Alzheimer's gene found to affect women over men ALZHEIMER'S DISEASE

A gene that's been known for two decades as the largest inheritable risk for developing Alzheimer's disease mostly affects the brains of women, not men, according to a team of researchers from Stanford and UCSF.

The gene variant known as APOE4 is the most common genetic risk factor for Alzheimer's - only about 15 percent of people carry the gene, but it's found in more than half of all Alzheimer's patients.

The variant was first connected to Alzheimer's in 1993, but doctors and scientists for the most part have been unaware of any gender differences, despite early studies that showed an increased risk for women with the gene.

The new research, which is being published Wednesday in the Journal of Neuroscience, looked at two biological indicators - or biomarkers - associated with Alzheimer's disease: decreased activity in a brain network related to memory, and increased levels of the tau protein in spinal fluid. Women with the APOE4 gene were more likely to test positive for both markers than men who had the gene and women who didn't have the gene.

Path to new research

The findings will not have any immediate clinical impact - very few people are encouraged to learn their APOE4 status because there is no treatment for Alzheimer's. But the results could open a torrent of new research possibilities, such as studying the relationship between hormones and Alzheimer's, or looking for other gender differences that could be making women with the gene more vulnerable, scientists said.

"We haven't been able to get much insight into how APOE is affecting increased risk. This might be a big clue," said Dr. Michael Greicius, medical director of the Stanford Center for Memory Disorders and senior author of the study.

The older study of the APOE4 gene found that women with one copy of the gene were four times more likely than anyone without the gene to develop Alzheimer's; men with a single copy had no increased risk. Both men and women, however, were up to 14 times more likely to develop Alzheimer's if they had two copies of the gene. But that's a rare combination - only 2 percent of the population has two copies.

The APOE4 gene, along with other genetic risk factors for Alzheimer's, has become increasingly important in research for treating the disease. Genetic research can help scientists better understand what causes Alzheimer's and it may lead to treatments that target specific biological mechanisms of the disease.

For example, scientists might find a connection between sex hormones and the gene or a genetic mutation tied to the X chromosome that interacts with APOE4, Greicius said.

Hope for early signs

The gene connection also could help scientists identify people who are showing early biological signs of developing Alzheimer's, years before they suffer memory problems. One of the major barriers to developing treatments has been identifying patients in the earliest stages of Alzheimer's, before the disease has caused too much damage to repair.

If scientists know to look for certain genes associated with Alzheimer's and know to look for certain biomarkers, they may be able to stop the disease progression, or at least slow it down. In theory, it would be similar to identifying a patient with high cholesterol decades before he suffers a heart attack, said Maria Carrillo, senior director of medical and scientific relations with the Alzheimer's Association.

"Studies like this open up all kinds of questions, and we can ask them at the earliest molecular changes," Carrillo said.

That's why the new research is exciting, Carrillo said - it clearly demonstrates that the APOE4 gene can be tied to two Alzheimer's biomarkers before patients exhibit any symptoms. None of the patients in the study had been diagnosed with Alzheimer's or even its precursor, mild cognitive impairment. They were all healthy adults, mostly in their 70s.

The first part of the study looked at the magnetic resonance imaging scans of 131 adults, both with and without the APOE4 gene, who had been previously scanned at UCSF.

Default mode

Among the female APOE4 carriers, those scans showed significantly decreased activity in the default mode network of the brain - a neural network that connects several memory centers, and is usually activated when people aren't actively thinking about anything specific, thus the "default" label.

It's unclear what role the default mode network plays in Alzheimer's, but studies have shown a relationship between dementia and reduced brain activity. Because the decreased activity is still a new biomarker in detecting Alzheimer's, scientists then used a second biomarker to confirm that there was a difference between the APOE4 carriers and those without the gene.

That second biomarker - an increased level of tau protein in cerebrospinal fluid - also showed a connection in women between the APOE4 gene and Alzheimer's.

The gender connection is interesting, said Dr. Frank Longo, chairman of the department of neurology and neurological sciences at Stanford, who was not involved in the study. But perhaps even more important to the field of Alzheimer's research is further proof that low activity in the default mode network may be one of the earliest signs of the disease, he said.

"People have been really struggling for something you could reliably find before symptoms start," Longo said. "The idea of looking at brain networks deteriorating is fascinating. It's kind of scary in a sense. But at the same time, it gives us a window of opportunity."

‌