Cure Alzheimer’s Fund and Rotary joined forces this fall to fund research into why women are more likely to get Alzheimer’s disease than men. The two organizations granted a total of $375,000 to the lab of Rudy Tanzi, Ph.D., at Massachusetts General Hospital. Tanzi, who serves as the Research Consortium chair for Cure Alzheimer’s Fund, will analyze existing databases of Alzheimer’s family genomes to identify gene variants that impact risk differently for women than for men.

Women and Alzheimer’s

Of the 5.4 million Americans living with Alzheimer’s disease, nearly two-thirds are women. While researchers and clinicians have observed this phenomenon for some time, the reasons why incidence among women is greater are unknown, and little research has been done to determine possible genetic underpinnings. Women do have a longer expected lifespan than men, but this difference alone does not explain the observed imbalance in incidence of the disease. At age 65, women face twice the lifetime risk of developing Alzheimer’s than men. At 75, their risk is nearly threefold.

Women also exhibit faster cognitive decline than do men. In one study, women with mild cognitive impairment, a diagnosis that often precedes Alzheimer’s, increased their rate of cognitive errors faster than did their male counterparts when tested over several years. This seems to show that not only are women at higher risk of Alzheimer’s, but they also are affected by the disease in different ways.

Rotary

While this is the first time Rotary and Cure Alzheimer’s Fund have co-funded a research grant, the two organizations have ties going back several years. The initiative started with a chance meeting between Jeff Morby, co-chairman and co-founder of Cure Alzheimer’s Fund, and Dick Pratt, a member of the Martha’s Vineyard Rotary Club. Members of that club joined others in New England and ultimately from around the world to champion more attention and resources to combat the global scourge of Alzheimer’s disease.

In 2013, Martha’s Vineyard Rotary officially partnered with Cure Alzheimer’s Fund to create the Alzheimer’s Disease Rotary Action Group (adrag.org). In addition to funding more research like Tanzi’s, the group hopes to promote awareness of Alzheimer’s and its impact by partnering with local communities served by Rotary around the world. The initiative to fund Tanzi’s work was a joint effort between the Martha’s Vineyard Rotary Club and the Toronto Rotary Club. Rotary funding for the project was provided by The Rotary Foundation, a nonprofit charity.

The project

Tanzi’s study about women and Alzheimer’s stood out to both Rotary and Cure Alzheimer’s as an excellent co-funding opportunity. The percentage of women in Rotary is growing rapidly, as are members from the Indian subcontinent, a population dealing with increased rates of Alzheimer’s. Many current Rotary members have a parent, spouse or other loved one suffering from the disease.

Tanzi will be working with three databases of genetic samples from Alzheimer’s families: one from the National Institute of Mental Health (NIMH), one from the National Institute on Aging (NIA) and one from the National Cell Repository for Alzheimer’s Disease (NCRAD). This wealth of genetic data already has been screened by Tanzi and others for genes and variants that appear statistically associated with risk for Alzheimer’s. However, no one has attempted to mine the databases for risk factors specific to men or women.

“Studying sex-based differences is a harder problem, computationally speaking,” Tanzi explained. “On Chromosome 23—XX in women, XY in men—you sometimes have multiple copies of a gene, or silenced genes. Historically, these complications have pushed geneticists doing genome-wide association studies to omit the sex chromosome, or avoid breaking out men and women in their results.”

Tanzi will work with Christoph Lange, Ph.D., at the Harvard School of Public Health, to write new high-powered algorithms for sex differentiation risk analysis. The grant from Rotary and Cure Alzheimer’s Fund will allow them to tackle this difficult problem that many scientists have long avoided.

The potential reward for doing such work is great. “This is important for the treatment of all patients—not only women,” Morby said. Identifying a gene that seems to be protective in men, for instance, might point to a therapy that would benefit both sexes. One specific goal is to gain a better understanding of the APOE gene; while having the APOE4 variant of this gene increases risk for any carrier, women are at significantly higher risk as carriers of the gene than men are. More broadly, the study will provide insight into the mechanisms behind Alzheimer’s pathology and expand our understanding of what goes wrong in the disease.

More studies

Cure Alzheimer’s Fund plans to support further studies into sex-based differences in Alzheimer’s disease. Murali Doraiswamy, M.D., of Duke University, currently is being funded for a study looking at trends in cognitive, biomarker and genetic data that may indicate why women are at greater risk. Doraiswamy will perform second- and third-level analysis on the data to determine not just individual genes linked to risk, but interactions among different risk factors. He also is collaborating with Tanzi to share data and learn from one another’s findings.

“We are delighted to collaborate with Rotary as we tackle one of the most difficult conundrums relating to the disease,” said Morby. “Understanding the difference in response of women and men to the disease has been a subject that researchers have been reluctant to take on because of its complexity. Cure Alzheimer’s Fund is proud to take on this challenge with the support of an international service organization like Rotary.”