Genetics and Alzheimer’s disease. While the vast majority of cases of Alzheimer’s disease (AD) are not strictly related to heredity, there are instances where there is a clear genetic cause for its occurence. A number of genes have been linked to the development of AD, some as indicators of susceptibility and others as definitive disease causing mutations, more info.
Mutations in betaAPP. The first gene to be identified as having been mutated in some inherited forms of AD encodes a protein known as the beta-amyloid precursor protein (betaAPP). Contained within the sequence of this protein is a small sub-fragment, or peptide, known as beta-amyloid. This peptide was originally identified as a major component of the plaques that are essentially always present in brains of patients with AD. In actuality, the small amyloid fragment was characterized first, and only later was APP identified as the protein precursor from which it is derived. The beta-amyloid fragment has been shown to be quite toxic to nerve cells.
betaAPP gene mapping WIth its linkage to the development of a familial form of Alzheimer’s disease, the subsequent localization of this gene to human chromosome 21 proved particularly intriguing. It is chromosome 21 that is abnormally present in an extra copy in individuals with Down’s syndrome (trisomy 21). And if they live long enough, many people with Down’s syndrome unfortunately, will also develop AD. This information suggests that while certain mutations in the betaAPP gene can cause AD, so can the presence of an extra copy of the betaAPP gene. This last point however, remains unproven.
Multiple APP mutations have now been identified. So what do the AD-related mutations in betaAPP cause biochemically? It appears that the mutations that are most strongly associated with the development of AD cause a shift in the typical pattern of breakdown of the amyloid precursor protein. Like most other proteins in our cells, after some specified period of time, dependent upon circumstances, betaAPP will be degraded by the cellular machinery. In the vast majority of cases, betaAPP is chewed up in such a way that the self-contained sequence for the toxic beta-amyloid fragment is destroyed as well. In many of the mutant forms of the protein a greater percentage of the total molecules of betaAPP are degraded in a slightly different way. This shift in degradation pattern leads to an increase in the generation of the toxic beta-amyloid fragment with its negative implications for nerve cells in the brain.
So why does beta-amyloid accumulate in the brain in AD? Interestingly, betaAPP is expressed throughout the body, yet it appears that only the brain is injured in AD. Why? In the brain itself, not all regions are equally affected by AD, why not? For these and many other questions, in short, no one knows for sure. Yet, there are features of nerve cells that tend to make them more vulnerable to toxic insults like those associated with the accumulation of the beta-amyloid peptide. Another possibility is that the normal complement of proteins made by nerve cells is clearly different from those made by other types of cells and this makes them more susceptible to the toxic effects of beta-amyloid. One thing is certain; our brains do not make a regular habit of replacing dead or damaged nerve cells, so better understanding the biochemical problems at the root of AD should ultimately allow us to reach an important goal, to preserve the nerve cells we have.