There’s been a steady stream of news from the Alzheimer’s Association International Conference (AAIC) in Copenhagen, held July 12-17. The international summit brings together 4,500 professionals from 80 countries involved in Alzheimer’s treatment, patient care, and research.
Never in the history of Alzheimer’s disease (AD) has so much attention focused on ways to prevent it. “First and foremost, it may be modifiable. It’s not a fate without the possibility of change,” says William E. Klunk, MD, PhD, professor of psychiatry and neurology at the University of Pittsburgh, who led a news briefing at AAIC.
Indeed, from Copenhagen, new research findings have validated the importance of a number of “modifiable risk factors” that can be alleviated by healthy behaviors. If started early enough, these targeted interventions can have a major impact on delaying or preventing AD symptoms in vulnerable individuals.
Determining who’s “at risk” for AD is another major research focus at this year’s AAIC. There are proposed new screening techniques that may surprise you.
FINGER Points to Modifiable Risk Factors and Their Role in Prevention
Among the biggest news at AAIC is the FINGER study (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability), the largest-ever randomized clinical trial devoted to Alzheimer’s prevention. Its two-year results show that in individuals at risk for AD, exercise, diet and other behavioral changes significantly improved overall cognitive functioning after two years, compared with controls.
In FINGER, 1,260 participants aged 60-77 years were randomly assigned to one of two groups. A control group received regular medical attention and cognitive testing, but no intervention for modifiable risks. The other group participated in a program of nutritional guidance, physical exercise, cognitive training, social activities, and management of heart health risk factors. Among these “lifestyle interventions” were:
- Group sessions and individual sessions to improve their diet by adding fruits, vegetables, and fish, and avoiding saturated fats
- Intensive exercise several times each week that consisted of weight training to build muscle mass and cardiovascular training
- Cognitive training exercises practiced in group and individual sessions
- Scheduled consultations with nurses and physicians to track cholesterol, blood pressure, and other cardiovascular risks
After two years, the intervention group performed significantly better than controls on a comprehensive cognitive examination and also on specific tests of memory, executive function (complex aspects of thought such as planning, judgment, and problem-solving), and cognitive processing speed.
There will be an extended, 7-year follow up to these initial FINGER results. It will measure the incidence of AD and dementia in both groups, and also evaluate biomarkers of AD, such as amyloid deposits observed with MRI and PET brain imaging.
Staying in the Game of Mental Fitness
An analysis has confirmed what many AD specialists have already put in practice – the idea that brain-stimulating activities help to preserve brain volume and functions. While other research has shown to be helpful after AD is diagnosed, this may be the first study to demonstrate a preventive effect. The study also is unique in that it highlighted game playing (cards, checkers, crosswords and other puzzles) over reading and other cognitive activities.
Stephanie Schultz, B.Sc., of the Wisconsin Alzheimer's Disease Research Center, analyzed data on 329 participants in the Wisconsin Registry for Alzheimer's Prevention (WRAP). All participants had AD risk factors, such as a parent with AD (74%), or carrying the apolipoprotein E ε4 risk allele, a genetic mutation associated with AD (40%). Their mean age was 60 years.
Each subject had been assessed using a comprehensive neuropsychological battery, a structural T1 MRI, and a Cognitive Activity Scale (CAS), which reflected how often they engaged in 10 common cognitive activities, such as reading books, attending lectures, and playing games.
Imaging results showed that parts of the brain responsible for memory, thinking, and executive functioning, were significantly larger in subjects who were frequent game players compared with infrequent players. These structural changes were observed in some of the brain areas most affected in early AD, Schultz said during an AAIC news briefing.
In addition, results from the cognitive assessment showed that frequent game players had significantly higher scores for verbal learning and memory, also affected by early Alzheimer’s, as well as on cognitive speed and flexibility.
It may be that game playing “serves a unique role in preserving brain and cognitive health," Schultz concluded.
Screening for Alzheimer’s Disease: A New Reality?
If some AD risk factors can be modified successfully, it makes sense to screen for individuals who are at greatest risk of developing AD, in order to target interventions like those seen in the FINGER study. Several clinical studies have proposed new, inexpensive, and somewhat unusual ways to screen for Alzheimer’s on a widespread basis.
The Nose Knows – A ‘Scratch and Sniff” AD Screening Tool
Researchers at Columbia University and Harvard University have independently shown that diminished “olfactory function,” or smelling ability, is predictive of cognitive impairment and may be a clinical sign of early AD.
Although BrightFocus did not direct support the Harvard study, one of its authors, Reisa Sperling, MD, PhD, is a BrightFocus grantee. A neurologist, Dr. Sperling directs the Center for Alzheimer's Research and Treatment at Harvard’s Brigham and Women’s Hospital, Boston. She also is lead investigator for the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) early-AD screening and treatment trial, which is now recruiting participants aged 65 and older at sites across the United States, Canada, and Australia. Dr. Sperling’s BrightFocus-supported research is directed to PET imaging in AD.
In both the Harvard and Columbia studies, elderly adults were administered the 40-item University of Pennsylvania Smell Identification Test (UPSIT), followed by cognitive testing and/or brain imaging. The gold standard of smell identification, UPSIT is a deliberately simple “scratch and sniff” test of common odors.
In the Harvard study, the UPSIT was administered to a subgroup of 215 clinically normal elderly adults participating in the Harvard Aging Brain Study, followed by other testing that included brain and PET scans, genetic testing, and blood and spinal fluid tests. The results showed that lower UPSIT scores correlated with poorer memory performance, and that finding was confirmed by other physical markers of AD, including neurodegeneration (determined by measuring the size of brain structures involved with memory), and amyloid deposits in the brain.
The Columbia study enrolled 1,037 non-demented elderly individuals from multiple ethnic groups (White, African-American, and Hispanic) living in New York City. Participants were followed over six years to see what changes happened to them. Those results, too, showed that lower odor identification scores on UPSIT were significantly associated with cognitive decline and the transition to dementia and Alzheimer’s disease.
The Eyes Have It—Detecting Beta Amyloid in the Eye
As another potential method of screening for Alzheimer’s disease, researchers have linked beta amyloid deposits in the eye with increased Alzheimer’s risk. Optical imaging technologies to detect these beta amyloid deposits have been developed and are being tested.
A U.S.-Australian collaborative study is testing an experimental technology pioneered at Cedars-Sinai Medical Center in Los Angeles, now being developed by the California-based NeuroVision Imaging, LLC. Volunteers, who were drawn from the Australian Imaging and Biomarkers Lifestyle Study of Aging, took a supplement containing curcumin, which binds to beta amyloid peptide and has fluorescent properties, after which retinal amyloid plaques were detecting using the new imaging system. Preliminary results from 40 of 200 participants in the study showed a significant correlation between retinal amyloid levels in the eye and brain amyloid levels detected using PET imaging, sufficient to differentiate subjects who did and did not have AD. In this preliminary group, researchers also detected a 3.5% increase in retinal amyloid plaque accumulation over several months—suggesting that it might be possible to use retinal amyloid to monitor AD progression and response to therapy.
One of the investigators behind this trial is 2013-16 BrightFocus grantee Maya Koronyo-Hamaoui, PhD, an associate professor of neurology and biomedical science at Cedars-Sinai. She was involved in the very early development of the retinal amyloid imaging technique, and published the results of her studies done on rodents and autopsied human retinas. (That work is unrelated to her current BrightFocus grant, which supports research into how beta amyloid is cleared from brain tissue.)
“The retina, unlike other structures of the eye, is part of the central nervous system, sharing many characteristics of the brain,” Dr. Koronyo-Hamaoui said in a recent interview with ScienceDaily. “A few years ago, we discovered at Cedars-Sinai that the plaques associated with Alzheimer's disease occur not only in the brain but also in the retina. By 'staining' the plaque with curcumin, a component of the common spice turmeric, we could detect it in the retina even before it began to accumulate in the brain. The device we developed enables us to look through the eye—just as an ophthalmologist looks through the eye to diagnose retinal disease—and see these changes."
Beta amyloid can also be found in the lens of the eye, and another U.S. company, Cognoptix, Inc., reported results from a trial involving their new technology to detect amyloid deposits on eye lenses. In this case, a topical ointment that binds to amyloid is applied to the eye surface, followed by imaging using a laser scanner. Scan results from 20 subjects with probable AD were compared with 20 age-masked controls, and successfully distinguished subjects with AD from healthy controls. Here, too, there was a consistently high degree of correlation between amyloid in the eye and brain plaques detected with PET imaging. The authors believe their system shows promise as a technique for early detection and monitoring of AD.
If approved and marketed, optical imaging techniques like these could detect changes associated with AD some 15-20 years before a conventional diagnosis. That’s important, because toxic changes to the brain begin happening a decade or more before AD symptoms become evident. Preclinical detection is seen as the main avenue to effective treatments that can stop the disease in its track.
Another advantage is that eye scans aren’t nearly as costly, time-consuming, and uncomfortable for patients as other AD imaging and early detection technologies like PET scans and cerebrospinal fluid analysis. Because of that, they could make screening possible and more widespread. That could be immensely useful for targeting interventions to people who need them most. For every one in nine Americans who is expected to develop Alzheimer’s after age 65, knowing who you are ahead of time could take some getting used to. Then again, it could be the key to aging well.
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