When is a Senior Moment Just a Senior Moment? The Latest on Alzheimer’s Disease Research

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Presented by: Geoffrey A. Kerchner, MD, PhD
Assistant Professor of Neurology and Neurological Sciences, Stanford Center for Memory Disorders
Stanford University School of Medicine
January 23, 2014

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It happens: we lose the keys. We forget where we left the cell phone. Or we can’t remember the name of a good friend we’ve known for years.

Those simple missteps can be enough to strike terror in people who are aging and wondering—am I getting Alzheimer’s disease?

The answer isn’t easy, according to Geoffrey Kerchner, MD, PhD, director of clinical trials for the Stanford Center for Memory Disorders.  There is still no single blood test or imaging scan that can definitively determine whether someone has Alzheimer’s. But the good news is that doctors have developed some new diagnostic tools, using biomarkers, to assess the likelihood that a patient has Alzheimer’s.

Most of the time, forgetting the keys or the name of an old friend are the kind of lapses that come with normal aging. But the truth also is that Alzheimer’s disease was the sixth leading cause of death in the United States in 2013, and it accounts for two-thirds of the cases of cognitive decline in people over the age of 60.

“It’s an immense disease,” Kerchner told an audience at the Stanford Health Library lecture on Jan. 23. More than 5 million Americans have Alzheimer’s disease. And the statistics on how often it strikes people as they age are daunting.

Before age 60, Alzheimer’s disease is very uncommon, Kerchner said. But its frequency increases exponentially as people age into their 70s and 80s, and by some estimates, as much as half of the 85-and-older population is afflicted by the disease.

“It is the rare 95-year-old who does not have at least mild cognitive decline and who does not have microscopic evidence of Alzheimer’s disease at autopsy,” Kerchner said.

Those odds are enough to leave many of us wondering by age 50 or 60 whether our occasional slips of memory are the first telltale signs of the illness. It’s normal to have some decline with age, however. The number of nerve cells in the brain peaks in our 20s, and they gradually begin to die off after that.

But when someone has a new and worsening inability to remember something obvious that just happened minutes ago, Kerchner said, that can be the hallmark of beginning Alzheimer’s disease.

There may be “no problem with [remembering] what happened five years ago. But what happened five minutes ago, that’s where the person has problems,” said Kerchner, assistant professor of neurology and neurological sciences.

Another sign of beginning problems may be difficulty remembering how to navigate  familiar places. “Do I turn right or left at this intersection? I don’t remember any more, even though I’ve been here so many times in my life,” Kerchner said, giving one example.

Another person may have increasing trouble balancing a checkbook, or need persistent reminders to pay the bills. Somebody else may have repeated trouble finding the right word to name a familiar object.

The problem must be clearly getting worse over time, rather than a stable pattern, to be considered a sign of Alzheimer’s.

“People who truly have Alzheimer’s disease, usually from one year to the next, from January 2014 to January 2015, have a pretty clear and noticeable change,” Kerchner said.

While Alzheimer’s disease can develop in anyone, there are certain risk factors that make it more likely to occur. Age is the biggest factor. “By leaps and bounds, it accounts for most of the incidence of Alzheimer’s disease,” Kerchner said.

Genetics plays a weaker role, too. The APOE4 gene is one that gives people an increased risk. Kerchner said that he and most doctors don’t recommend that healthy people get tested for APOE4, however, because it doesn’t really say whether someone will get Alzheimer’s disease.

Family history is a factor. “You don’t directly inherit it from a parent, but if there’s a whole lot of it in the family, you might be at more risk of it,” Kerchner said. Other conditions that increase risk include Type 2 diabetes, vascular disease, head trauma and low education level.

Doctors can help evaluate these factors for a person worried about memory decline.

When symptoms seem to be getting worse, especially when they interfere with the daily tasks of living, it’s time to see a physician.

To assess the likelihood of Alzheimer’s disease, doctors may start by giving a patient a series of neuropsychological tests that evaluate memory, language, visual spatial function, IQ and other cognitive functions. Results are compared with scores from others the same age and similar education to see if the patient’s scores are significantly lower than expected.

Simultaneously, it is important to rule out other medical causes of memory or other cognitive problems.  Tests can be done to detect hypothyroidism, which can cause cognitive problems, or for vitamin B12 deficiency, both uncommon but easily salvageable causes of cognitive change. Brain scans can be done to detect a tumor or stroke damage that can affect memory and cognition. In fact, there are many illnesses that may cause cognitive decline aside from Alzheimer’s disease, and some of these are treatable, underscoring the importance of seeing a doctor.

At this point, doctors in past years had to stop. They had no other tools to determine whether a patient had Alzheimer’s. They often had to make a “diagnosis by exclusion,” based on eliminating these other causes for cognitive decline.

Now, newer tests are available, based on biomarkers, to further assess the likelihood of Alzheimer’s.  Biomarkers are biological measures that serve as proxies, or indications of the probability we have a disease.

The biomarker tests now used to assess the likelihood of Alzheimer’s rely on two biological markers of the disease: the proteins, beta-amyloid and tau, which accumulate in the brain.

Beta-amyloid, regarded for a long time as a suspect in Alzheimer’s disease, accumulates in the brain over years to form amyloid plaques. Tau, the other protein, also accumulates to form tangles in the brain’s nerve cells. Doctors must see evidence of both in a person with cognitive decline to make a definitive diagnosis of Alzheimer’s disease.

Both proteins can be detected in a test of cerebrospinal fluid, the liquid that circulates in the brain and spinal cord, in a procedure called lumbar puncture.

Amyloid plaques can also be detected with brain scans called PET, or positron emission tomography. Tau plaques may be detected with a similar technology, and Stanford is starting a clinical trial of tau-PET scans soon.

Researchers continue to debate whether amyloid or tau is the biggest culprit in Alzheimer’s, although both are implicated. Research has shown that amyloid begins to accumulate in the brain early, long before old age. “We’re guessing that amyloid probably deposits about 20 years before the first time you lose your keys,” Kerchner quipped. “I probably have amyloid in my brain.”

Tau accumulation in the brain may start later than amyloid. Still, research shows that cognitive decline from Alzheimer’s disease doesn’t start until after the accumulation of amyloid or tau.

MRI scans can also be done to measure brain atrophy (or shrinkage) that occurs with neurodegeneration and the death of nerve cells. Other tests, including fluorodeoxyglucose (FDG)-PET, can measure low brain metabolism.

“The human brain is remarkable. It can withstand immense amounts of damage,” Kerchner said. By the time cognitive symptoms of Alzheimer’s show up, “the brain looks like a war zone under a microscope.”

That may partly explain the poor results so far of drugs tested to treat or stop the decline of Alzheimer’s. The damage may be too deep to repair. Three treatments on the market—Aricept, Exelon and Razadyne—offer only modest help with memory decline that doesn’t change the course of Alzheimer’s disease. A fourth drug, Namenda, also has a mild impact.

Researchers are aiming for a treatment that alters the fundamental course of the disease—slowing, stopping or even preventing cognitive decline. Many recent trials have failed, but numerous other trials are ongoing and show promise. One drug candidate, a “beta-secretase inhibitor” pill designed to block amyloid production, is featured in an upcoming Phase III clinical trial at Stanford.

Some researchers think the key to preventing or stopping the damage from Alzheimer’s is to give a drug to people early, before symptoms show up.

There are many advertisements for supplements or vitamins promising to protect people from Alzheimer’s disease, and Kerchner said there is little to no evidence that they work. Some may even do harm.

“Gingko biloba has now been proven in multiple studies to do absolutely nothing. Zilch,” Kerchner said. As for vitamin E, at most it has a very weak benefit; and at high levels, it may increase the risk of stroke, brain hemorrhage and heart attack. Hormone replacement therapy in women is “risky,” Kerchner said. Studies show it increases the chance of heart attack and breast cancer, and can increase the risk of dementia in some women.

Other advertisements promote brain-training software to preserve cognitive function and protect against Alzheimer’s.

“There’s no evidence that those things are any better than just being active in real life,” Kerchner said. “Buying an expensive software package isn’t harmful to you, it’s harmful to your checkbook perhaps.”

Developing hobbies, working at a job, keeping adventures in daily life—all can promote stimulation that may have protective effects against Alzheimer’s.

Kerchner said there is one treatment that shows immense benefit to prevent or slow down the symptoms of Alzheimer’s disease: exercise.

“There is a mountain of medical literature, and reams upon reams of papers published” showing the protective effect of exercise, Kerchner said. “It is still the most biologically potent thing that a person can do that we know of to keep your memory stable.”

“It prevents dementia in people who are currently normal. In people who already have cognitive decline, it can slow the rate of decline,” he said.

About the Speaker
Geoffrey A. Kerchner, MD, PhD, is an assistant professor of neurology and neurological sciences, with a special interest in Alzheimer’s disease, mild cognitive impairment, dementia and behavioral neurology. He received his MD and PhD from the University of Washington and completed his internship, residency, and fellowship at the University of California, San Francisco. He is board certified in neurology by the American Board of Psychiatry and Neurology.

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About Dr. Kerchner

Stanford Center for Memory Disorders

Clinical Trials at Stanford