Four papers published this fall in leading science journals refer to the identification of new genes that confer risk for, or protection against, Alzheimer’s disease.

The articles:

Bertram L and Tanzi RE. Thirty Years of Alzheimer’s Disease Genetics: Systematic Meta-analyses Herald a New Era. Nature Reviews Neurosci 2008; 9:768-78.

Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, Schjeide BM, Hooli B, DiVito J, Ionita L, Jiang H, Laird N, Moscarillo T, Ohlsen KL, Elliott K, Wang X, Hu-Lince D, Ryder M, Murphy A, Wagner SL, Blacker D, Becker KD, Tanzi RE. Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE. Am. J. Hum. Genet. 2008; In Press.

Schjeide BM, McQueen MB, Mullin K, DiVito J, Hogan MF, Parkinson M, Lange C, Blacker D, Tanzi RE, Bertram L. Assessment of Alzheimer’s disease case-control associations using family-based methods. Neurogenetics 2008; In Press.

Schjeide, B.-M.M., Hooli, B., Parkinson, M., Hogan, M.F., Divito, J., Mullin, K., Blacker, D., Tanzi, R., and Bertram, L. Follow-up of genome-wide association results suggests GAB2 as an Alzheimer’s disease susceptibility gene. Arch. Neurol. 2008;  In Press.

The genes described in these four papers are subsets of 70 AD candidate genes identified by Dr. Rudy Tanzi and his colleagues at Massachusetts General Hospital, thus far, as part of the Alzheimer’s Genome Project. These newly identified genes appear to function individually, or in some cases interactively, to increase or protect against risk for Alzheimer’s disease. This first milestone achievement of the Alzheimer’s Genome Project™ represents one of the most important breakthroughs in Alzheimer’s research in recent history, and will greatly facilitate the development of effective therapies for the disease.

In particular, the four papers describe how newly available technology is improving understanding of the genetic mechanisms underlying the disease. The study described in the American Journal of Human Genetics is the largest genetic analysis of Alzheimer’s disease carried out to date. The paper reports five DNA markers exhibiting genetic association with Alzheimer’s, one of which corresponds to the gene for APOE, the only gene previously established to increase risk for late-onset Alzheimer’s. Of the other four novel sites, the strongest marker was located on chromosome 14 and was further supported by an independent analysis comparing 1,400 Alzheimer’s patients with healthy controls.

“The genetic association of Alzheimer’s with this novel chromosome 14 gene, which like APOE appears to influence age of onset, is sufficiently strong to warrant intensive follow-up investigations into its role in the process of nerve cell death in this disease,” says Tanzi. “This gene also is in the general vicinity of the presenilin-1 gene, which we know is an early-onset Alzheimer’s disease gene. We don’t know if that proximity is a coincidence, and we currently don’t know what the new gene does, although there is some indication it may control the activity of other genes.”  

Another of the identified markers is in a gene known to cause spinocerebellar ataxia, a movement disorder that involves the death of nerve cells in other parts of the central nervous system, and a third is in a gene involved with the innate immune system, part of the body’s defense against bacteria and viruses. The fourth marker is in a gene that produces a synaptic protein—not surprising, since it is known that loss of synapses correlates well with dementia in Alzheimer’s.

“Virtually all current research into therapies is based on the Alzheimer’s genes that we already know about, so each new gene we find not only enhances our ability to predict and diagnose the disease, but also provides valuable new clues about biochemical events and pathways involved in the disease process,” adds Tanzi, who was a co-discoverer of all three of the known early-onset Alzheimer’s genes. The team is continuing to investigate the implications of these novel genes as well as the possible impact of less strongly associated genes also identified in this study.  

This is exciting groundbreaking research that should advance our knowledge of the causes of Alzheimer’s disease and guide the development of novel therapeutics to treat and prevent the disease. “This project is the most comprehensive search for the genes that cause Alzheimer’s disease published to date,” Tanzi said. “Our hope is to use this new information to not only better diagnose and someday predict risk for Alzheimer’s but to also learn from these genes the biological causes of Alzheimer’s. The knowledge gained from understanding the Alzheimer’s-associated defects in these genes will almost certainly accelerate the development of novel therapeutics and hopefully lead to a potential cure for this devastating disease.”