Beta Amyloid Alters Cognition Even in Healthy Adults

Allison Shelley

February 06, 2012

February 6, 2012 — Beta amyloid accumulation, even in healthy aging, is associated with a decline in mental function, report investigators. Their new study suggests that subtle cognitive changes increase as amyloid progresses.

Positron emission tomography scans in healthy adults show low and high levels of beta-amyloid protein.

"Approximately 20% of our sample over the age of 60 showed a marked elevation of amyloid," lead investigator Karen Rodrigue, PhD, from the University of Texas at Dallas, told Medscape Medical News. "Our findings seem to suggest that there may be a steady, linear increase in amyloid burden with aging."

The findings, published online February 1 in Neurology, add to the growing consensus that brain changes associated with Alzheimer's disease begin many years before clinically detectable symptoms emerge, Dr. Rodrigue said.

However, "this study highlights 1 area in which we have very little understanding," she pointed out. "Why are some people able to maintain cognitive function in a healthy range despite the presence of accumulating brain pathology?"

Investigators looked 137 highly educated, cognitively healthy adults. Participants underwent positron emission tomography scanning with radiotracer 18F-florbetapir.

The researchers estimated beta amyloid load in 8 cortical regions, conducted genotyping for apolipoprotein E, and tested for processing speed, working memory, fluid reasoning, episodic memory, and verbal ability.

They found that beta amyloid deposition is distributed differentially across the cortex and progresses at varying rates with age across cortical brain regions.

A subset of cognitively normal adults aged 60 years and older showed markedly elevated deposition, and also had a higher rate of positivity for the apolipoprotein E4 allele, known to be associated with higher Alzheimer's risk, than adults without amyloid elevations (38% vs 15%).

The researchers also found that beta amyloid burden was associated with lower test scores on working memory, reasoning, and speed of processing information.

Asked by Medscape Medical News to comment on the findings, Rachelle Doody, MD, from the Baylor College of Medicine in Houston, Texas, said, "This paper confirms that individuals are more likely to accumulate amyloid as they age, and that this is especially the case if they are E4-positive."

However, she says that the work does not show that individuals who accumulate amyloid will develop Alzheimer's disease, or that the presence of amyloid has a definite effect on cognition.

Limitations of the Marker

Dr. Doody says that the link between more beta amyloid and lower cognition was weaker and more qualified than the authors expected.

It was stronger in the high-beta-amyloid subset, and only true for a subset of cognitive measures in the whole group. "This suggests that beta amyloid may not be a good way to pick out those normals who are likely to advance to Alzheimer's unless it is higher than a certain threshold, which would limit its utility."

Dr. Doody compliments the work and what she refers to as "strong investigators." She applauds their careful subject selection and characterization and technical proficiency in neuroimaging and neuropathology.

Still, she points out, there was a small number of patients in each age group, especially E4-positive individuals. "There are always more neuropsychological tests that could have been informative, such as controlled oral fluence, episodic memory, and visual recall."

Although the authors examined amyloid levels in several different age groups, and talk about the progression of amyloid accumulation, Dr. Doody notes the data are actually cross-sectional and not longitudinal.

Dr. Rodrigue agrees that her team's data are limited by the cross-sectional design of the study. "Longitudinal data mapping the accumulation within individuals over time is needed to verify our findings," she said.

"Understanding the underlying protective mechanisms for this phenomenon is another question we are investigating in the laboratory," Dr. Rodrigue added.

"A key question for future research is whether some adults with high levels of beta-amyloid will maintain good mental function for a long period of time, and whether higher beta-amyloid deposits in healthy adults always predetermines cognitive decline," senior investigator Denise Park, PhD, also from the University of Texas in Dallas, said in a news release.

This study was funded by the National Institutes of Health and the Alzheimer's Association. The ligand for the study was provided by Avid Radiopharmaceuticals. One coauthor works as a consultant for Avid, and holds stock in the company, and also works as a consultant for Bayer Schering Pharma. The other investigators and Dr. Doody have disclosed no relevant financial relationships.

Neurology. 2012;78:387-395. Abstract

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