The day to day operation of living tissue is fantastically complex - not to mention the changes in that operation that stretch out over decades, and the interaction of those changes with lifestyle choices, and the way these changes affect who you are and the medical conditions you suffer. This is one reason that proposed medical research strategies like SENS attempt to find easier paths to cures; paths that do not require a full understanding or extensive manipulation of metabolic processes, the operation of living tissue.
Recent research into the genetics of Alzheimer's disease is illustrative of the complexity of our biology. When looking at medical conditions that result from years or decades of multi-stage, interacting, convoluted changes in biochemistry and cellular behavior, the operation of genes is just another part of the puzzle. It's a highly connected system, which means that knowledge of genes is not a magic map to a cure in most cases; sometimes we get lucky, but Alzheimer's doesn't have that look to it. It's the result of some set of slow failures in functionality that happens to everyone; some folk are unfortunate enough to fail faster due to their genes, or have chosen lifestyles that have much the same effect. But we need Alzheimer's repair and prevention for everyone if we are to take advantage of gains in healthy life span attained through pushing back the onset other common age-related disease.
a team of researchers analyzed the faulty processing of the amyloid precursor protein (APP) - long associated with Alzheimer's disease - and linked it to a new gene (SORL1). The five-year study included multiple centres such as Columbia University, Boston University and the Mayo Clinic and tested over 6,000 DNA samples from Caucasians, Hispanics, Israeli-Arabs and African Americans and uncovered two consistent patterns that linked the SORL1 gene to people afflicted with Alzheimer's.
"Instead of scanning all the genes in the entire genome, we had an idea of what an Alzheimer's disease-causing gene would look like based on past discoveries," says senior author University Professor Peter St. George-Hyslop, director of the Centre for Research in Neurodegenerative Diseases (CRND) at the University of Toronto. "We knew that the abnormalities in APP processing and the accumulation of its toxic amyloid beta (Aβ) peptide derivative cause Alzheimer's, so we hypothesized that other genes associated with APP regulation might also cause the disease."
SORL1 governs the distribution of APP inside nerve cells of the brain. When working properly, the SORL1 protein regulates APP by diverting it into specific certain regions of the cell. When the level of the SORL1 gene is reduced, APP accumulates in a different region of the cell, where it is degraded into Aβ fragments - abnormal protein fragments - which then cause Alzheimer's disease.
The study confirmed that carriers of the APOE4 gene type (allele), which confers higher risk for Alzheimer's, are just like other people their age throughout most of adult life in terms of core mental functions.
Performance on all tests (except for reading vocabulary, which tends to hold up with age) declined across age groups, a sign of normal cognitive aging. However, APOE4 did not affect performance at any age. Thus the researchers conclude that at least between ages 20 and 64, people with APOE4 age normally in those central cognitive functions.
This finding suggests that APOE4 heightens the risk for Alzheimer's in old age through an additional, as-yet-unknown process that accelerates or intensifies normal changes, pushing them into the range of disease. Jorm provides an analogy. "In general, hair becomes thinner with age," he says. "However, there are some people who have an additional hereditary factor that makes them bald at an early age."
As a researcher points out in the first paper above, "The recurring theme that genetic causes of Alzheimer's all seem to impact the accumulation of amyloid β-peptide in the brain, and that potential therapies which block Aβ production or toxicity seem to block the disease in animal models, suggests that we're on the right track." That is to say, that research today is predominantly aimed at attempting to understand and manipulate enormously complex metabolic processes in order to effect a change in a known quantity - the buildup of amyloid. Quantifying the usefulness of new findings in this context is a very resource-intensive job; the job is still ongoing for APOE4 after nearly 14 years of work, for example.
There is great value in the knowledge derived from investigating mechanisms. Just as cancer research is yielding a far greater understanding of cellular aging, and AIDS research yields a far greater understanding of viruses and the immune system, Alzheimer's research leads to a greater understanding of biochemistry in the brain. That is a great help to many other areas of medical science - but it isn't necessarily the fastest path to help sufferers. It does make it ever easier to strike off on a faster path, however.
If the buildup of amyloid is indeed the key pathological difference that causes AIzheimers, then efforts to remove it would seem to be the way to go - identify the damage, and repair it, in other words. I place more near-term practical value at this time on work in that direction, such as immunotherapies and vaccines, or efforts to repair the body's natural mechanisms for clearing amyloid. A working strategy to repair Alzheimer's will be a far better tool than therapies aimed at slowing the progression of damage.