Most of us think of genetic mutations as damaging DNA changes that either directly cause a disease or increase one’s risk of developing an illness later in life.
Because mutations occur in a mostly nonrandom fashion, the majority of mutations are expected to be more likely deleterious or neutral rather than beneficial. An analogy is that if a person who had never seen or heard of a car were to open a car’s hood and rearrange or remove one piece of the engine, the result would mostly likely be neutral or damaging to the car’s function.
In spite of the expected negative or neutral consequences of most genetic changes, some mutations with positive effects do occur and remain a source of great interest to researchers. A recent example of one such mutation was reported last month by Thorlakur Jonsson, Ph.D., of deCODE genetics in Reykjavik, Iceland, and colleagues, who studied Alzheimer’s disease and adult-onset cognitive decline in Icelanders (Nature 2012;488:96-9).
Dementia is a significant medicocognitive condition of later life, affecting over 24 million persons worldwide, with the vast majority of these cases being caused by Alzheimer’s disease. Estimates rise steadily for the continued increased prevalence of dementia as populations age, from approximately 5% at age 60 years to greater than 25% by age 90. Mild cognitive impairment, which often precedes a diagnosis of dementia, is estimated to affect 10%-20% of those older than 65 years, and will likely also increase in prevalence as aging trends continue. It is estimated that only 1% of persons experience no cognitive decline at all, even in old age.
The pathological diagnosis of Alzheimer’s disease requires documented findings of amyloid plaques and neurofibrillary tangles in the brain either by biopsy or postmortem examination – procedures that are performed in only a minority of patients. Current disease models implicate the accumulation of amyloid-beta as being involved in directly causing the disease, although some have argued that amyloid buildup could be a marker of disease, rather than be directly involved in disease generation.
Dr. Jonsson and colleagues studied the coding portions of the genome in 1,795 Icelanders, and then looked for genetic mutations that affected the risk of both Alzheimer’s disease and cognitive decline. The amyloid-beta precursor protein (APP) had previously been linked to early-onset, genetic forms of Alzheimer’s disease, so the team scanned the APP gene for novel mutations that had an impact on the risk of cognitive function.
To increase the power of their study, the group used computer modeling to impute (that is, predict) the genetic status of biological relatives for whom cognitive status was known, but who had not actually undergone any genetic testing. By using these inferred genetic results, the investigators were able to study their questions in nearly 300,000 subjects. This gave them enough statistical power to compare the genetic status of persons with Alzheimer’s disease vs. other persons who have lived to at least age 85 years without a diagnosis of Alzheimer’s disease.
They identified a mutation at amino-acid position 673 in the APP protein where the normal alanine residue had been replaced by a threonine (A673T). This A673T mutation was found in only 0.5% of Icelanders, but was associated with a 5.3 odds ratio for protection against a diagnosis of Alzheimer’s disease. Interestingly, another genetic mutation at the same amino acid position (A573V) had been previously linked to Alzheimer’s disease, suggesting that this was an important position in the APP protein. The A673T mutation also appeared to be predictive of having a normal score on a cognitive performance scale (OR, 7.5), and carriers of A673T had a 50% greater chance of living to at least age 85 years.
By comparing the function of the A673T mutation in a biochemical assay, the authors also showed reduced cleavage of the APP protein, compared with the wild-type mutation. These data support the notion that the breakdown rates of the APP protein are indeed relevant to the pathogenesis of Alzheimer’s disease, as opposed to their having a bystander role. As an extension of this notion, drugs that are designed to reduce APP cleavage rates could have a protective effect against Alzheimer’s disease and cognitive decline in general.
As with many studies, this work represents another modest step along the road to understanding and reducing the burden of a human disease. Some commercial genetic testing companies are likely to quickly adopt and market the A673T mutation as an "Alzheimer‘s protection" marker. The general rarity of this mutation should give informed consumers pause about leaping to the conclusion that such a test is a good value for the money. However, the data are sure to fuel interest from pharmaceutical companies that hope to develop an Alzheimer’s disease treatment that would hold more promise than those currently available.