Genes Influencing Rate of Cognitive Decline in AD Identified

Alzheimer's Association International Conference (AAIC) 2013. Poster P4-007. Presented July 12, 2013.

Alzheimer's disease is characterized by progressive decline in cognitive functioning, especially in memory but also executive functioning (including planning, attention and problem solving) and global cognition. Each person may experience Alzheimer's differently, and there are considerable differences in rates of decline between affected individuals.

"If we can understand more about the genetic basis of this variability in rate of decline, it could help illuminate the biological pathways involved in disease progression," said Richard Sherva, Ph.D., research assistant professor in the department of Biomedical Genetics at Boston University School of Medicine. "It also could inform the development of therapies to slow the progression of disease."

Sherva and colleagues are utilizing research funds awarded by the Alzheimer's Association to study the genetics of the rate of Alzheimer's-related cognitive decline in a large population from a completed clinical trial. By expanding their work into a multi-institutional consortium (known as Genetic Architecture of Rate of Alzheimer's Decline, or GENAROAD, led by Drs. Robert Green and Paul Crane), they have amassed a relatively large sample of Alzheimer's cases with the longitudinal data necessary to study the topic in depth.

At AAIC 2013, Sherva reported genome wide association studies (GWAS) from participants in multiple research studies including the Alzheimer's Disease Neuroimaging Initiative (n=301), National Alzheimer's Coordinating Centers (n=865), Religious Orders Study/Rush Memory and Aging Project (n=323), and AddNeuroMed study (n=123). The combined GWAS identified at least four genetic variants strongly associated with rate of decline in Alzheimer's, including SPON1, MANB4A, KCNJ14, MAP3K1 and HIBADH.

"We found that the genes that influence rate of decline are largely different that those that influence Alzheimer's risk in general but are genes involved in pathways related to Alzheimer's risk," Sherva said. "The most interesting gene we identified is called SPON1, which has functions related to beta-amyloid generation and also regulates brain cell connectivity."