Stephen Salloway – Courtesy of Butler Hospital

You are the founding director at Butler Hospital’s Memory and Aging Program. Tell us about the work of the program over the years.

The Memory and Aging Program has really been at the leading edge of Alzheimer’s disease (AD) research for more than 25 years. Our team has played a role in many of the major breakthroughs in Alzheimer’s research during that time, across the entire continuum of research, from prevention to diagnosis to treatment. We are studying ways to better predict who is at risk for developing Alzheimer’s, approaches to prevent or slow its development through healthy lifestyle modifications, better diagnostic tests to promote early detection and treatment breakthroughs, such as donanemab.

 None of this would be possible without the selfless contributions of thousands of study volunteers who have stepped forward to make a difference in the fight against Alzheimer’s disease. They are the true Citizen’s Army making breakthroughs happen. This has required dedication and long-term commitment. Many earlier studies had negative results but we have tried to learn from each trial to make the next one better and more likely to succeed. Thank you Rhode Islanders for playing an oversized role in this fight.

Let’s hear about the recent development regarding donanemab. Eli Lilly and Company recently announced that this investigational drug significantly slowed cognitive and functional decline in people with early symptomatic Alzheimer’s disease. Why is this big news?

 The positive results of the Trailblazer 2 study follow on positive results with similar drugs aducanumab and lecanemab and provide convincing evidence that lowering amyloid plaques can slow the rate of decline for people with AD. We are at a turning point where it will soon be possible to use specific treatments to begin to slow the disease process. This will open the door for testing new drugs and drug combinations to obtain an even bigger effect and we are already testing whether medication like donanemab and lecanemab can prevent AD in cognitively normal people at risk.

How does donanemab work?

 Donanemab works by targeting the amyloid plaque build-up in the brain that is associated with the development of AD. The TRAILBLAZER Phase 3 study demonstrated a dramatic reduction in amyloid plaques. The medication was stopped when the plaque level on a PET scan was below the cut-off for AD. By 12 months 80% of participants on donanemab were considered amyloid negative on PET and could stop treatment. AD is caused by the build-up of amyloid plaques and tau tangles. Participants in the study also had another PET scan called tau PET to determine how advanced the disease was in the brain. It turns out that people with lower levels of tau had the best response to donanemab. Participants also had a blood test to measure phosphotau, which may become a marker of how well patients are responding to treatment.

The announcement followed the so-called TRAILBLAZER-ALZ 2 Phase 3 study. The Memory and Aging Program at Butler Hospital participated in the Phase 2 study. Give us an overview.

MAP didn’t participate in this latest Phase 3 study, but in the TRAILBLAZER-ALZ Phase 2 trial, which then led to the Phase 3 study. I was an author of the phase 2 results of donanemab published in the New England Journal of Medicine.

MAP and Rhode Island Hospital were among 61 research sites across the U.S. and Canada for the Phase 2 trial. The Phase 2 study utilized new imaging technology, tau Positron Emission Tomograhy (PET) imaging with flortaucipir tracer, that was developed specifically for the detection of tau protein in the brain. These tracers were developed in part at MAP in partnership with Rhode Island Hospital.

TRAILBLAZER-ALZ 2 was a randomized, double-blind, placebo-controlled study. It enrolled people with early symptomatic Alzheimer’s disease (AD), which includes mild cognitive impairment (MCI) and mild dementia, with confirmed amyloid and tau on PET scanning. The medication was given monthly by infusion and MRI’s were monitored periodically for safety. The study lasted 18 months and the medication was stopped when the amyloid level was below the cut-off for AD.

Patients on donanemab remained in a milder stage of AD longer and better able to carry out daily activities. The primary endpoint (iADRS) showed 35% slowing of decline (p<0.0001), and an important key secondary endpoint (Clinical Dementia Rating-Sum of Boxes, or CDR-SB) showed 36% slowing of decline (p<0.0001) over 18 months. The study also assessed the safety of donanemab. The main side-effect with amyloid-lowering antibodies is fluid shifts or swelling in the brain called ARIA, (amyloid-related imaging abnormalities). ARIA occurred in 24% of participants and was higher in those that have 1 or 2 copies of the ApoE4 gene. ARIA is usually transient and without symptoms but 6% of participants had symptoms and 1.6% had serious symptoms. Careful monitoring with MRI is required with appropriate adjustment of medication when indicated. 

What are some of the other studies that the Memory and Aging Program has participated in.

There are many exciting projects underway. We are working closely with a Swedish group, led by Dr. Oskar Hansson, on the Biofinder:Brown study to develop new blood tests for AD. The study is recruiting people 50-80 without cognitive impairment who may be at risk for AD. We are also testing lecanemab to prevent AD in the AHEAD study in cognitively normal people ages who 55-80 who  are building amyloid plaques. We are very excited about a new study to lower tau build-up through a gene-modifying treatment in people with early AD. We want to thank Rhode Islanders for helping us meet and exceed our recruitment goals for the have recently completed enrollment for the US POINTER study. US POINTER is testing whether exercise, healthy diet, brain training and heart health can improve memory in people at risk for AD. We have many projects focused on expanding brain health research in underrepresented populations and we are developing new community partnerships to make this happen. We are also studying special populations, early onset AD (DIAN and LEADS) and an observational study for people with CADASIL, a genetic disorder that causes stroke and vascular dementia.

We understand that the Memory and Aging Program has a new director. Who is he and what was his position before coming to Butler?

 Yes, we’re thrilled to have Edward “Ted” Huey, MD, as the program’s new director. He’s an incredible scientist and person and brings the perfect blend of scientific inquiry and empathetic patient care that this role requires.

Dr. Huey is a distinguished physician-scientist. He comes to Butler Hospital and Brown University from Columbia University, where he served as director of the Frontotemporal Dementia Center and as an associate professor of psychiatry and neurology at the Taub Institute for Research on Alzheimer’s Disease (AD) and the Aging Brain. He also led the Columbia Alzheimer’s Disease Research Center Outreach, Recruitment, and Education Core and was the medical director of Columbia’s Huntington’s Disease Society of America Center of Excellence.

Dr. Huey’s research has focused on patients with Alzheimer’s disease (AD) as well as frontotemporal lobar degeneration (FTLD), and related disorders. He has a particular interest in the causes, assessment, and treatment of behavioral and neuropsychiatric symptoms in neurodegenerative disorders including AD, FTLD, and Huntington’s disease. We’re excited that he’ll be bringing studies of those conditions to the Memory and Aging Program as well. It will open up a whole new, but very much related, area of research and exploration to our team and our study participants.

 You are still on the Memory and Aging Program team – and also the Martin M. Zucker professor of Psychiatry and Human Behavior and professor of Neurology at the Warren Alpert Medical School of Brown University. Tell us about your work now.

Working closely with Dr. Huey, I am helping to lead some of the important projects listed above such as US POINTER and Biofinder:Brown. I also hope to help make new treatments like donanemab available when they are FDA-approved and covered by insurance. I hope to work closely with the MAP team and other scientists to bring the new tests and treatments into primary care settings. I am also working closely with a talented team of clinicians and scientists as Associate Director to develop Brown’s new Center for Alzheimer’s Disease Research.

How many Rhode Island residents live with Alzheimer’s now? And how many people in America?

 An estimated 6.7 million Americans age 65 and older are living with Alzheimer’s dementia, according to the most recently reported statistics from the Alzheimer’s Association – that’s 1 in 9 people age 65 or older. In Rhode Island, the Alzheimer’s Association estimates there will be about 27,000 people with Alzheimer’s dementia by 2025, which would be about a 12.5% increase since just 2020. 

 It’s really a local, national and global public health crisis. There are currently over 50 million people living with dementia around the world, with numbers expected to increase to nearly 152 million by 2050. Almost 10 million new cases of dementia are diagnosed each year worldwide, with one new case every 3 seconds and a significant increase in the caregiving burden placed on society and families. In the US alone, there was an increase of 8 million new caregivers from 2015 to 2020. The current annual societal and economic cost of dementia is estimated at $1 trillion, an amount that is expected to double by 2030 unless effective means for early diagnosis and treatment of the disease are found.

As you well know, the toll of Alzheimer’s on patients and caregivers is enormous. What hope is on the horizon?

Healthy lifestyle approaches can be adopted around the world to promote brain health. New ways of detecting AD risk and treating it early before trouble starts will become increasingly available. Implementing effective care management programs to keep people at home longer with better quality of life.

Do you think there will ever be a cure?

There will be step-wise progress to making AD a much more manageable and treatable condition. Treatments will increase in efficacy and be started earlier. Instituting effective prevention strategies will be key to successful brain aging.

What are some of the symptoms of early Alzheimer’s?

The symptoms depend on the stage of the disease, but early Alzheimer’s symptoms may include things like frequently finding it hard to remember things, being repetitive in speech or actions, getting lost in familiar places, putting things away in odd places, having trouble handling money and paying bills, and taking longer than usual to finish everyday tasks. Some of these things may happen from time to time with anyone, but if someone is experiencing multiple of these symptoms on a regular basis, it could be signs of early disease and they should be evaluated.

What should someone do if they are experiencing them?

The first step is to talk with your primary care provider about your concerns. He or she can help to determine if what you’re experiencing is normal everyday forgetfulness or if it’s something more. If it’s more, you should get a referal for a neuropsychological assessment, which involves a series of specially designed memory and thinking tests. There are genetic tests available to assess your risk as well, if you have a strong family history of the disease.

And lastly, are there any measures can people take now to reduce the risk of Alzheimer’s?

From what the studies have shown us so far, it’s much like the prevention steps recommended for may other diseases. Eat a healthy, Mediterranean-style diet. Exercise regularly. Stay active socially and intellectually and keep your heart healthy by making sure problems with blood pressure, blood sugar and cholesterol are well controlled. The more active you remain, and the more you focus on building and sticking to healthy lifestyle habits, the more you’ll cut your risk for a great many diseases, including Alzheimer’s.