Summary: Genetic variations linked with Alzheimer’s provide clues on potential treatments. Many drugs currently in trials are based on these clues.
With advances in technology, software and the Human Genome Database, Dr. Rudolph Tanzi is optimistic about the future for personalized medicine, where prevention and treatments could be tailored to a person’s specific genetic profile.
Because an estimated 70 percent of Alzheimer’s genetics is still unknown, researchers have a lot of work to do before this vision can be realized.
Scientists study genetic variations and how they are linked with pathologies and symptoms to determine who is at risk for developing diseases. But there’s another important reason they study genetic variations: to look for clues about potential treatments.
To understand why genes might hold clues about treatments, it helps to know that genes contain the blueprints for making proteins, which carry out most of the functions of a cell. If one or more of the thousands of proteins working in a cell is missing or malfunctioning, disease can result. So studying the genes associated with Alzheimer’s disease may lead to a better understanding of the proteins those genes encode, and how they might go awry. These proteins are then “targets” for potential treatments – by manipulating them, we may be able to treat or even prevent Alzheimer’s.
This search for potential Alzheimer’s treatments through the study of genes was the focus of Dr. Rudolph Tanzi’s keynote speech at the Alzheimer’s Association Wisconsin Annual State Conference in May. Dr. Tanzi is Professor of Neurology at Harvard University, and the author of Decoding Darkness. He also runs the Genetics and Aging Research Unit at Massachusetts General Hospital.
Dr. Tanzi’s Brief History of Alzheimer’s Gene Research
In the early 1980’s, Dr. Tanzi says, he was working with Dr. James Gusella who discovered the Huntington Disease gene. Dr. Tanzi was inspired to try to accomplish the same thing with Alzheimer’s; eventually his lab would be involved with the discovery of all three of the early onset familial Alzheimer’s genes.
In the mid-1980’s, two different teams of researchers found that the plaques in Alzheimer’s brains are made up of a protein called beta amyloid. One of the researchers, George Glenner, found that the plaques in Alzheimer’s are similar to those in Down Syndrome. “Because people with Down Syndrome have three (instead of the usual two) copies of Chromosome 21, Glenner predicted that beta amyloid was made from a gene found on Chromosome 21,” says Dr. Tanzi.
A few years later, researchers did in fact find a gene called amyloid precursor protein (APP) on Chromosome 21. “APP is a long protein, and when it gets cut apart, it results in beta amyloid,” Dr. Tanzi explains. Later research linked variants of APP to early onset Alzheimer’s disease.
By the mid-1990’s, two more gene variants, called presenilin 1 (PSEN1) and presenilin 2 (PSEN2) had also been linked to early onset Alzheimer’s disease. The PSEN genes are related to the presenilin enzymes [proteins] that cut APP to make beta amyloid.
With these discoveries, scientists knew that variations in three genes were linked to inherited or familial early onset Alzheimer’s disease. But even these genes don’t account for all familial early onset Alzheimer’s. Twenty-one mutations have been identified in the APP gene, accounting for seven percent of familial Alzheimer’s. One hundred sixty-five mutations in PSEN1 account for about 40%, and eleven mutations in PSEN2 account for three percent. This means that rare variations in these three genes account for only about 50 percent of familial early onset Alzheimer’s.
For late onset Alzheimer’s, variations in one gene is a confirmed risk factor. “As you probably know, the APOE4 variant increases the risk of developing Alzheimer’s,” Dr. Tanzi says. “About ten percent of the population carries two alleles or copies, which is associated with a tenfold increase in risk. Another 20 percent carry one allele, which brings threefold increase. About 75 percent of us carry the APOE3 variant, which is neutral with regards to risk of Alzheimer’s, and about two percent have the APOE2 variant, which in combination with APOE3 decreases the risk.”
What Alzheimer’s Genes Tell Us About Treatments
“All four genes point to excessive accumulation of beta amyloid peptides [proteins] in the brain as a common event,” Dr. Tanzi says. “Either you produce too much, and this may be early onset, or you clear too little, which may be the case with late onset. Normally, beta amyloid is produced by the brain and eight minutes later, cleared out. APOE variants affect how rapidly you can clear it out.”
But does this accumulation of beta amyloid really cause Alzheimer’s? “You will have heard that the amyloid hypothesis might not be correct,” says Dr. Tanzi. “The problem is that plaques are end-game stuff. You have to back up to where a single beta amyloid peptide is made. At that point, it’s neutral. But if it binds with zinc or copper, it forms assemblies called oligomers. These assemblies lodge in the synapses, and cause short-circuits in synaptic function. It looks more and more like this is what causes the problem. If the oligomers clump together, you get plaques. Maybe way before the plaques, oligomers cause cognitive problems. In the end, Alzheimer’s is a disease of the synapses. It’s really the loss of connections between nerve cells that causes problems.” This view is the basis for drugs under development by his company, Prana Biotechnology.
According to Dr. Tanzi, most drugs currently in trials are based on newer discoveries linked to APP, PSEN1 and PSEN2. Here’s his rundown of some of the treatments being tested:
Vaccines - This approach traps beta amyloid in the blood using antibodies. A new approach, passive immunization, involves making antibodies in lab. Vaccines are being tested in Phase 2 trials.
M1 Muscarinic Agonists - “First, you need to know that you can’t remove beta amyloid intact, but a ‘good’ enzyme – alpha secretase – cuts beta amyloid in half.” Dr. Tanzi says. M1 muscarinic agonists work to activate alpha secretase.
Gamma and Beta Secretase Inhibitors - “There are also ‘bad’ enzymes – beta and gamma secretases – that release beta amyloid. Developing gamma and beta secretase inhibitors is a huge industry. The problem is that both of these enzymes have to clip other proteins too. Gamma secretase can make two forms of beta amyloid – either AB40, which may have a normal role, or AB42, which is more likely to form oligomers. Now there are gamma secretase modulators that instead of eliminating the enzyme, tweak it to produce more AB40 than AB42. But a great concern is that in trials, this has caused problems with microhemorrhages.”
Substances That Reduce the Trace Metals [Zinc and Copper] Needed to Form Oligomers - Dr. Tanzi’s company is working to develop a Metal-Protein Attenuating Compound (MPAC) based on this approach. “It’s not a chelator, because you need metals for other things,” he says. “It just prevents oligomers from forming. One candidate, Clioquinol, showed a 50 percent reduction in beta amyloid in mice, but there were problems with a contaminant,” he says. “PBT2, a second generation MPAC, reduces beta amyloid levels, rescues communication among nerve cells, and improves mouse cognition after five days of treatment. It’s now being tested in Alzheimer’s patients in Sweden”
According to Dr. Tanzi, other possible approaches include:
*increasing blood flow to the brain which turns on the gene for an enzyme called neprolysin, which degrades beta amyloid. It’s not clear whether this can be done safely.
*preventing hypoxia, or lack of oxygen, to regulate beta secretase activity.
*ACAT inhibitors (his wife’s research) – these cardiovascular drugs lower beta amyloid levels, and can be administered nasally.
There’s a lot of work to do. Dr. Tanzi estimates 80 percent of all cases of Alzheimer’s are inherited, but 70 percent of Alzheimer’s disease genetics are unknown. He heads up an initiative called the Alzheimer’s Genome Project, which is working towards identifying that elusive 70 percent.
“We’re seeing the next wave of genetics,” he says. “There have been huge advances the last two years in technology, software and the Human Genome Database. The ultimate goal is to target drugs to your specific genes that put you at risk. This is called pharmakinetics, pharmagenetics or personalized medicine.”
One obstacle to progress, at least in the U.S., is the fear that genetic information could be used to deny employment or insurance. Because of this, an important first step towards preventative medicine in the U.S. is to pass the Genetic Information Nondiscrimination Act, and to add long term care insurance to the bill.
“By 2050,” says Dr. Tanzi, “we will not wait for life-threatening illness to strike.” That seems like a long way off. In the meantime, let’s hope he and other researchers identify new genetic variations linked to Alzheimer’s, and that these discoveries lead to effective treatments.