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Sunday, July 14, 2019

Association of Lifespan Cognitive Reserve Indicator With Dementia Risk

Key PointsQuestion  Is high lifespan cognitive reserve (CR) indicator associated with a reduction in dementia risk, and how strong is this association in the presence of high brain pathologies?
Findings  In this cohort study including 1602 dementia-free older adults, high lifespan CR was associated with a decreased risk of dementia. This association was present in people with high Alzheimer disease and vascular pathologies.
Meaning  Accumulative educational and mentally stimulating activities enhancing CR throughout life might be a feasible strategy to prevent dementia, even for people with high brain pathologies.
Abstract
Importance  Evidence on the association of lifespan cognitive reserve (CR) with dementia is limited, and the strength of this association in the presence of brain pathologies is unknown.
Objective  To examine the association of lifespan CR with dementia risk, taking brain pathologies into account.

Vision And Hearing Loss May Raise Risk Of Dementia In Older Adults

Two studies reported at the Alzheimer’s Association International Conference (AAIC) 2019 in Los Angeles found that experiencing multiple sensory impairments, such as vision and hearing problems, are associated with an increased risk of developing dementia in older adults.
Emerging science shows that sensory dysfunction can increase the risk of dementia, and the new research presented at AAIC 2019 further demonstrates the impact of multiple co-occurring sensory impairments.
Research from the University of Washington School of Public Health showed that impairment of either vision or hearing increases the risk of developing dementia, and that impairment in both senses further increases those odds. Meanwhile, researchers at the University of California, San Francisco studied the combined effects of loss of smell, touch, vision and hearing; they found that even mild impairments in multiple senses were associated with an increased risk of dementia and cognitive decline.
“We’re beginning to learn through these new research findings that sensory impairments, even those that are very mild, may also be associated with increased risk of dementia, especially when there are several of them at the same time,” said Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer. “We need more research to confirm these initial findings and to see if correcting the sensory impairments can reduce dementia risk.”
Combined Visual and Hearing Impairment Increases Risk of Dementia in Older AdultsWhile recent studies have shown that loss of sensory function increases risk of developing dementia, very little is known about the impact of co-occurring sensory impairments. In order to understand the effect of dual sensory impairment on the development of dementia, Phillip Hwang, MPH, a doctoral epidemiology student at the University of Washington, and colleagues examined the association between hearing and vision impairment and risk of Alzheimer’s or other dementia in 2,051 people from the Ginkgo Evaluation of Memory Study aged 75 or older who did not have dementia at the time of study enrollment.
Baseline sensory impairment was established through self-reported responses to a set of questions on hearing and vision. Over seven years of follow-up, incident dementia was assessed based on clinical diagnosis using DSM-IV criteria, and Alzheimer’s disease was determined using criteria developed by the National Institute of Neurological and Communicative Disorders and Stroke — Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA; the ADRDA is now known as the Alzheimer’s Association).
The researchers found that the number of sensory impairments was associated with risk of all-cause dementia and Alzheimer’s disease (both p≤0.01) in a graded fashion. Having either visual or hearing impairment increased the risk of developing dementia by 11% and Alzheimer’s by 10%. Having both visual and hearing impairment raised the risk of developing dementia by 86% and Alzheimer’s by 112%.
“These findings suggest that co-occurring hearing and vision problems in late-life are strongly associated with increased risk of all-cause dementia and Alzheimer’s dementia,” said Hwang. “Impairment of more than one sense seems to increase risk of dementia synergistically.”
“Assessment of visual and hearing function may help identify older adults at high risk of developing dementia,” Hwang added.
Even Mild Multisensory Impairment is Associated with Dementia and Cognitive DeclineWilla D. Brenowitz, PhD, MPH, a postdoctoral researcher at the University of California, San Francisco, working with Kristine Yaffe, MD, and colleagues conducted a study of impairments in vision, hearing, smell and touch to investigate the effect of multisensory impairment on dementia risk.
The researchers studied a group of 1,810 older Americans aged 70-79 from the Health, Aging and Body Composition Study who did not have dementia at the time of enrollment. They assessed sight, hearing, touch and smell to create a summary multisensory function score for each participant. Incident dementia over 10 years was assessed using a combination of hospitalization records, anti-dementia medication prescriptions and cognitive decline as measured by the Modified Mini-Mental State Exam (3MS).
The researchers found that participants with lower sensory function scores — thus, greater levels of impairment — had significantly increased risk of both dementia and cognitive decline (both p<0.001). Risk of dementia was nearly seven times greater for those participants in the lowest scoring quarter of sensory function in the study population compared with those in the highest scoring quarter.
However, even mild impairment in multisensory functioning was strongly associated with these risks. A four-point difference in score (out of 12 points) was associated with a 68% higher risk for dementia (95% CI: 31%, 101%) and an annual decline of 0.24 points on the 3MS (95% CI: 0.36, 0.12 points).
“Our findings suggest that testing for changes in multisensory function may help identify those at high risk for dementia,” Brenowitz said. “Sensory function in multiple domains can be measured during routine health care visits using non-invasive or minimally invasive tests. In addition, some forms of hearing and vision loss can be treated or corrected, which provides potential opportunities for intervention. However, we need more research to determine if treatment or prevention of sensory impairments could reduce risk of dementia.”
Results from the two studies reported at AAIC 2019 demonstrate that sensory impairment, particularly across multiple senses, is strongly associated with an increased risk of developing dementia or Alzheimer’s disease. The findings suggest that assessment of sensory function by clinicians and caregivers should play an important role in diagnosis and care of older adults and those at risk of developing these diseases.

5 habits can reduce dementia risk—but you’ve got to go all in

The evidence is mounting that healthy lifestyle changes—exercising roughly 2.5 hours per week, eating a plant-based, low-carb diet, limiting drinking, quitting smoking, and engaging in mentally stimulating activities like crosswords—can help keep Alzheimer’s at bay.
In new work being presented today at the Alzheimer’s Association International Conference in Los Angeles, CA, researchers from Rush University in Illinois found that these five changes were associated with slightly lower dementia rates across two study groups. The only catch? They only worked if individuals went all in with several of them.
Nearly 3,000 older adults participated in the study, which has not yet been published in a peer-reviewed journal. They came from two groups, the Chicago Health and Aging Project and the Rush Memory and Aging Project. In the first group, participants followed up with their doctors every three years; the second had annual checkups. For the duration of the study, they tried to adhere to these five habits. During office visits, they reported to their doctors how many healthy habits they stuck to. Doctors also kept track of whether or not participants were diagnosed with Alzheimer’s disease.
Participants stayed in the study for a median length of six years. The patients who stuck with more healthy habits were less likely to develop Alzheimer’s. In total, 626 individuals were diagnosed with Alzheimer’s during the study. Among those who followed none or only one of the healthy habits, roughly one person out of every 100 developed Alzheimer’s. Among those who adopted four or five lifestyle changes, that rate was only one in 300.
The cumulative effect of their benefits likely stems from the fact that each of these changes is effective in the same way, according to Klodian Dhana, a geriatrician at Rush University who presented the research.“I like to think of it as a balance,” says Nilufer Ertekin-Taner, a neurogeneticist at the Mayo Clinic in Jacksonville, Florida who was not affiliated with the work. On one side of the scale are risk factors for dementia, and on the other there are protective factors against it. While adopting one lifestyle change may not be enough to tip the scale towards protection, several can do the job at once.
Because this was an observational study, it’s not clear if certain lifestyle changes were more or less beneficial than others—or how. One theory is that they bolster heart health. All of the changes, except for participating in cognitively stimulating games, help the cardiovascular system, and heart disease is a known risk factor for dementia.
Adhering to a healthy lifestyle certainly can’t guarantee that you won’t develop dementia. There are genetic risk factors for Alzheimer’s disease, too. Outside of three single mutations that always lead to Alzheimer’s (which make up only about 1% of total cases), scientists still aren’t sure how these genetic mutations put a person at higher risk of developing the disease.
Yet even in these cases, adopting a healthier lifestyle may help. Separate research published in the journal JAMA today suggests that even those at a high risk of developing dementia based on their genes may be able to lower that risk if they also adopt healthy lifestyle changes.
In the face of disappointing results from decades of research into potential treatments, it’s comforting to know that something could work to reduce the chances of developing Alzheimer’s. Earlier this year, the World Health Organization issued guidelines that echoed the benefits of healthy living for dementia prevention, in the wake of dozens of failed clinical trials. Just this week, drug giants Novartis and Amgen abruptly ended a late-stage clinical trial for a drug that blocks the formation of a protein that leads to amyloid-beta, one of the signatures of the disease.
Not that researchers will stop pursuing pharmaceutical treatments for Alzheimer’s disease. Realistically, some older adults may face barriers to adopting these lifestyle changes, like confounding health problems that limit their diet or mobility. Lifestyle changes could hold the key for these future therapeutics, says Henriette van Praag, a neuroscientist at Florida Atlantic University who was also unaffiliated with the work. If researchers can harness the physiological benefits of some of these lifestyle changes, perhaps those can become the targets of future drug developments themselves.

Gilead to Boost Stake in Belgian Biotech Galapagos as Part of $5.1 Billion Deal

Gilead Sciences Inc. will pay $5.1 billion to boost its stake in Galapagos NV and gain rights outside Europe to the Belgian biotechnology company’s treatments in development, in a broad research collaboration aimed at increasing growth at the drugmakers.
Under the terms of the deal, to be announced Sunday, Gilead will make a $3.95 billion payment to Galapagos. It also will invest $1.1 billion, or EUR140.59 ($158.49) a share, to increase its stake in the drugmaker to 22% from 12.3%. That represents a 20% premium to the 30-day weighted average share price of Galapagos, which trades in Amsterdam and on Nasdaq and has a market value of around $7.9 billion.
Assuming Galapagos shareholders sign off, Gilead could eventually boost its ownership stake to as much as 29.9%, officials of the companies said in interviews over the weekend. Gilead will get two seats on Galapagos’s board of directors as part of the deal.
Gilead, which has been looking for new products to regain its once-heady sales growth, is securing access for a decade to one of the industry’s most promising but also risky pipelines. Galapagos has six compounds in human testing, including potential drugs for conditions such as knee osteoarthritis and pulmonary fibrosis that would sell in multibillion-dollar markets.
Galapagos, meanwhile, gets a large infusion of cash to advance its drug-research efforts. The deal also could help Galapagos remain independent since Gilead will agree not to make a bid for more than 29.9% of the company over the course of the agreement, and other potential suitors would likely be turned off by Gilead’s deep involvement with the company.
The companies know each other well: For more than three years, they have partnered on development of a drug for rheumatoid arthritis. They expect to seek approval to sell that drug, filgotinib, by the end of the year. As part of the broader collaboration they undertaking, Galapagos will get expanded European commercial rights to the drug, which analysts say could be a big seller.
Gilead, based in Foster City, Calif., is under pressure to keep its roughly $22 billion in annual revenue from declining further. Its top line has fallen from a peak of $33 billion in 2015 amid slowing sales of its blockbuster hepatitis C offerings including Sovaldi and Harvoni. In 2017, Gilead spent around $11 billion to buy Kite Pharma Inc., which specializes in a new kind of cancer treatment, but sales of its drug Yescarta have been disappointing.
Instead of pursuing a full-blown takeover of Galapagos, however, Gilead has opted for an unusual — although not unheard of — research partnership.
Among the big pharmaceutical companies that have struck such broad-based research deals are Sanofi SA, whose deal with Regeneron Pharmaceuticals Inc. has produced a number of approved drugs and significant sales for each company.
The Galapagos partnership would be among the first notable transactions for Daniel O’Day, Gilead’s new chief executive, who had firsthand experience with perhaps the most successful research collaboration in the industry, a tie-up between Roche Holding AG and biotech Genentech. Mr. O’Day came to Gilead in March from Roche, where he also played a role in its research partnership with Japanese drugmaker Chugai Pharmaceutical Co.
Mr. O’Day said in an interview that the structure of the deal ensures Galapagos’s independence and allows Gilead to protect the value of its investment.
“Megamergers can often distract the organization from pursuing the science and following the innovation,” he said. “I prefer a transaction like this.”
Galapagos, of Mechelen, Belgium, has sought to discover the first drugs to treat intractable diseases through a novel program, which looks for new targets by exploring what happens in diseased human cells when genes are revved up or down. Then the company develops so-called small-molecule drugs to hit these new targets. If the drugs work, the payoff could be huge, but there is a risk they won’t because the research is so cutting edge.
Gilead shares a focus on small-molecule drugs and the company has been exploring some of the same areas as Galapagos, such as fatty-liver disease, which is marked by the buildup of scar tissue.
Galapagos Chief Executive Onno van de Stolpe said the companies began seriously considering expanding their partnership earlier this year.

Price Controls Best Way to Cut Health Costs?

Are price controls really the best solution to lower healthcare costs?
“I’m a card-carrying economist — my card may be revoked, [but] I’ll just say ‘Yes,'” said Dan Polsky, PhD, professor of health economics at Johns Hopkins University in Baltimore, speaking Monday at an event on U.S. health spending sponsored by the Robert Wood Johnson Foundation and Altarum, a health policy think tank.
“We’ve tried market-based methods,” said Polsky. “The assumptions one makes in economics class about how a market functions — none of them exist in healthcare … it’s not working. I’m all for giving price controls a try.”
Other economists agreed.
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Dan Polsky, PhD, professor of health economics, Johns Hopkins University (Photo by Joyce Frieden)
“We don’t let PEPCO just run wild and charge whatever rates they want for electricity,” said Chapin White, PhD, an adjunct senior policy researcher at the RAND Corporation, a policy analysis firm here, referring to the local electric utility. “The regulation of prices follows the features of that industry. I feel like in the healthcare industry, on the Medicare and Medicaid side we’re doing price controls and — news flash — they work. They constrain spending growth … On the private side, we’ve done a massive experiment in letting private health plans and providers negotiate without price controls, and we’ve seen the result: it’s incredibly expensive, and it’s unsustainably expensive.”
The discussion continued during the question-and-answer session. “My bias is that the healthcare market is screwed up,” said audience member Bob Murray, MBA, former executive director of the Maryland Health Services Cost Review Commission, which sets payment rates under that state’s unique all-payer hospital rate system.
“The rest of the world has figured this out … if [price controls] are the conclusion we ultimately get to, where do we start? There is a range of options from setting limits to doing benchmarks, which a number of states are looking to do, or hard-core rate-setting like Maryland,” Murray said.
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Chapin White, PhD, adjunct senior policy researcher, RAND Corporation (Photo by Joyce Frieden)
Well, said White, “you definitely don’t start by paying hospitals 100% of Medicare’s rates for privately insured [patients]; that [low rate] would be financially disastrous for the hospitals and the patients they serve. Start where you are and put price trends on a lower trajectory.” White said he discussed this issue via email with some officials in North Carolina recently. “The notion that made sense to me was to start by demanding that health plans pay hospitals a percentage of Medicare — set an upper limit that no hospitals can be paid more than 300% of Medicare, then start narrowing the variation and pushing the trajectory down.”
However, he added, while that plan could work for North Carolina, it would be terrible for a state like Michigan, where payment rates are quite different. “It’s very location-specific.”
The current healthcare payment system, White said, is the result of what he called the “three-legged glitch,” which he illustrated with a drawing of a three-legged stool:
  • Leg 1: Bilateral negotiations between health plans and hospitals over prices and networks; hospitals can refuse to contract with a plan if they want to
  • Leg 2: An uncapped obligation for the cost of out-of-network care, with “bill charges limited only by a CFO’s [chief financial officer’s] imagination,” White said
  • Leg 3: Widespread “unshoppability” for hospital care due to three types of monopolies — first, a hospital’s natural monopoly because parts of the hospital such as neonatal intensive care units have to be staffed 24 hours a day by licensed personnel, which requires tremendous resources that few actors can provide; second, “human-made” monopolies, such as those that happen when all local members of a particular specialty join into a single practice, which is then bought by a single hospital system; and third, emergencies, when people have to come through the hospital doors regardless of what plan they have and whether that plan negotiated a contract with the hospital
Not all types of health insurance plans have all three “legs,” White said. For instance, Medicare Advantage has legs 1 and 3, but unlike leg 2, its out-of-network costs are capped. “The biggest problem is with private employer-sponsored plans dealing with hospitals and certain specialties — there you have a price problem.”
Sometimes people suggest price transparency as a way to solve the problem, “but price transparency by itself isn’t going to do much,” said White. For example, it’s well known that one particular health system in Boston is a high-priced system, “but what are you going to do about it? Knowing the outlines of a price problem does not fix it.”
Of those three “glitches,” the uncapped out-of-network liability glitch is likely the most easy to fix, White added. “There has been lots of attention on ‘surprise billing’ in this Congress, but that’s really just nibbling at the issue … The much bigger glitch is on the hospital side. The major hospital associations have come out very much against setting limits on out-of-network care because it hurts their bottom line.”
Despite all the reimbursement issues that doctors and hospitals face, the competition for becoming a physician hasn’t slowed down a bit, said Michael Chernew, PhD, professor of healthcare policy at Harvard Medical School in Boston.
“I have 150 students in my class and about half of them want to be doctors. We seem to have not hit low enough fees to slow down the incredible demand for medical school,” he said, adding that there are still other problems with the profession, such as trying to get more people to become primary care doctors, and getting more physicians to work in rural areas. “This gets to the core question about how the prices are set and how you think the Medicare system is doing,” Chernew said.

Broad’s Zhang on new CRISPR platform, editing RNA, eliminating Alzheimer’s risk

Broad Institute star scientist Feng Zhang is back in the spotlight, adapting CRISPR technology in a shift from permanently editing DNA to revising RNA — temporarily if needed. And he illustrated the promise of this approach by deactivating APOE4, which may be a ticking time bomb for people at risk of developing Alzheimer’s.
CRISPR/Cas9 gene editing tech has taken the lab by storm, in part because of the work Zhang and his one-time colleagues Jennifer Doudna and Emmanuelle Charpentier accomplished. They’re still scrapping over the patents to the original Cas9 work. But Zhang, who founded Beam Therapeutics with David Liu and Keith Joung, has moved on in search of better tech, and in a paper published in Science, says they have made real progress in switching from DNA to RNA editing.
They call this new advance RESCUE: RNA Editing for Specific C to U Exchange. And it builds on REPAIR: RNA Editing for Programmable A to I.
Using Cas13, Zhang’s team was able to take the APOE4 gene — believed to carry the added risk of spurring Alzheimer’s — and changed it to a benign APOE2. The RNA editors converted “the nucleotide base adenine to inosine, or letters A to I. Zhang and colleagues took the REPAIR fusion and evolved it in the lab until it could change cytosine to uridine, or C to U.”
But there are also ways to achieve a temporary change that could benefit patients without creating potential risks.
In a separate cell experiment, Zhang and his group were able to orchestrate a transitory spike in β-catenin activation and cell growth. That kind of temporary impact could erase threats of cancer, associated with uncontrolled cell growth while treating wounds.
“To treat the diversity of genetic changes that cause disease, we need an array of precise technologies to choose from. By developing this new enzyme and combining it with the programmability and precision of CRISPR, we were able to fill a critical gap in the toolbox,” says Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT.
It’s an intriguing experiment, but don’t look for the experiment in cells to make the leap into practice anytime soon. MIT’s Jonathan Gootenberg summed it up for WBUR:
“It’s a first step in a very large journey. We’re still at the base of the mountain, you might say.”

Lifestyle Interventions May Offset Alzheimer’s Risk of Genetics, Pollution

New research reported at the Alzheimer’s Association International Conference (AAIC) 2019 in Los Angeles suggests healthy lifestyle choices — including healthy diet, exercise, and cognitive stimulation — may decrease risk of cognitive decline and dementia. Researchers also found lifestyle modifications may reduce risk even in the face of other risk factors, including genetics and pollution, and provide maximum memory benefit when combined.
Five research studies reported at AAIC 2019 suggest:
  • Adopting four or five healthy lifestyle factors reduced risk of Alzheimer’s dementia by 60% compared to adopting none or only one factor.
  • Adherence to a healthy lifestyle may counteract genetic risk for Alzheimer’s disease.
  • Having a higher cognitive reserve, built through formal education and cognitive stimulation, may benefit the aging brain by reducing risk of dementia among people exposed to high levels of air pollution.
  • Confirmation that early adult to mid-life smoking may be associated with cognitive impairment at mid-life, as early as one’s 40s.
  • Alcohol use disorder significantly increased risk of dementia in older women.
“While there is no proven cure or treatment for Alzheimer’s, a large body of research now strongly suggests that combining healthy habits promotes good brain health and reduces your risk of cognitive decline,” said Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer. “The research reported today at AAIC gives us attainable, actionable recommendations that can help us all live a healthier life.”