Alzheimer's Association Launches $20 Million Lifestyle Intervention Trial in the U.S. to Prevent Cognitive Decline

– Results from 4,000 Participants re: Impact of Brain Amyloid Imaging on Medical Management –

– Possible Blood Test for Amyloid –

LONDON, July 19, 2017 — The Alzheimer's Association today announced the launch of a $20 million U.S. two- year clinical trial to test the ability of a multi-dimensional lifestyle intervention to prevent cognitive decline and dementia in 2,500 older adults with no current cognitive symptoms but who are at increased risk for later cognitive decline. The announcement was made at the 2017 Alzheimer's Association International Conference (AAIC 2017) in London.

The large U.S. study to PrOtect through a lifestyle INTErvention to Reduce risk (US POINTER) will include physical exercise, nutritional counseling and modification, cognitive and social stimulation, and improved self- management of medical conditions. Recruiting for the study will begin in 2018.

At AAIC 2014, Miia Kivipelto, M.D., Ph.D., Professor at the Karolinska Institutet, Sweden and the National Institute for Health and Welfare, Helsinki, Finland, and colleagues reported on the results of the FINGER Study – the first randomized controlled trial showing that it is possible to prevent cognitive decline using a multi-domain lifestyle intervention among older at-risk individuals. The results highlighted the value of addressing multiple dementia risk factors as a strategy to protect brain health. The FINGER model is now being replicated in the United States, Europe, Singapore, and Australia – including people from a variety of geographical and cultural backgrounds.

"We now can effectively prevent and treat heart disease with a combination of drugs and lifestyle. The same is true with some cancers; the same with HIV/AIDS. The same may also be true for Alzheimer's disease and other dementias in the not too distant future," said Maria C. Carrillo, PhD, Alzheimer's Association Chief Science Officer.

"We must test all options to treat and prevent this horrible disease. We must find the answers for the millions dying with Alzheimer's and their families, and the tens of millions more who will become affected if we do not act now. The Alzheimer's Association is extremely proud to launch this clinical trial with our scientific partners," Carrillo said.

Also announced today at AAIC 2017:

• Interim results of the IDEAS Study, which is testing the impact on medical management of brain PET scans to detect amyloid protein. Amyloid forms the hallmark brain plaques of Alzheimer's disease.
• A possible blood marker for amyloid build up in the brain.
• New insights into how amyloid and tau proteins spread through the brains of people with Alzheimer's. Abnormal tau forms brain tangles – the other hallmark lesion of Alzheimer's.

U.S. study to PrOtect through a lifestyle INTErvention to Reduce risk (US POINTER)
Increasing age is the greatest risk factor for Alzheimer's disease. With the aging of the global population – and the slow progress of developing and testing drug treatments – prevention is pivotal in managing the inexorable rise in global cases of Alzheimer's and other dementias.

In 2014, a large-scale two-year study in Finland in healthy older adults at increased risk of cognitive decline and dementia (the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability, or FINGER Study) found that a two-year combination therapy involving physical exercise, nutrition, cognitive stimulation, and self-monitoring of heart health risk factors had a protective effect on cognitive function. These results were first reported at AAIC 2014 in Copenhagen.

According to Co-Principal Investigator Laura Baker, PhD, of the Wake Forest School of Medicine, Winston- Salem, North Carolina, the U.S. study to PrOtect through a lifestyle INTErvention to Reduce risk (US POINTER) is modeled on the FINGER study. It will test whether two years of a combined intervention that includes physical exercise, nutritional counseling and modification, cognitive and social stimulation, and improved self- management of medical co-morbidities benefits cognitive function in older adults at increased risk of cognitive decline and dementia. The comparison group will receive health education and support through in-person group meetings on health- and aging-related topics, and annual feedback on laboratory tests.

Starting in 2018, 2,500 study participants 60-79 years old will be identified using a medical record search to select those with medical conditions that have been linked to an increased risk for dementia (e.g., hypertension and other cardiovascular events, elevated blood sugar). Information about family history of Alzheimer's, physical activity level, and current cognitive status and mood will be collected in follow-up interviews to further identify eligible participants. Local Alzheimer's Association offices nationwide will participate in intervention delivery. National partnerships will be developed with community-based organizations to deliver the exercise, nutrition, social and medical aspects of the intervention.

The success of the intervention will be evaluated based on two-year change in a global measure of cognitive function focused on short-term memory, attention and concentration.

"As of now, there are no approved medications that have produced results similar to the FINGER Study. There is a pressing need to test the effectiveness of a multicomponent lifestyle intervention in larger and more diverse populations, such as the United States," said Baker. "The lifestyle intervention in US POINTER is an important multi-dimensional strategy to protect brain health and potentially reduce risk of dementia."

An update on FINGER and overviews of the Singapore (SINGER) and Australia (Maintain Your Brain) prevention studies will also be reported at AAIC 2017. The worldwide effort, collectively referred to as WW- FINGERS, supports a collaborative network of trials and experienced investigators to facilitate harmonization of research methods, and sharing of experiences and data for maximum global scientific impact.

Clinical Impact of Brain Amyloid PET Scans – Interim Results from the IDEAS Study
Launched in 2016, the four-year Imaging Dementia-Evidence for Amyloid Scanning (IDEAS) study is evaluating the impact of brain amyloid PET scans on patient management and health outcomes. Participants are more than 18,000 Medicare beneficiaries age 65+ with mild cognitive impairment (MCI) or atypical dementia who meet published Appropriate Use Criteria (AUC) for clinical amyloid PET. Before brain amyloid PET scans – which detect amyloid plaques, a core feature of Alzheimer's – amyloid plaques could be seen only during autopsies, making it much harder to give living patients a definitive diagnosis.

At AAIC 2017, Principal Investigator Gil Rabinovici, MD, of the Memory and Aging Center, University of California, San Francisco, and colleagues reported early results from IDEAS assessing changes in patient management in the first 3,979 participants for whom case report forms were completed by participating dementia specialists both before and 90 days after the PET scans.

The pre-PET form documented the specialist's management plan assuming no access to amyloid PET; the post- PET form recorded the medical management plan approximately 90 days after receiving results from a brain amyloid PET with an FDA-approved beta-amyloid imaging agent.

The researchers measured the rate of change between pre- and post-PET medical management, including one or more of: Alzheimer's disease drug therapy, other drug therapy, and counseling about safety and future planning. Participants' median age was 75 (range: 65-95); 64.4% were diagnosed with MCI, 35.6% met criteria for dementia. The most common suspected cause of cognitive impairment prior to PET was Alzheimer's disease (76.3%). Rates of amyloid PET positivity were 54.3% in MCI and 70.5% in dementia.

Changes in medical management were seen in 67.8% of MCI patients (47.8% change in AD drugs, 36.0% change in other drugs, 23.9% changes in counseling), and in 65.9% of dementia patients (47.7% change in AD drugs, 32.2% change in other drugs, 15.3% change in counseling). Amyloid PET scans also reduced the need for additional diagnostic testing such as neuropsychological testing (from 26.3% recommended pre-PET to 11.0% recommended post-PET) and spinal fluid testing (from 10.5% to 1.0%).

"Our original hypothesis was that having amyloid PET scan results would change medical management in 30 percent of cases," Rabinovici said. "Our interim results suggest we are well on track to see an effect of at least that magnitude, and perhaps greater, when the final results are available."

"We look forward to reporting the results from the full study population. We are very grateful to the Centers for Medicare & Medicaid Services for their support of the IDEAS Study as our results indicate that access to this technology is making a real difference in the care of patients," Rabinovici added.

The IDEAS Study is led by the Alzheimer's Association and managed by the American College of Radiology.

The IDEAS Study was developed in response to CMS' 2013 National Coverage Decision (NCD) on amyloid PET imaging in dementia and neurodegenerative disease (CAG-00431N) not to cover the scans because "the evidence is insufficient to conclude that the use of positron emission tomography (PET) amyloid-beta (Aβ) imaging is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of … Medicare beneficiaries with dementia or neurodegenerative disease." Under the NCD, Medicare will provide coverage for one amyloid PET scan per patient enrolled in an approved clinical study.

A working group convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) developed AUC for brain amyloid PET scans. The AUC indicate that amyloid PET should only be considered in patients with clear, measurable cognitive deficits when there is substantial diagnostic uncertainty after a comprehensive evaluation by a dementia specialist. According to AUC, amyloid PET may have greatest value in patients with either: (1) progressive, unexplained mild cognitive impairment (MCI); or (2) dementia of uncertain cause due to atypical or mixed symptoms, or unusually early age-of-onset.

A Blood Biomarker for Amyloid Plaques?
There is substantial evidence implicating amyloid-beta in the cause and/or progression of Alzheimer's disease. Currently, a spinal tap or PET scan can detect deposition of amyloid in the brain, which precedes and increases the risk of progression to Alzheimer's disease dementia. However, due to the invasiveness of a spinal tap and the radioactivity, limited availability and cost of PET scans, there is an urgent need for a simpler, more practical test for amyloid deposition, such as a blood test.

In order to investigate a blood-based amyloid biomarker, Randall Bateman, MD, and scientists at Washington University School of Medicine in St. Louis adapted their previously reported Stable Isotope Label Kinetics (SILK) method to measure amyloid in the blood – how fast it is created and how fast it is cleared away.

Participants were 41 older adults either with or without amyloidosis in the brain; they had either clinically diagnosed late-onset Alzheimer's or were cognitively normal age-matched controls. All participants had brain PET amyloid imaging and/or cerebrospinal fluid (CSF) amyloid measures to detect brain amyloidosis. Blood sampling was conducted over 24 hours, and analyzed in a blinded fashion so researchers didn't know which samples were from amyloid positive or amyloid negative people.

The scientists found the longer, stickier form of amyloid (known as Aβ42) was created and removed significantly faster in amyloid positive participants compared to amyloid negative participants. The findings were similar to prior studies done in CSF, suggesting that the amyloid levels detected in blood can accurately reflect the amyloid buildup in the brain. Additional results of a larger validation study will also be reported at AAIC 2017.

"These findings are important because they support the idea that blood amyloid interacts with and is derived from the brain," Bateman said. "We're excited because the results also suggest that blood-derived amyloid-beta may be useful as a rapid and inexpensive screening test for brain amyloidosis, and may be able to identify people who are at higher risk of Alzheimer's disease very early in the process."

"Having a simple and inexpensive blood test for screening is likely to greatly accelerate clinical trials to find Alzheimer's drugs. And, it could facilitate widespread treatment when effective anti-amyloid therapeutics are developed," Bateman added. "We envision that one day soon, as part of a regular screening for cholesterol and blood pressure, a person may also get a blood test to find out if the amyloid protein is building up in the brain, and then go on specific treatments to prevent the onset of Alzheimer's disease dementia. This would be similar to the already successful approach of screening for and treating high cholesterol to reduce the risk of heart attacks and strokes."

This research was supported by an Alzheimer's Association Zenith award grant and an NIH R01 study.

Amyloid and Tau Spreading Pathways in the Brain, Correlated with Genetics
The ability to employ advanced imaging technology to "see" both of the hallmark proteins of Alzheimer's (amyloid and tau) in the living brain is a significant recent advance in the field. It may prove to be transformational not only in our understanding of the disease and its progression but also in its potential to accelerate drug discovery.

According to Jorge Sepulcre, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, Boston, understanding the "spreading" phenomenon of abnormal tau and amyloid-beta proteins in the brain is critical to knowing what is causing the devastating cell damage and relentless symptoms of people with Alzheimer's.

Sepulcre and colleagues developed a novel imaging approach to investigate the spreading pathways of tau and amyloid deposits over time, as well as their genetic vulnerabilities, in a longitudinal sample of elderly participants in the Harvard Aging Brain Study. Eighty-eight (88) study participants, average age about 76, were divided into two independent samples: (1) a cross-sectional sample of 69 people; and (2) a 1-2 year follow-up longitudinal sample of 19 subjects.

The researchers found that tau and amyloid appear to accumulate along distinctive pathways in the brain; the same communication pathways, or neural networks, we use for daily brain function. According to their findings, tau - which we know starts in the middle of the brain memory center - spreads forward and out toward the front of the brain. Amyloid, which starts in the back of the brain, spreads further back and outward from the middle. Specifically:

• Medial/inferior temporal lobe areas project pathways of Tau-spreading toward anterior pole, lateral and posteriomedial temporal cortex, and orbitofrontal cortex.
• Posterior cingulate cortex spreads Aβ toward surrounding areas and lateral parietal lobe.

The scientists discovered that 354 genes were significantly associated with the tau spreading pathway, including the MAPT gene, which was previously associated with Alzheimer's disease risk. They also found 216 genes, including the CLU gene, significantly associated with the amyloid pathway. Additional analysis characterized the tau spreading genetic profile as "axon-related" and the amyloid-spreading genetic profile as "dendrite-related". APOE, the gene with the highest impact on Alzheimer's risk, was found to be the most central gene linking tau- and amyloid-spreading pathways.

"Our results reported at AAIC 2017 suggest that tau and amyloid advance through different brain systems over time," Sepulcre said. "We also discovered certain genetic traits that may confer tau or amyloid vulnerability in the brain."

"The findings may improve our ability to track responses to potential therapeutic interventions in the future," Sepulcre added. "In addition, when more effective drug therapies become available, these results may help doctors determine which patients should get which therapies, and the optimum time to take them."

The Alzheimer’s Association International Conference (AAIC) is the world’s largest gathering of researchers from around the world focused on Alzheimer’s and other dementias. As a part of the Alzheimer’s Association’s research program, AAIC serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.
AAIC 2017 home page: aaic.alz.org/
AAIC 2017 newsroom: aaic.alz.org/pressroom.asp