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New research casts doubt on the use of cognitive tests for predicting Alzheimer’s risk. Catherine Falls Commercial/Getty Images
  • Previously, experts considered modest decreases in clinical cognitive testing scores to be predictors of future risk of progression to Alzheimer’s disease.
  • Lower education, lower income, and social isolation contribute to lower cognitive testing performance — called “cognitive frailty.”
  • In a new study, despite lower test scores, the cognitively frail participants performed complex mental tasks at a similar level as healthy controls.
  • University of Cambridge researchers concluded that clinical cognitive testing alone was not accurate in predicting an individual’s likelihood of progressing to mild cognitive impairment (MCI) or Alzheimer’s disease.

Currently, more than 6 million people in the United States live with Alzheimer’s disease. According to estimates, this number will rise to more than 13 million by the year 2050.

Although deaths due to heart disease have decreased by 7.3%, those resulting from Alzheimer’s disease have increased by 145.2%. In addition, expected public health costs relating to Alzheimer’s disease could rise from current estimates of $355 billion per year to $1.1 trillion by 2050.

Regarding all causes of dementia, an article suggests that a gross underestimation of dementia risk is at play. The authors project that globally, 152 million people or more will live with dementia by 2050.

Researchers have been searching for meaningful treatments or a cure. However, only five drugs in the U.S. and four in the European Union have received approval for treating Alzheimer’s disease since 1994.

These drugs are not curative, but they intervene in the disease process by reducing symptoms or decreasing brain cell inflammation. These medications represent the scarcity of options for people living with the condition.

A lack of trying is not to blame for this shortage of treatment options. Scientists and clinician-researchers have attacked Alzheimer’s disease on several fronts.

Most research in the past decades was based on the “amyloid cascade hypothesis,” which refers to the significant presence of a protein called amyloid that first instigates inflammation, disrupts neuron function, and ultimately contributes to a breakdown of messaging in the brain.

For Medical News Today, Dr. Scott Kaiser, director of geriatric cognitive health for the Pacific Neuroscience Institute at Providence Saint John’s Health Center in Santa Monica, CA, elaborated:

“I suspect that these are multifactorial processes. Rather than saying that the amyloid hypothesis is or is not correct, let’s just start looking at [it] as part of a broader, complex equation. [T]here are multiple factors […]. The amyloid burden is just one of the factors. There are some questions around how much amyloid buildup is causative rather than just a byproduct, a marker. I think those are areas of exploration.”

– Dr. Scott Kaiser

Dr. Kaiser added: “I anticipate that the definitions of dementia and various types of dementia and various clinical syndromes surrounding dementia will change […] in the near future. They will continue to evolve.”

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This basic science research has led to the most recent treatment breakthrough in Alzheimer’s disease: developing anti-amyloid monoclonal antibodies to remove the amyloid plaques known to disrupt brain communication.

The Food and Drug Administration (FDA) has recently approved aducanumab (Aduhelm), the first drug in its class, for limited use, and related drug trials are ongoing. Although research has demonstrated the reduction of brain amyloid deposits using this drug, its clinical benefit is still under investigation.

Increasingly, clinicians and scientists are embracing a combination therapy approach to treating Alzheimer’s disease, using disease-modifying and symptomatic therapies.

Beyond drug therapeutics, researchers are also viewing Alzheimer’s disease through a lifelong lens of individual and public health. Why do some people develop the condition and others do not? And, as therapeutic options improve, how do we identify those at risk and those in the early stages of the disease for intervention?

Prof. James Rowe — a University of Cambridge researcher and senior author of the paper — and his collaborators endeavored to answer these questions and investigate underlying causes in their new study.

The findings appear in the Journal of Neuroscience.

Clinical researchers are increasingly focused on accurately identifying those people who may be at risk of developing Alzheimer’s disease. One such group of individuals is those whom the medical community classifies as cognitively frail — people who do not perform well on cognitive testing that they undergo as part of a comprehensive health evaluation.

On Monday, scientists from the Cambridge Centre for Frontotemporal Dementia and Related Disorders revealed the results of their study comparing cognitively frail people with those living with healthy cognition, MCI, and Alzheimer’s disease.

First author Dr. Ece Kocagoncu noted that the team’s work is unique in that it is “[t]he first to take a multimodal, in-depth approach and test the cognitively frail using electroencephalogram (EEG), magnetoencephalogram (MEG), and magnetic resonance imaging (MRI).”

With Prof. Rowe and other colleagues at the University of Cambridge, Dr. Kocagoncu first recruited participants using a large-scale cross-sectional population from the Cambridge Centre for Ageing and Neuroscience study (Cam-CAN Frail project).

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From this intensive in-home community-based study, the researchers identified people to undergo extensive cognitive testing and assigned them to categories.

By definition, cognitively frail people are those who find cognitive testing difficult yet exhibit none of the memory or learning deficits clinically observed in MCI or late Alzheimer’s disease.

For MNT, Dr. Kocagoncu elaborated on the study design:

“To measure their neural activity,” she continued, “we used a special task we designed — called the crossmodal oddball task — in the scanner. This task was specially designed to separate healthy individuals from patients with Alzheimer’s disease.”

“It measures the ability to make connections between pieces of information (associative processing) and to recognize novel information (novelty processing), which are functions known to be impaired in Alzheimer’s disease.”

The results were not predictable.

On the EEG and MEG (neurophysiologic tests), the cognitively frail individuals performed robustly — that is, just as well as those without cognitive impairment. And, structurally, the brains of cognitively frail people were similar to those of individuals who were cognitively healthy.

The brains of the cognitively frail individuals were clearly different than those of the people with MCI or Alzheimer’s disease. What does this mean? Dr. Kocagoncu explained:

“Our results were surprising and really encouraging! We found that when we take a close look at the brain structure and neural function of the cognitively frail, they are just like healthy older adults. They don’t show any volume loss in the brain areas associated with Alzheimer’s pathology and show no functional impairments in associative and novelty processing.”

In this way, Dr. Kocagoncu and her Cambridge colleagues proved that cognitive frailty was not a hard and fast predictor of future MCI or Alzheimer’s disease.

So, what does this mean for screening individuals in the community who may score in the range of the cognitively frail?

The scientists conclude that cognitive frailty may be on the spectrum of normal aging rather than a precursor to Alzheimer’s disease.

Dr. Kocagoncu mused, “First, tests that are often used in the clinic to help diagnose dementia — such as the Mini-Mental Status Examination (MMSE) — are unlikely to give an accurate picture of our cognitive health when used alone.”

“The results of the cognitive tests should be interpreted with caution, and we should consider other factors that might be contributing to suboptimal performance.”

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“Second, the cognitive underperformance might be instead a result of an accumulation of psychosocial, lifestyle, and medical risk factors.”

“Factors like malnutrition, social isolation, stress, depression, sedentary lifestyle, hearing/vision impairment, cardiovascular disease, chronic inflammation, and lower education levels are known to contribute to worsening cognitive function.”

– Dr. Kocagoncu

Prof. Rowe, Dr. Kocagoncu, and their colleagues postulate that their research opens the door for further study. They note that the use of increasingly available biomarkers — blood measures of Alzheimer’s disease-specific proteins — can further help identify people at risk for or in the early stages of Alzheimer’s disease.

Their lab plans to take a closer look at risk factors associated with cognitive frailty, as well as protective factors associated with healthy cognitive aging.

Dr. Scott Kaiser concluded:

“We know there are modifiable risk factors. By addressing these risk factors, you can reduce the risk of dementia. [S]omething on the order of one-third of the cases of dementia could be prevented altogether by addressing a profile of risk factors. Some of them are individual, like diet, exercise, and sleep. Others are more public health-related, like air pollution and even noise pollution.”

“[W]e need to be addressing these factors across the lifespan […] — early detection is critical. [W]e need to detect problems early so we can be more aggressive to address factors early that might fuel disease, even if it’s cardiovascular risk factors, [i.e.,] be more aggressive about treating high blood pressure, hyperglycemia, and high cholesterol.”

“[T]he fact of the matter is we have an aging population and, as a result, an increasing burden of people who are significantly cognitively impaired […]. We need to start thinking about modifiable risk factors, from prenatal to end of life, [in order] to prioritize brain health, irrespective of the particular pathophysiology.”

For MNT, Keiland Cooper, Ph.D.(c), a neuroscientist in the Department of Neurobiology and Behavior at the University of California, Irvine, summarized the study:

“This paper fits into an ongoing discussion and evolving framework within the field on how to categorize patients, perhaps galvanized by the recent prevalence and use of biomarkers. I find the paper’s perspective interesting in this regard, and I’m excited to see further use of biomarker-based studies to potentially distinguish or find similarities between groups, especially over longitudinal time courses.”