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Alzheimer’s Association International Conference

Access timely, concise peer-reviewed reports from the Alzheimer’s Association International Conference selected by the Neurology Today editors.

Friday, July 27, 2018

CHICAGO—The anti-amyloid-beta antibody BAN2401 used at the highest dose reduced cognitive decline by two measures in early Alzheimer's disease (AD) and reduced amyloid burden after 18 months, according to results presented by the drug's manufacturer here at the Alzheimer's Association International Conference.

"This is the first large clinical trial to support the amyloid hypothesis," said Lynn Kramer, MD, chief clinical officer of the neurology business group at Eisai.​

The results were eagerly awaited, but several experts not associated with the trial were mostly restrained in their response to the data. They said questions remain about the methodology, which involved response-adaptive randomization, and that further assessment of the drug is needed in a larger phase 3 trial.

The findings come several months after Eisai, developing the drug with Biogen, announced that the drug hadn't met its more rigorous, 12-month endpoint in its interim analysis. That endpoint involved a much higher threshold, while the new 18-month endpoints were based on a standard statistical analysis, Dr. Kramer said. A standard analysis was not done at the 12-month mark in order to preserve the integrity of the trial as it continued on, he said.

In the 856-person trial, all patients had amyloid-beta at baseline and were randomized to placebo or to one of five active treatment groups, from 2.5 mg/kg biweekly to 10 mg/kg biweekly. After initial randomization, a computer program assessed the results every three months and determined the dosing group that would most likely benefit patients, and they were re-assigned accordingly.

Researchers found that the 10 mg/kg dose given biweekly produced the best results. Patients receiving this dose had a 30 percent slower decline than patients on placebo on the Alzheimer's Disease Composite Score — a measurement developed by the drug manufacturer that was meant to capture early dementia symptoms more effectively than standard scales (p=.034). The same dose slowed decline by 47 percent compared to placebo on the Alzheimer's Disease Assessment Scale cognitive subscale (p=.017).

Researchers also found that the highest dose significantly reduced amyloid-beta burden on positron emission tomography by 70 units on the centiloid scale (p<.0001).

Overall, there were no differences in serious treatment-related adverse events across the groups. But amyloid-related imaging abnormalities thought to represent edema was seen in 9.9 percent of patients in the highest dose group, compared to just 0.8 percent in the placebo group. Researchers said they were mild to moderate findings and that they typically resolved within four to 12 weeks.

Dr. Kramer said the company plans to talk to regulatory authorities around the world to seek accelerated approval and to get guidance on how to go about future studies of the drug.

Independent experts said they were encouraged that the findings were another indication that reducing amyloid can improve cognitive symptoms in AD, but their enthusiasm was tempered.

David S. Knopman, MD, FAAN, professor of neurology at Mayo Clinic in Rochester, MN, noted that the initial gross point difference on the ADAS-Cog for BAN2401 over placebo — the drug was 3 points better — was not much different from what has been seen for prior Alzheimer's therapies, such as donepezil, that in the long run have proven rather disappointing.

"The question is: What does that effect size mean?" Dr. Knopman said. "Over a year, who knows?" Longer and larger phase 3 trials are needed to truly gauge how the drug is likely to affect patients' lives, he said.​

The hope with this drug is that it would be disease-modifying and that the difference in cognitive decline between the treatment and placebo group would continue to widen, Dr. Knopman said.

Julie A. Schneider, MD, MS, professor of neurology at Rush University Medical Center, said the unusual methodology means it will take time to fully grasp the results. "We're really going to have to study how this was done in order to feel more confident about the findings," Dr. Schneider said.

She said that she was hoping for a steeper decline in the treatment group compared to the placebo group. "We really want to see a change in the slope in the decline," she said, "rather than just a bounce up."​

Dr. Kramer is an employee of Eisai Co, the manufacturer of BAN2401.

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van Dyck CH. Anti-amyloid-β monoclonal antibodies for Alzheimer's disease: Pitfalls and promise. Biol Psychiatry 2018; 83(4): 311-319.

Friday, July 27, 2018

CHICAGO—An analysis of data on hormone therapy and cognition provides a clearer picture on how to counsel women about the therapy's risks and benefits, according to a new report presented here at the Alzheimer's Association International Conference.

"Altogether, data suggest that hormone therapy is not associated with cognitive harm when therapy is initiated proximal to the menopausal transition, and/or when women are healthy," — particularly, among those who do not have diabetes, said Carey E. Gleason, PhD, associate professor of medicine at the School of Medicine and Public Health at the University of Wisconsin, who presented the analysis. But the long-term effects of menopausal hormone therapy on cognition are not yet known, she said.

In 2002, questions about hormone therapy were raised when an ancillary memory study of the Women's Health Initiative, WHIMS, found that cognitive harm was associated with the treatment. Those findings contradicted previous findings that menopausal hormone therapy was beneficial to cognition. But the findings prior to WHIMS were drawn from observational studies, and the prevailing view was that they may have been the result of a healthy user bias, that is, that positive results regarding cognition were related to the overall favorable health habits of women who use hormone therapy.

But criticisms of the WHIMS findings emerged: The women enrolled were well past menopause, at age 65 and up, and the women in the treatment arm were given conjugated equine estrogen (CEE) with medroxyprogesterone acetate (MPA), which contain non-native hormones, Dr. Gleason said.

In the Kronos Early Estrogen Prevention Study-Cognitive and Affective (KEEPS-Cog), which she helped lead, women were given CEE or estradiol, the native gonadal hormone, or placebo, within three years of their last menstrual period. A total of 662 women were included in the final analysis. On average, women stopped therapy at age 58.

"KEEPS-Cog found no cognitive effects with hormone therapy," Dr. Gleason said, though she noted there were mood benefits in the CEE group compared to placebo (p<.001).

At one of the centers involved in the trial, researchers performed additional brain scans to assess amyloid deposition. Women positive for apolipoprotein E 4 who took estradiol had lower amyloid concentrations after therapy. This was not observed among those who were not positive for the risk gene, Dr. Gleason said.

Another trial — the Early vs. Late Intervention Trial with Estradiol-Cognitive Endpoints, or ELITE-Cog — enrolled women within six years of, or 10 or more years past menopause. They were treated with estradiol for up to five years. The findings suggested no cognitive benefit or harm for either group, but Dr. Gleason noted that the women in the study were generally "very healthy."

In another analysis of Women's Health Initiative data, including younger women between ages 50 and 54, investigators found no cognitive effects. But WHIMS researchers reported that women with type 2 diabetes randomized to receive CEE had an elevated risk of cognitive impairment and probable dementia, compared to age-matched women without diabetes, and those with diabetes on placebo.

Dr. Gleason said the "very personalized" approach may be best when considering menopausal hormone therapy.

"A woman who is interested in treating depression symptoms associated with menopause may consider CEE as an option to treat menopausal mood symptoms, because that's where we found efficacy, not in the estradiol formulations," she said. "For a woman who is diabetic and menopausal, the WHIMS data suggests that she should not be on hormone therapy. We're just scratching the surface here."

In a continuation of the KEEPS study, researchers will re-enroll women in the original study to collect brain scans, and cognitive and mood testing data 12 years after they were randomized to CEE, estradiol, or placebo.

"Midlife in general and the menopausal transition specifically represent a prime risk period for neurological changes," she said. "Now we can look further into that whole question of the long-term effects of menopausal hormone therapy in relation to Alzheimer's disease pathology."

Commenting on the study, Pauline Maki, PhD, senior director of research at the Center for Research on Women and Gender at the University of Illinois at Chicago, said the findings re-emphasize the crucial point that estrogen therapy has different effects on the brain depending on when you take it.

But data are still needed on the effects on specific symptoms, she said.

"One thing that wasn't discussed is the fact that when you take hormone therapy early, you relieve hot flashes, improve sleep, mood, and other [symptoms] that research shows are a toxic hit to the brain," Dr. Maki said. "I think this idea of personalized medicine for estrogen is the answer."

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AAIC Abstract F2-01-03: Gleason CE, et al. An update on menopausal therapy trials.

Friday, July 27, 2018

CHICAGO—A blood pressure target of 120 mmHg was associated with a l9 percent lower risk of developing mild cognitive impairment (MCI) compared to the standard blood pressure goal of 140 mmHg, according to data presented here at the Alzheimer's Association International Conference.

The findings come from the cognitive assessment portion of the Systolic Blood Pressure Intervention Trial (SPRINT-MIND) which randomized 9,361 people either to a systolic blood pressure target of lower than 120 mmHg or the standard target of lower than 140 mmHg.

"These results are preliminary but they are groundbreaking," said Jeff Williamson, MD, the presenting author and professor of gerontology and geriatric medicine at Wake Forest Baptist Health. "This large randomized clinical trial shows that what's good for your heart is also good for your brain. That's a really important message, particularly in the area of controlling blood pressure."

Researchers found a significant reduction in MCI (HR=0.81; p=.02) and a non-significant reduction in probable dementia (HR=0.83; p=0.10) in the intensive control group. The combination of MCI and probable all-cause dementia was also significantly lower in the strict control group (HR=0.85; p=.02).

Treatment was started in 2010, and after a year, the average systolic blood pressure was 121 mmHg in the intensive group and 136 mmHg in the standard treatment group. After the cardiovascular benefits were revealed and the treatment was stopped early, the blood pressure was no longer managed by the research teams. For this reason, during the closeout, the intensive group blood pressure average was 125 mmHg and the standard group was essentially unchanged, Dr. Williamson said.

Two years after treatment was stopped due to cardiovascular benefits in the intensive group, the average blood pressure in the intensive group rose to 129 mmHG while the standard group's average blood pressure still remained essentially unchanged, Dr. Williamson said. Average follow up was 3.2 years, he noted.

"Even for those persons who cannot reach a goal of 120 mmHG, don't let the perfect impede the possible," he said. "Right now many people's blood pressure isn't even controlled below 140, and so if we can get people closer to this result…clinicians and their patients should focus on doing that."

Lowering of blood pressure goals should be safe for many patients, he said, noting there were no more falls or orthostatic hypotension in the intensive group, although they were more susceptible to electrolyte abnormalities such as lower sodium and potassium on blood work. Those in the intensive group also were more likely to report dizziness.

Laurie M. Ryan, PhD, chief of the dementias of aging at the National Institute on Aging, said the non-significant finding on reduction of probable dementia should not be discouraging. In part, the trial was hampered in collection of that data because it was stopped early due to its positive primary results.

"MCI is a risk factor for dementia and (by) showing that you can decrease the risk for MCI, you are, in fact, potentially decreasing risk for dementia because it's a precursor," Dr. Ryan said.

"Physicians will have more information now to make the right choices," she said. "You've got to manage blood pressure. That is a critically important piece and something that individuals can do to modify their own risk, by working with their physician to take some control."

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Background on the SPRINT MIND study

Thursday, July 26, 2018

CHICAGO—A virtual reality program, which simulates the experience of living with dementia, builds empathy and insight into caregiving among teens, according to findings presented here at the Alzheimer's Association International Conference.

The tool has helped improve an already existing art therapy program, called Bringing Art to Life, for people with dementia, said Daniel Potts, MD, who started the program after his father became a skilled and avid painter after becoming non-verbal due to dementia.

"The virtual reality addition seemed to take it up a notch," he said. "Respondents all said that it was very engaging and helped them to interact better with people with dementia" with whom they were paired in the art therapy program.

Users of the virtual reality program wear a headset and are placed into a world — in the form of five-minute "journeys" — in which they use their own hands projected as the person whose experience they are sharing.

One simulation involves Alfred, a 74-year-old African-American man with suspected mild cognitive impairment, age-related macular degeneration, and high frequency hearing loss. The aim is to experience how his condition affects his relationships with his family and doctor, and to try to navigate the health care system with these impairments. Another simulation features Beatriz, a middle-aged Latina woman with Alzheimer's disease.

"It delivers a really complex but powerful, high-impact teaching moment," said Carrie Shaw, MS, who developed the virtual reality program at her Los Angeles-based Embodied Labs.

Debriefings of high-school students who've used the program as part of their involvement in Bringing Art to Life have found that they come away with a deeper understanding of how the brain works and what Alzheimer's disease is. They also have developed ideas for better care practices, such as talking more slowly or providing better lighting in rooms where people with dementia spend their time.

Researchers have also found an increased interest in pursuing a career in health care and decreased use of words associated with stereotyping when talking about aging, Shaw said.

Dr. Potts said he's hoping the virtual reality tool, together with the Bringing Art to Life, catches on clinically.

"We'd love for that to be the case," Dr. Potts said. "Neurologists need to be advocating more for expressive arts as a means of living well. We need to be helping not just diagnose people and putting them on meds, but helping them to live well."

Darby Morhardt, PhD, a clinical social worker and research associate professor at the Northwestern Cognitive Neurology and Alzheimer's Disease Center, who is not involved with the program, said the virtual reality's allure to high school students and medical students makes it especially valuable.

"If we want to really want to change people's thinking about dementia, we need to get to them early in life," she said. "We certainly need more health care professionals that have a better understanding of this disease and a more compassionate, empathic response."​

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AAIC Abstract P2-520: Shaw C, et al. Enhancing dementia care and building empathy through the integration of virtual reality technology and art therapy.

Tuesday, July 24, 2018

CHICAGO—Slow recruitment in Alzheimer's disease (AD) trials and a lack of diversity in cohorts prompted officials with the National Institute on Aging (NIA) to discuss a multipronged attack to boost recruitment in studies and the quality of data collected here at the Alzheimer's Association International Conference.

The efforts, outlined in a special session on trial recruitment, include new National Institutes of Health inclusion criteria that is scheduled to go into effect in January 2019, a review of the makeup of cohorts in AD trials historically, identification of hurdles that seem to be impeding recruitment, and an ongoing funding opportunity for research into the science of recruitment itself.

The need for improved recruitment and data collection has never been more urgent, because of the number of trials in the accelerated push for new therapeutics, said Marie Bernard, MD, deputy director of NIA, who helped lead a session here at the Alzheimer's Association International Conference.

"We need to get these things moving," she said. "We need to have data that is representative of a broad variety of individuals so that we can make sure that whatever treatments are put forward are generalizable."

The new NIH inclusion criteria will require anonymized, individual-level data on age, sex/gender, and race/ethnicity.

Researchers with the NIA reviewed data for the 165 trials on AD and AD-related dementias that were listed on the Clinicaltrials.gov. They found that about 68 percent of the participants in the trials were non-Hispanic white, 18 percent African American, and about 8 percent Hispanic, Dr. Bernard said.

"There are opportunities for enhancing the improvement of groups beyond non-Hispanic whites," she said. Researchers also found that more of the subjects were male than female, even though, "that's not the way — in the real world — it works."

"Women live longer and tend to have more problems with Alzheimer's disease," she said.

Trial data also revealed 18 broad exclusion categories, often necessary, including concomitant medications, cardiovascular issues, and renal dysfunction.

Dr. Bernard said the array of exclusion factors are helping to slow recruitment. Recruitment is also hampered by other factors, such as the need for an unimpaired partner, and a lack of awareness of Alzheimer's trials among practitioners and the general public, she said.

The NIA is also working on a national recruitment strategy, which will recommend specific tools researchers and research centers can use to improve "messaging, partnering, building study site capacity and other opportunities."

The agency also emphasized at the AAIC its ongoing funding for researchers working on "innovative participant recruitment and retention methods." Because of recent boosts to the budget, Dr. Bernard said, the NIA is planning to "fully fund all of the projects that we find to be highly meritorious based upon peer review."

She emphasized the need for research centers to think locally in terms of recruitment — what works in one region may not work in another, so local hurdles need to be identified and overcome. For instance, Dr. Bernard recalled her days working in academic research in Oklahoma, where researchers drew subjects from Native American tribes, who had specific viewpoints on what is done with brains and genetic information.

"The way that you might approach people in tribal communities who are involved in an Alzheimer's-type study might be very different from the way that you approach a college professor in Boston," she said.

Jim Hendrix, PhD, director of the global science initiatives at the Alzheimer's Association, said these are important steps.

"We know that, after funding, the biggest challenge for Alzheimer's research is getting people enrolled in clinical trials," he said. "Another big challenge is simply that in Alzheimer's, as in many other diseases, our clinical trial subjects, our clinical trial population, is not as diverse as the American population is: They tend to be overwhelmingly white, middle-class or upper-middle-class, they tend to be more well-educated than the average American. And if we really want to develop new drugs and learn about Alzheimer's disease specifically, we need to have trials that reflect the actual population of the country."

Dr. Hendrix added he hopes that new clinical practice guidelines unveiled at the AAIC, on diagnosis and referral for primary care physicians, will have an effect on trial awareness and enrollment.

"We don't diagnose with specialists, usually," Dr. Hendrix said. "It's usually through a primary care physician, and the primary care physicians are not necessarily tapped in to our clinical trials."

The study was funded by the National Institutes of Health. The sources interviewed reported no disclosures.

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AAIC Abstract 23461: Bernard MA, et al. New NIH policies on inclusion — Implications for Alzheimer's clinic study recruitment and tools to help.