated with early-onset AD, the APOE gene mutation acts as a risk factor (Strittmatter, 2000). APOE is found in all of the major pathological phenomenon found in the brains of AD patients, including neuritic plaques, neurofibrillary tangles, and amyloid accumulations found in the vasculature of the brain.

The functional significance of APOE is linked with the transport of lipids-like cholesterol, growth and regrowth of neuronal processes during development, and similar processes found following injury to the brain (Poirier et al., 1994). Disruption of these functions could limit the brain's ability to compensate for neuronal damage caused by a variety of factors. The APOE gene shows functional polymorphism represented by three alleles (2, 3, and 4). The APOE-4 allele specifically appears to account for the increased risk for Alzheimer's disease associated with APOE (Chartier-- Harlin et al., 1994; Saunders et al., 1993) while the APOE-2 isoform has been shown to promote polymerization of beta-amyloid (Schmechel, Saunders, Striggmatter, Crain, Hulette, Joo, Pericak-Vance, Goldgaber, & Roses, 1993). Increased frequency of the APOE-2 isoform, in vitro, has been linked to reductions in beta-amyloid polymerization (Ma et al., 1994) and subjects with higher frequencies of the APOE-2 isoform show lower incidences of Alzheimer's disease (Talbot, Lendon, Craddock, Shears, Morris, & Goate, 1994; West, Rebeck, & Hyman, 1994), suggesting that increased APOE-2 isoforms may act to inhibit pathological processes like beta-amyloid accumulations and associated neuritic plaques. Strittmatter and collegues have provided further evidence that the APOE-2 isoform, and not the other isoforms, binds to unphosphorylated tau protein and inhibits its phosphorylation. According to this view, the critical role of APOE in preventing AD brain pathology is via the APOE-2 isoform, which would inhibit the formation of PHF and associated neurofibrillary tangles (Strittmatter, 2000).