The Alzheimer’s Genome Project™ (AGP) , funded by Cure Alzheimer’s Fund (CAF), is making great scientific progress. This work is providing new understanding of AD pathology and revealing novel genetic information. The more we know about how the disease works, the better the chances are for identifying therapeutic intervention and finding a way to stop it before it starts or interfere once it has started. This is the kind of progress we set out to achieve at CAF and are proud to report on the success of this critical work.

Four Years Ago

Cure Alzheimer’s Fund agreed to support the effort to identify all the genes affecting risk for Alzheimer’s disease (AD). Until the mid-1990s, the AD research field had agreed on only four genes as contributing to AD pathology. Three of these were co-discovered by Dr. Rudy Tanzi and his colleagues at Massachusetts General Hospital and Harvard Medical School. All four genes were shown to be involved in the production or clearance of the Abeta protein, which is thought to be at the heart of AD pathology. Most researchers agreed there were many more genes affecting AD pathology, but they were very hard to find and confirm given the limited technology, databases and analytical computer programs at the time. The advent of “gene chips,” the sequencing of the whole human genome in the early 2000s, and major advances in statistical genetics made it now possible to expand upon genetic studies for many complex diseases. The idea was simple in principle—collect samples from families with AD clusters, look at a human genome apparently free of disease and compare it with the genomes of relatives affected by AD. Then focus on those genes or combination of genes that are different in some way in the genomes of those with and without the disease.

This is exactly what Rudy Tanzi and his colleagues proposed to do in late 2005, and they have made great progress. With the help of new technology that provided DNA on computer chips for much more rapid analysis than had been possible, the complete “normal” human genome, and the largest collection of family-based AD DNA in the world, the Tanzi team agreed to a budget of about $3.5 million and a timetable of three years to identify all or most of the remaining genes that affect risk for AD.

Identifying More Than 120 New Alzheimer’s Disease Candidate Genes

The investigation followed two tracks. One was internal to the Tanzi lab, working with the more than 1,000 families and 4,000 individuals from the various AD family-based samples the lab obtained from the National Institute of Mental Health (NIMH), the National Cell Repository for Alzheimer’s Disease (NCRAD), complementary data sets from Australia and Sweden, and samples from MGH/Harvard colleagues Brad Hyman and Deborah Blacker. The second track was to analyze data from all other researchers publishing papers about their identification of AD genes, all of which were collected on a Cure Alzheimer’s Fund-sponsored website called AlzGene (www.alzgene.org). This site not only lists all genes identified by other researchers, but does a “meta analysis” of all the papers’ data to help researchers determine which genes are genuine AD candidate genes and how they rank in terms of genetic power against other such genes. You can see these rankings on the website.

From this intensive, two-track system emerged more than 120 genes newly identified as possible AD genes, or, as the team likes to call them, AD candidate genes. This was done “on time and on budget”—a major scientific and management achievement! Four of the most strongly associated genes were described in a paper published by Dr. Tanzi and colleagues in 2008; this  earned recognition as one of the Top Ten Medical Breakthroughs of 2008 by TIME magazine/CNN.

Understanding How the Candidate Genes Affect Alzheimer’s Pathology

The objective now that an entirely new set of genes influencing AD pathology has been identified has been to determine which of these genes has the greatest effect on the pathology, either in terms of increasing risk OR increasing protection against the disease. Phase 2, in other words, focuses on the highest-priority “hits” as defined by genetic ranking to see what those genes actually do and whether the biological processes in which they are involved might be amenable to modification by drugs. More precisely, in Dr. Tanzi’s words, the objective was to “identify the causal genetic variants and/or mutations responsible for AD.”

For example, gene “A” in its original state may have no relationship to AD pathology at all. However, gene “A” may have developed a mutation over time that now creates a gene that contributes to AD pathology. In Tanzi’s genetic studies, statistically significant association is observed between the gene mutation and the inheritance of AD. Those mutations that show up most often (prevalence) or those that seem to have the most certain or profound effect on brain pathology and dementia (penetrance) are the top priority genes for further investigation. Of these genes, those that provide the greatest opportunities for drug discovery and development then are assigned the highest priority.

Further investigation of these highest-priority genes is called “functional analysis,” because the task now is to determine exactly how the gene affects AD pathology. As researchers look more carefully into these newly identified genes, they are finding that virtually all of them have something to do with either (a) effects on the processing of the APP protein from which Abeta is derived; (b) the production, clearance or in some cases the aggregation of Abeta protein molecules; (c) effects on other AD-related proteins such as Tau; and/or (d) cell death. Another common theme is effects on the brain’s defense system, called the innate immune system. When this system is triggered, Abeta production is enhanced. Dr. Tanzi is finding that many of the new AD candidate genes gauge how robustly the brain’s defense system reacts to such insults as strokes, head bangs, infections and neurotoxins. If one’s genetics leads them to overreact to an insult, the brain produces excessive Abeta. While this may help protect the brain from such things as infection in the short term, too much Abeta in the longer term can cause AD.

Results

Two examples of this functional analysis phase are instructive. One of the genes featured in the TIME/CNN recognition is called ADAM10. The gene has two rare mutations that can cause late-onset (sometimes called “sporadic” onset) AD. Not many people have these mutations, but when they do occur, the individual bearing them has a much higher chance of getting late-onset AD than the general population. ADAM10’s normal activity reduces the level of Abeta production. Both of these mutations impair the activity of ADAM10. The mutations, in other words, contribute to AD pathology by “taking the brakes off” the production of Abeta, which is normally controlled at least in part by the “normal,” nonmutated ADAM10 gene. Enough work and confirmation of this process has been done by Tanzi’s lab, CAF Research Consortium member Dr. Sam Gandy at Mount Sinai Medical School and others to confirm ADAM10 as a genuine Alzheimer’s gene.

The second example is a discovery that may lead to a whole new way of looking at Alzheimer’s pathology and how to prevent it from taking hold or stopping it after it has begun. As mentioned above, Dr. Tanzi identified a number of the newly pegged AD candidate genes as being involved in the innate immune system of the brain. Rob Moir of Massachusetts General Hospital/Harvard Medical School, working in Dr. Tanzi’s unit, found that Abeta may play a role in the innate immune system as an anti-microbial peptide that can fight infection. That means that Abeta may in fact have a positive, constructive role to play in the brain, but becomes toxic and leads to AD when it accumulates in excessive amounts.

What follows from both these examples is that rather than trying to extinguish completely the production of Abeta as some drugs have tried to do, or trying to limit its presence in the brain to negligible levels as others have tried, the more successful approach may be to modulate the process of production and clearance to maintain the “appropriate” level of Abeta in the brain to allow it to do its more positive and helpful work, but not to accumulate to excessive levels. Along these lines, Cure Alzheimer’s Fund is supporting a drug discovery program in Dr. Tanzi’s lab and Dr. Steven Wagner’s lab at the University of California, San Diego to develop “gamma secretase modulators,” drugs that will safely lower Abeta levels in the brain without wiping them out.

These and other discoveries will come more rapidly now that the whole Alzheimer’s genome has been mapped or “sequenced” and if the resources are available to follow up and confirm the strong AD candidate genes and their role in Alzheimer’s pathology. The more we know about them and how they do their work, the more able we are to stop them from starting AD pathology and to slow or stop it once it starts.