Posts Tagged ‘Alzheimer disease’

Is Screening for Pre-dementia a Good Idea?

Does screening for minor memory changes wrongly label persons with dementia? Yes, say some experts, who worry there is not enough good evidence yet to screen for pre-dementia.

Minor memory changes, often called pre-dementia or mild cognitive impairment (MCI), are arguably an inevitable consequence of aging.

Although up to 15% of those with MCI will progress to dementia each year, more than half of them will not progress.

Many in whom dementia develops do not meet definitions of MCI before diagnosis.

Pre-dementia was included in a new set of diagnostic guidelines for Alzheimer disease issued in May 2011 by 3 consensus groups organized by the National Institute on Aging and the Alzheimer’s Association.

For the first time, the guidelines included biomarkers — such as functional MRI and PET scans, amyloid imaging, and cerebrospinal fluid analysis — specifically for MCI and preclinical phases of the disease.

“The people with preclinical Alzheimer disease have at most mild impairments in their cognition.

They span a spectrum defined at one end as being cognitively normal to, at the other end, needing more time to do their usual, everyday tasks—and even unable to do some of life’s harder tasks, like tax preparation—but they’re not demented,” said Jason Karlawish, MD, Professor of Medicine and Medical Ethics and Health Policy at the Perelman School of Medicine at the University of Pennsylvania.

Dr Karlawish led a recent survey of Alzheimer researchers who agreed that amyloid test results could be released to research participants, if guidance and counseling were put in place.

“For a person with MCI, the benefits of learning amyloid imaging results include an accurate diagnosis of the cause of cognitive impairment,” said Dr Karlawish.

“This, in turn, can motivate a person to adopt brain-healthy behaviors, trimming a medication list that often includes a host of symptomatic medications for anxiety and depression and cognitive impairment, and planning for the future.”

However, Dr Karlawish thinks that the concept of preclinical Alzheimer disease is not yet ready for practice.

“It remains a diagnosis in the shadows between research and clinical care,” he said.

“For now, someone who is labeled being amyloid positive can enroll in a clinical trial to test a drug that targets brain amyloid.”

One such trial will start later this year.

The Anti-Amyloid in Asymptomatic Alzheimer’s disease Study will assign 1000 cognitively normal, amyloid imaging-positive, older adults to a drug that clears amyloid or a placebo.

Screening for Minor Memory Changes

The drive to screen older persons for minor memory changes is leading to unnecessary investigation and potentially harmful treatment, according to experts from around the world who gathered at the recent “Preventing Overdiagnosis” conference in New Hampshire.

A team of specialists from Australia and the United Kingdom said that an expansion of the diagnosis of dementia will end up including up to two-thirds of persons older than 80 years and up to one-fourth of non-demented older persons being labeled with dementia.

With no drugs available to prevent the progression of dementia or to treat MCI, once patients are labeled, they may be vulnerable to untested therapies, say the specialists.

Perhaps our aging population has become a commercial opportunity to develop screening, early diagnostic tests, and medicines marketed to maintain cognition for a condition that is just part of the normal aging process.

Taking Alzheimer Research Down New Protein Paths

I have been asked to write Commentaries for ConsultantLive, an online publication that reaches about 70,000 unique visitors every month, most of them primary care physicians, for which I am a regular contributor.

Here’s my first one on what’s happening in Alzheimer research.

Researchers around the world have devoted themselves to devising ways of blocking the production or accumulation of beta-amyloid, the protein that accumulates as plaques in the brains of persons with Alzheimer disease.

Now scientists are studying other protein targets, including tau, which accumulates in Alzheimer brains and disrupts the activity of brain networks, and the regulator protein CD33.

Last month, Dan Skovronsky, MD, PhD, Eli Lilly & Company vice president of tailored therapeutics, announced that the drug company was pursuing several potential treatments targeting the neurofibrillary tangles caused by tau and had just bought the rights to 2 tests for measuring tangles in the brain.

“The whole field has been amyloid-centric, amyloid-driven, but we need more than that.

That’s why we’re investing in tau,” Dr Skovronsky told The Wall Street Journal. “The most meaningful impact in Alzheimer’s might involve targeting multiple pathways and using combinations of drugs.”

Targeting Tau

Targeting a reduction in levels of the tau protein is likely to be a useful therapeutic approach in Alzheimer disease in parallel with efforts to target beta-amyloid levels, according to research that has identified a new set of genetic markers for the disease.

“We identified several genes that modulate tau levels in the cerebrospinal fluid.

These genes may be useful therapeutic targets for Alzheimer disease,” senior investigator Alison M. Goate, DPhil, Professor of Genetics in Psychiatry at Washington University School of Medicine in St Louis, told ConsultantLive.

Higher levels of tau and a phosphorylated version of tau (p-tau) in the cerebrospinal fluid are thought to reflect both tangle formation and neuronal cell death.

Because tau levels are proportional to the cell death, higher tau levels are associated with more severe dementia, Goate noted.

In the April 24 online edition of Neuron, Goate and colleagues reported that they had identified several genes that are associated with tau levels, and “thus targeting these pathways may provide a more specific means of reducing tau or p-tau levels,” she said.

If drugs could be developed to target tau, they might prevent much of the neurodegeneration that characterizes Alzheimer disease and, in that way, help prevent or delay dementia, Goate suggested.

Blocking CD33 Activity

Another potential strategy for developing treatments to stem the disease process is based on unclogging removal of toxic debris that accumulates in patients’ brains by blocking activity of CD33.

“Too much CD33 appears to promote late-onset Alzheimer’s by preventing support cells from clearing out toxic plaques, key risk factors for the disease,” said Rudolph Tanzi, PhD, of Massachusetts General Hospital and Harvard University, in an NIH statement.

“Future medications that impede CD33 activity in the brain might help prevent or treat the disorder.”

Tanzi and colleagues have found overexpression of CD33 in support cells, called microglia, in postmortem brains from patients who had late-onset Alzheimer disease.

What’s more, they found reduced amounts of CD33 on the surface of microglia and less beta-amyloid in the brains of persons who inherited a version of the CD33 gene that protected them from Alzheimer disease.

There also is evidence to suggest that CD33 works along with another Alzheimer risk gene in microglia to regulate inflammation in the brain.

Early detection of Alzheimer disease is critical to give persons at risk a better chance of receiving effective treatment.

Perhaps studies of proteins other than beta-amyloid will lead to useful therapeutic targets.