Researchers have long suspected that some of the genetic risk for Alzheimer’s is transmitted in the egg, since maternal inheritance seems to be more common than paternal inheritance (Edland et al., 1996). In the last few years, scientists have bolstered that hypothesis with data from people who do not have Alzheimer’s—at least not yet—but know that a parent did. Having a mother with Alzheimer’s decreases gray matter volume (Honea et al., 2010) as well as brain glucose metabolism (see ARF related news story on Mosconi et al., 2007). Mosconi and colleagues now link maternal history more directly to Alzheimer’s with their study of amyloid-β. The work takes the maternal inheritance case “to the next level,” said Russell Swerdlow of the University of Kansas School of Medicine in Kansas City, Kansas, who was not involved with the study.

Mosconi and coauthors used Pittsburgh Compound B (PIB) to image amyloid-β in the brains of 42 subjects, ranging from 50 to 80 years old. All were healthy, both physically and mentally. Fourteen had no family history of Alzheimer’s, 14 had a father with the condition, and 14 had a maternal history. People with any family history of Alzheimer’s had more amyloid-β deposits than those with a clean family record, but those whose mothers were affected had the most PIB label retention. People with a paternal history had amyloid-β in some parts of the brain, but subjects with a maternal record had widespread accumulation, typical of Alzheimer disease. Maternal-history participants also retained 20 percent more PIB tracer than paternal-history subjects, Mosconi said. However, she noted that amyloid-β is not a certain predictor of AD.

The combined inheritance and biological data suggest several possible mechanisms for inheritance of AD risk factors. The first to come to mind, Mosconi said, is X-chromosome linkage. However, if the risk factor were carried on the X chromosome, researchers would expect that men would be more susceptible, since they lack a second X chromosome that could mask X-linked mutations. For example, the X-linked colorblindness gene is more likely to affect the vision of men than women. No such pattern has been noted for Alzheimer disease, Mosconi and Swerdlow noted. Another possibility, Swerdlow suggested, is that one or more genes for Alzheimer’s risk are sex-influenced, inherited from both parents but modified by epigenetic factors to confer more risk when the faulty allele comes from mom.

Mosconi finds a third possibility is perhaps the most appealing, particularly given her earlier findings on metabolism and inheritance (Mosconi et al., 2007). “We’re talking about maternal transmission…and we’re talking about glucose metabolism…to me that equals mitochondrial DNA,” she said. Other lines of evidence support this hypothesis (reviewed in Swerdlow and Khan, 2009). Cytochrome oxidase, a mitochondrially encoded enzyme, is sluggish in people with Alzheimer’s, Swerdlow noted. He and several colleagues have studied the effects of mitochondrial DNA by swapping normal mitochondrial DNA for mitochondrial DNA from AD patients. After several generations, cytochrome c oxidase activity went down and reactive oxygen species went up, suggesting that mitochondrial and not nuclear DNA is responsible for those changes (Swerdlow et al., 1997).

In finding maternal inheritance in the PIB study, Mosconi said, “I was a little surprised, because there really is no direct relationship between mitochondrial DNA and amyloid.” Perhaps, she suggested, a minor mitochondrial mutation could lead to a lifetime buildup of oxidative stress, eventually promoting amyloid formation. The mitochondrial gene hypothesis would become truly compelling, Mosconi said, if the researchers also had data on the maternal grandmothers of their subjects, which would be the source of their mitochondrial DNA. Unfortunately, she said, reliable family histories rarely extend back that far. Researchers must also find a non-maternal explanation for the portion of AD risk that is paternally inherited. Other researchers noted that there is no compelling genetic evidence linking mitochondrial DNA with AD.

Mosconi said that, as long as funding is available, she would like to follow these subjects longitudinally. They also would make ideal candidates for a trial of preventive measures. “There is surprisingly little information on these people who are at high risk for AD,” Mosconi said.

That may change. The current study is part of a growing trend, Swerdlow said, in studying people well before the end stage of Alzheimer disease, before symptoms even. For example, researchers at the University of Wisconsin in Madison are tracking middle-aged people with a family history of AD and have found maternal inheritance a risk factor for brain atrophy (see ARF related news story). “A study of family history, like [Mosconi’s], may hold the key to understanding the early course of preclinical AD,” wrote Mark Sager, of the University of Wisconsin, in an e-mail to ARF.—Amber Dance.

Reference:
Mosconi L, Rinne JO, Tsui WH, Berti V, Li Y, Wang H, Murray J, Scheinin N, Någren K, Williams S, Glodzik L, De Santi S, Vallabhajosula S, de Leon MJ. Increased fibrillar amyloid-{beta} burden in normal individuals with a family history of late-onset Alzheimer’s. Proc Natl Acad Sci U S A. 2010 Mar 15. Abstract