Alzheimer's Disease Gene Identified

Internal Medicine World ReportMarch 2007
Volume 0
Issue 0

Genetic Etiology Could Lead to New Drugs

Nature Genetics

A major piece in the puzzle of Alzheimer’s disease (AD) has fallen into place, suggesting a potential therapeutic target for the disease, according to results of a new study published in (2007; 39:168-177).


An international group of investigators has linked variations in the gene to late-onset AD in 6 different ethnic groups, although they did not identify the exact mutations in the gene that were responsible for the disease.

“The principal implication of the discovery of a genetic association between variants in the SORL1 gene and Alzheimer’s disease is that it provides a new piece of knowledge about how this disease comes about,” coinvestigator Peter St. George-Hyslop, MD, director, Center for Research in Neurodegenerative Disease, University of Toronto, told IMWR. “In a disease which is presently untreatable, each new piece of information about the disease mechanism is incredibly valuable. These basic science discoveries, however, are really still just research observations.”


The initial research included 2 large sets of genetic data from families in which more than 1 family member was diagnosed with AD. Analysis showed that many of these families had variations in the gene.


The study was then expanded to include families of Northern European, Caribbean, Hispanic, white, African American, and Israeli-Arab descent, providing DNA samples from more than 6000 volunteers. Again, the same association between gene variations and AD was found.



Previous research demonstrated that faulty processing of the amyloid precursor protein (APP) and subsequent accumulation of amyloid beta was associated with the development of AD. The cell biology experiments in this new study showed that controls the distribution of APP within the nerve cells of the brain and that, under healthy conditions, protein regulates APP and recycles it to a specific part of the nerve cell.


When is malfunctioning and its protein level is low, however, APP accumulates in a different part of the cell, where it is degraded into the amyloid beta fragments or plaques that cause AD.


Several variations in gene sequencing were identified; at least 2 and possibly more gene variants play a part in disrupting the healthy functioning of the gene. Dr St. George-Hyslop noted that this was not unusual, and that in many diseases, multiple sequencing variations can affect a single gene. He added that more work is needed to find the actual disease-causing variants themselves and to determine what proportion of AD cases are attributable to variants in this gene.

“This is an elegant study that identifies an important new genetic risk factor for Alzheimer’s disease,” commented Benjamin Wolozin, MD, PhD, of Boston University School of Medicine. “One of the impressive strengths of this study is the detailed manner in which they confirmed the finding.”?

He added, “Another strength of this observation is that they were able to link it directly to a biochemical effect related to the metabolism of beta-amyloid and its precursor, amyloid precursor protein.?This observation is important, because it provides important support for our understanding of the causes of Alzheimer’s disease (the amyloid cascade hypothesis), and it provides a potentially novel target for drug discovery.”

This major study was funded by several international bodies, including the US National Institutes of Health and the National Institute on Aging, the Canadian Institutes of Health Research, the Alzheimer Society of Ontario, and the Alzheimer Association of the United States.

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