Sun, Nov 10th, 2013

Alzheimer’s risk before symptoms: Do you want to know?

Anne Kolesar thought she had packed well for her biking trip last month in Pennsylvania’s “Grand Canyon,” with clothes for cold weather and snacks. But after driving about a hundred miles, she looked through her rearview mirror and realized: Oops, no bike!

Kolesar, 61, laughs heartily as she tells this story. But hovering over the incident is her knowledge that she has an elevated genetic risk of Alzheimer’s disease.

“I do feel like there’s this sword, sort of hanging over my head, that might drop, and I don’t know when,” said Kolesar, who splits her time between Pittsburgh and Indiana, Pennsylvania. ” And I’m not sure how you know.”

It’s not just that she watched her father’s mental faculties deteriorate over the past 20 years or that her aunt and grandmother also succumbed to the disease. Kolesar participated in a clinical trial that revealed to her that she has one copy of the APOE-4 genetic variant. This gene has been linked to up to 25% of Alzheimer’s cases, according to the Alzheimer’s Association.

Screening for forms of APOE isn’t part of routine medical practice. But Kolesar was curious about her risk, so she volunteered to participate in a research study that tested participants for APOE variants.

Alzheimer’s disease has no cure or effective long-term treatment. Many drug trials have failed to show lasting delays or reversals of symptoms in people who already have dementia.

That’s why scientists are exploring what signatures Alzheimer’s disease might create in the body before symptoms ever begin. Besides genes such as APOE-4, they are looking at proteins associated with plaques and tangles in the brain.

The hope is that understanding both risk factors and the timing of the development of disease pathologies will lead to successful treatments in people who haven’t begun to show any impairments in memory or thinking.

But to set up human experiments aimed at prevention, researchers need to identify a whole new category of patient: Those in the “preclinical” stage of Alzheimer’s. By performing brain scans and testing cerebrospinal fluid, scientists can single out individuals likely to show symptoms of Alzheimer’s within up to 15 years. That’s not about genetics per se; it’s about the appearance of biomarkers before symptoms begin.

An important ethical question is emerging: Should people without symptoms be told that they are, indeed, “preclinical”? Is it useful or meaningful to know that you could be 15 years away from the inevitable?

“Medically and socially, we have to get ready for this era of using biomarkers and imaging for early detection,” said Rudy Tanzi, a professor of neurology at Harvard Medical School and leading Alzheimer’s researcher.

Better not to know?

An ongoing study at Washington University School of Medicine in St. Louis does not inform participants of the genetic or biomarker risk profile for Alzheimer’s disease. The Washington University Adult Children Study aims to study these risks, but researchers don’t think participants’ individual results are appropriate to give them because even the researchers entirely aren’t sure what they mean.

“This is a hot topic of discussion amongst the participants and the investigators” at an annual breakfast meeting with participants, said Dr. David Holtzman, a neurologist at the medical school. “We’ve been doing a study the last year to try to determine the best way to proceed. Should we make (the biomarker results) available to them or not?”

Currently, the answer is no.

All of the study volunteers begin the study cognitively normal, between 45 and 74. Participants are enrolled according to two criteria: Those who have at least one biological parent with an Alzheimer’s diagnosis before 80, and those who had two parents who lived to at least 70 without developing Alzheimer’s.

Researchers are presenting the latest findings from this study at the Society for Neuroscience conference in San Diego this weekend.

In this study, participants’ cerebrospinal fluid is tested for decreases in beta-amyloid — suggestive of plaque buildup in the brain — and tau proteins, which are associated with neurofibrillary tangles and neuronal degeneration. They also get a genetic test for APOE status, the strongest genetic risk factor for Alzheimer’s.

The idea is to follow participants over many years to monitor changes in these key biomarkers and see how they vary in relation to APOE status and future cognitive symptoms.

Consistent with their hypothesis, lead researcher Courtney Sutphen and colleagues found that people with at least one copy of APOE-4 are likely to develop biological signatures of Alzheimer’s pathologies earlier in life than those who don’t have any APOE-4 copies.

It’s possible that some changes in the APOE-4-positive group begin even before 45, researchers said, but that would have to be tested with younger participants.

That doesn’t mean that APOE-4 positivity guarantees the early formation of Alzheimer’s-linked biomarkers — beta-amyloid and tau proteins — or that these biomarkers guarantee symptoms of Alzheimer’s.

That’s partly why the Adult Children Study does not disclose biomarker results to the participants, said Anne Fagan, a research professor in the department of neurology at Washington University School of Medicine.

“Perhaps even more importantly, there’s also the possibility that if you tell someone they’re APOE-4-negative, they think they’re out of the woods,” she said. “And that’s not true either. Many, many people who are APOE-4-negative get the disease. So knowing one’s genotype is not really clinically meaningful at this point.”

In perhaps five or 10 years, though, if a drug exists to prevent the disease before the onset symptoms, that’s when the biomarker information will become clinically relevant, she said. Additionally, knowing one’s APOE genotype may provide information regarding the timing of the development of such pathologies.

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