Alzheimer’s disease (AD) is characterized by the age-dependent deposition of beta-amyloid within vulnerable regions of the brain, particularly the frontal cortex and hippocampus.
Beta-amyloid aggregates have a pathogenic effect, leading to progressive neuronal loss that causes deterioration of the ability of those brain regions to orchestrate both higher order and basic neural processes. As the deterioration worsens, the affected individual faces dementia and a worsening quality of life, and eventually the condition is fatal. Age is the greatest known risk factor for AD with an incidence of 30–50% in people 85 years or older. For a given individual, the time at which AD manifests is the consequence of an additional series of risk factors, some of which might be due to environmental causes, but many of which are attributable to that individual’s genetic endowment.
Genetics of Alzheimer’s Disease:
Some of the genes whose protein products affect AD risk have been identified. For example, certain variations (mutations) in the gene that encodes the Amyloid Precursor Protein (APP), a cell membrane protein produced in all body tissues whose biochemical function is at present unknown, predispose individuals to early-onset AD. APP is a substrate for proteolysis by the endogenous proteases beta and gamma secretase, liberating beta-amyloid proteolytic fragments ranging from 37 to 43 amino acid residues. The 42-residue species is thought to be the most pathogenic, and forms aggregates, which, in addition to contributing to the plaques that deposit in the AD-affected brain, are thought to initiate processes that lead to cognitive deficits. AD-predisposing variations in APP cluster in the vicinity of the cleavage sites, affecting the rate at which pathogenic beta-amyloid fragments are generated, their stability, and their ability to form aggregates. Individuals inheriting such APP variations usually show signs of AD in their 50s, whereas sporadic AD is not common until individuals reach their 70s. Rare variations in two other genes, Presenilin 1 and Presenilin 2, also confer high risk to early-onset AD. These two genes encode independent proteins of similar structures that function as part of the gamma secretase protein complex. As a consequence of these genetic observations and considerable experimentation, the so-called “amyloid cascade” model that has emerged holds that biochemical events that increase the production and accumulation of beta-amyloid, particularly Aβ-42, accelerate the onset and progression of AD.
The Blood Brain “Barrier” and the implications of regulation of beta-amyloid in peripheral tissues:
The tacit assumption of the researchers in this field has been that local over-production of pathogenic beta-amyloid within the brain is the problem and that the likely solution would involve development of beta and gamma secretase inhibitors designed to penetrate the Blood-Brain Barrier (BBB) so as to reduce local generation of the beta amyloid. The BBB, which protects the mostly non-regenerating cells of the brain by isolating it, is normally impermeable to small polar molecules. Efforts to develop BBB-penetrating AD therapeutics have thus far been disappointing. Research at ModGene (Sutcliffe et al, J. Neurosci Res 89: 808, 2011) has now shown that cerebral levels of beta-amyloid are regulated by peripheral tissues. One implication of this discovery is that therapeutic penetration of the BBB is not only unnecessary, but also that avoiding brain penetration might avert potential adverse side effects. This represents a fundamental change in concepts concerning AD pathogenesis and treatment.