Background

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and a burgeoning unmet medical need that will only worsen as the average lifespan continues to increase. The prevalence of AD increases with every decade after the age of 60 and ~ 20% of the population can expect to get this devastating disease in their lifetime given the current average lifespan of  ~78 years. AD is strongly influenced by inherited factors. In fact, after age, the greatest risk factor for AD is family history. Studies of several thousand pairs of twins have revealed that at least 80% of Alzheimer’s disease involves the inheritance of risk-conferring gene defects—either gene mutations that directly cause the disease, or gene variants that increase susceptibility. To date, we know the identity of four AD genes. Over the last two decades, studies of these four genes, and particularly the three early-onset AD genes co-discovered by Cure Alzheimer’s Fund Research Consortium Chairperson, Dr. Rudy Tanzi, have guided virtually all laboratory research aimed at understanding AD and developing novel therapeutics. As invaluable as the known AD genes have been to solving the mystery of AD and guiding new therapeutic interventions, these four genes account for only 30% of the inheritance of Alzheimer’s disease. While the three early onset AD genes (APP,PSEN1, and PSEN2) account for roughly half of familial early-onset AD, for the most common late-onset (>60 years) form of AD, only one gene has thus far been established to increase susceptibility. This gene is known as the apolipoprotein E (APOE) gene. Since the discovery of the association between AD risk and the E4 variant of the APOE gene, increasing evidence indicates that this variant is neither sufficient nor necessary to cause the disease. We know that APOE works together with other genes to influence one’s inherited risk for AD. To date, the identity of the additional AD genes, which account for 70% of the genetic basis of AD, has remained unknown. 

Up until only a few years ago, the task of identifying the unknown AD genes was formidable , stymied by the genetic complexity of the disease and lack of technology and information databases necessary to tackle the problem effectively. However, beginning in 2001, the advent of new genetic technologies, e.g. genotyping arrays that screen up to a million genetic markers spanning the entire human genome, comprehensive human genome databases, and sophisticated statistical analysis programs made it feasible to identify the complete set of genes influencing risk for AD.

As history has already demonstrated, every new AD gene identified has offered new opportunities for drug discovery and more reliably diagnosing and predicting AD.

The ultimate goal of predicting the full set of AD genes is to someday allow us to predict one’s genetic risk for AD early in life (with appropriate legal protection against discrimination) and then empower those at risk with the safest, most effective preventative therapies before the disease strikes (personalized medicine).

The Cure Alzheimer’s Fund Alzheimer’s Genome Project™

The Cure Alzheimer’s Fund’s “Alzheimer’s Genome Project” (AGP) was established to identify the full set of AD genetic risk factors. The project has been conducted over the past three years in the laboratory of Dr. Tanzi at MGH. The AGP is an unprecedented, cutting-edge scientific research project aimed at identifying all of the genes that work individually or together to influence one’s risk for AD. Some of these genes are expected to have major effects on AD risk (or protection), while others have only minor effects. To find these genes, Dr. Tanzi and his team completed the largest family-based, genome-wide association screen conducted to date. Over 400 AD families were screened using Affymetrix genotyping arrays containing 500,000 genetic variants distributed throughout the human genome.

The overarching goal of the genome-wide association screen has been to determine which of these variants are genetically associated with the inheritance of AD in the families being tested.

AD-associated gene variants are then tested for replication and confirmation in >900 additional AD families. In addition to the genome-wide association screen, Dr. Tanzi and his colleague, Dr. Lars Bertram, have been carrying out bioinformatic analyses of the published AD genetics literature to determine which of the dozens of proposed AD candidate genes are genuine AD genetic risk factors. These findings are summarized and updated regularly on the website http://AlzGene.org (sponsored by the Cure Alzheimer’s Fund).

Ultimately, the goal of the AGP is to combine the results of the AD family-based genome-wide association screen with the bioinformatic results of AlzGene.org. with the end result bring a comprehensive list of the genes influencing lifetime risk for AD.

With the completion of the first phase of the AGP, we have identified 40 genes that exhibit novel genetic associations with either risk for, or protection against AD. This unprecedented achievement was the result of our family-based, genome-wide association screen. In addition, our AlzGene project has led to the identification of an additional 30 genes that confer either risk or protection for AD. Two separate papers describing the top five genes exhibiting novel genetic association with AD from our genome-wide association screen and the ten most interesting genes showing genetic association with AD based on our extensive bioinformatic analyses on AlzGene.org have been submitted to two different major journals and are currently undergoing peer-review.

The AGP, consisting of the results of our family-based genome-wide association screen and the AlzGene.org project have led to the identification of 70 genes containing variants that either confer risk for, or protect against AD. These genes carry out a wide variety of functions including:

• Cell-to-cell communication and signaling

• Protein maturation and trafficking

• Proteolytic and protease inhibitory activities

• Cellular growth factors

• Metal metabolism

• Cholesterol metabolism

• Neurotransmitter activity

• Calcium homeostasis

• Infection response

Summary and Next Steps

It is a fact that virtually our entire current understanding of the causes and pathological progression of AD has been made possible by studies of the four known AD genes (APP, PSEN1, PSEN2, APOE), discovered between 1987 and 1995. Since these genes account for only 30% of the genetic basis of AD, three years ago, the Cure Alzheimer’s Fund took advantage of major technological and analytical breakthroughs in human genetic studies to initiate the Alzheimer’s Genome Project aimed at determining the remaining 70% of the genetic basis of AD. We have made tremendous progress in the AGP, carried our over the past three years, leading to the identification of 70 genes exhibiting novel genetic association with AD.

The next steps include the initiation of biological (translational) studies aimed at determining how these genes increase risk for AD. This information will then be used to devise and guide screens for novel therapeutics aimed at preventing and treating AD at the level of disease progression, not just treating the symptoms, as current drugs on the market do. Our novel genetic discoveries warrant intensive study to determine genetically and biologically how they influence risk for, or protection against AD. Every new Alzheimer’s disease gene identified provides a unique opportunity to further our understanding of the biological basis of Alzheimer’s and guide the development of novel therapeutic strategies for prevention and treatment. Each new gene also increases our ability to predict the disease before symptoms hit. The eventual dovetailing of novel therapies and predictive genes will ultimately allow for a pharmacogenetic approach to predicting and preventing Alzheimer’s disease before it strikes. In the next phase of this project (translational studies), functional follow up of the novel AD genes discovered in the AGP should now guide us in the discovery and development of novel therapeutics to treat and prevent AD, and thereby accelerate efforts to reduce the suffering of patients and their caregiving familes as well as the impending financial and social costs of this devastating disease on our aging baby boomer population.