5 Questions: Frank Longo on Alzheimer's, new neuroscience center

In a recent interview, neurologist Frank Longo discussed Alzheimer’s disease, recent research breakthroughs and the new Stanford Neuroscience Health Center, which he co-leads.

Frank Longo

Frank Longo, MD, PhD, is professor and chair of neurology and neurological sciences and co-leader of the new Stanford Neuroscience Health Center, which opened in January. Within the center’s five floors are physician experts and care teams in 21 neuroscience subspecialties. All these clinicians come together in the new center to provide coordinated, leading-edge treatments for complex neurological conditions.

Longo, the George E. and Lucy Becker Professor in Medicine, runs a research lab that has secured funding from the Alzheimer’s Association, the Alzheimer’s Drug Discovery Foundation, the National Institutes of Health and others. He and his team, along with collaborator Stephen Massa, MD, PhD, at UCSF and the San Francisco VA Medical Center, pioneered the development of novel, small molecules that counteract the degenerative signaling mechanisms that occur in Alzheimer’s and other neurodegenerative disorders. One of these compounds is currently in clinical testing.

Longo recently spoke with writer Sara Wykes about Alzheimer’s disease, recent research breakthroughs and the new center, including its key features and services available to Alzheimer’s patients. 

Q: How does Alzheimer’s disease affect the brain?

Longo: Alzheimer’s affects the networks in the brain that are the cornerstone of our ability to learn and remember. Those networks are dynamic: If the connections, or synapses, aren’t used, they disappear. With Alzheimer’s disease, two proteins in the brain interfere with those synaptic connections: The amyloid protein breaks into fragments that are toxic to the connections, and the tau changes into abnormal folds and clusters that are also toxic to the connections. As we lose those connections, we lose our memories, our ability to recall them and our ability to form new ones. The accumulation of those two toxic forms of proteins, in conjunction with inflammation in the brain produced by other causes, including aging, is what breaks down the synapses.

We don’t yet know the exact cause for Alzheimer’s or for the accumulation of these toxic proteins. We do know that these processes are influenced by genetics. People with a parent who has Alzheimer’s are at a twofold risk of developing Alzheimer’s.

People with early onset Alzheimer’s — generally defined as dementia that appears before age 60 — have a 50 percent chance of passing the gene causing the disorder on to each of their children.

Q: How can I tell the difference between normal memory lapses and Alzheimer’s?

Longo: Our ability to recall memories naturally slows with age. Our intelligence remains the same, but we may need more time to recall certain things from our memory.

The next stage of memory change is called mild cognitive impairment. People other than the person who has MCI may notice a slowing of memory. The loss is not usually substantial enough to interfere with someone’s daily life.

For some, however, MCI progresses to dementia. Dementia is diagnosed when someone has a loss of function in two or more areas of cognition — such as memory, verbal ability, visuospatial function or judgment — severe enough to significantly affect day-to-day function. There are many potential causes of dementia, but Alzheimer’s is by far the most common.

Q: What research is happening here on Alzheimer’s disease?

Longo: We are very excited here at Stanford Medicine about our recent selection as one of a few National Institutes of Health-funded Alzheimer’s Disease Research Centers in the country. The NIH designation comes with a $7.3 million funding award over a five-year period to advance our research.

Associate professor of neurology Michael Greicius, MD, medical director at the Stanford Center for Memory Disorders and the director of the imaging section at the Stanford ADRC, has recently had great success in developing new imaging methods to examine Alzheimer’s patients. He uses functional MRI and PET scans to track, for the first time, the function of synapses and the accumulation of those extra proteins that interfere with memory function in Alzheimer’s patients.

He is also discovering genes that appear to protect the brain from accumulations of toxic amyloid and tau. He has identified people well into their 90s whose PET scans show they have normal cognitive function despite having large amounts of amyloid in their brains or the high-risk ApoE4 gene generally associated with earlier onset of dementia.

One of the most powerful substances known to promote the maintenance of synaptic connections is a protein called brain-derived neurotrophic factor. BDNF, like most proteins, would not cross the brain’s protective barrier if it were simply administered as a drug. In its natural protein form, BDNF also would be likely to have side effects. My research team pioneered the development of small molecules that mimic key features of BDNF. These small molecules can get across the brain barrier and prevent degeneration of synapses and other Alzheimer’s-related events. Studies in mice with Alzheimer’s are going well.

Most recently, a research team led by professor of neurology Tony Wyss-Coray, PhD, built upon the work of professor of neurology Thomas Rando, MD, PhD, an expert in the biology of aging, by showing that the cognitive abilities of old mice could be improved with an infusion of blood from young mice. Wyss-Coray and his team discovered that the most crucial element of the blood linked to that improvement was a protein in plasma called colony-stimulating factor 2. That’s another very exciting discovery because CSF2 is already FDA-approved for people who have received bone marrow transplants. From many decades of use, we also know plasma is safe.

Inspired by these mouse studies, clinical assistant professor of neurology Sharon Sha, MD, is running a trial in which blood plasma, obtained from the Stanford Blood Center from young, healthy volunteers, is being administered to Alzheimer’s patients to determine if that plasma can improve cognition.

We are also looking at new ways to combine some of the medications and treatments we already have to slow the disease process. We know from the example of HIV that, although the effects of one drug might be small, a combination of drugs can be highly effective.

Q: Some companies tout brain games or nutritional supplements as protective against Alzheimer’s. Do they work? What is the best prevention strategy?

Longo: In October 2014, the Stanford Center on Longevity and the Max Planck Institute for Human Development released a statement, signed by nearly 70 researchers, to share our concern that the claims made for these types of games are not supported by substantial scientific evidence. The question is not if you can improve your ability to play a certain computer game, but whether that improvement will appear in other tasks you might do. There is no reliable evidence to support such a spillover.

There are also no current reliable and sufficiently sized studies that show a direct link between an increase in cognition and adding coconut water or oil, omega-3 fatty acids, DHA, vitamin D or turmeric to your diet.

The most important and research-validated approach to reduce your risk is exercise. Research has shown that 30 minutes a day, five days a week, preferably at a moderate level, reduces the risk for Alzheimer’s.

Risk for Alzheimer’s can also be influenced by diet, high blood pressure and diabetes. We recommend a Mediterranean diet as a part of an overall plan to reduce your risk of Alzheimer’s, high blood pressure and diabetes.

We have also recently learned that disrupted sleep does not allow the brain to clear amyloids. That knowledge leads us to believe that long-term sleep disruption and the interference with amyloid clearing could also raise your risk of Alzheimer’s.

We can’t prevent the influence of aging on the risk of Alzheimer’s. The likelihood of Alzheimer’s increases with age, in part because toxic forms of amyloid protein, tau protein and inflammation in the brain all increase with age. By age 85, four out of 10 people will have been diagnosed with the disease. Nor can we change our genetic risk: About 2 percent of Alzheimer’s appears in people at a young age — in their 40s or 50s — because of their genetics.

Q: What are the treatment options for Alzheimer’s disease and other dementias?

Longo: Unfortunately, there are no currently available FDA-approved medications proven to delay onset or slow progression of the underlying brain degeneration and loss of synaptic connections that occur in Alzheimer’s disease. There are, however, two groups of FDA-approved medications that can temporarily boost the chemical neurotransmitters at synapses and so produce a modest improvement in cognitive function. We offer clinical-trial use of these medications. They do have side effects.

Along with these medications, we strongly encourage physical exercise, a healthy diet and weight, and continued cognitive engagement that could include socializing, hobbies or any other activities that encourage brain function. We work closely with our patients’ primary care physicians to make sure their patients have optimal levels of B12, vitamin D, thyroid hormone and other substances. We also keep an eye out for any trials, regardless of location, which might benefit our patients. 



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