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Possible Biomarkers for Alzheimer's Disease
Abstract & Commentary
By Mary Elina Ferris, MD, Clinical Associate Professor, University of Southern California. Dr. Ferris reports no financial relationship to this field of study.
Synopsis: Lower plasma levels of b-amyloid 42/40 in elderly persons followed over 9 years were associated with greater cognitive decline, mainly in those with low measures of past education and literacy.
Source: Yaffe K, et al. Association of plasma beta-amyloid level and cognitive reserve with subsequent cognitive decline. JAMA 2011:305:261-266.
Almost 1000 elderly americans were enrolled in a 10-year prospective observational study, which measured the plasma ratio of b-amyloid 42/40 and assessed other cognitive factors such as education and literacy. At onset, participants had no deficits in Activities of Daily Living and were free of life-threatening cancers. Cognitive function was measured at years 1, 3, 5, 8, and 10 with the Modified Mini-Mental Status Examination (3MS), which is a 100-point maximum battery of global cognitive function. Literacy was tested with a validated tool called Rapid Estimate of Adult Literacy in Medicine. Developing dementia also was ascertained from review of any dementia medications and hospitalizations at subsequent visits. Multivariate models were used to adjust for many individual characteristics and for characteristics that changed significantly over time.
While initial b-amyloid 42/40 levels were not associated with a low cognitive score, a low level was significantly associated with greater cognitive decline over the 9 years patients were followed. If the older adult had less education and low literacy (less than high school diploma or literacy below 6th grade level), there was even greater cognitive decline with a low b-amyloid 42/40 level. Participants with high education and literacy showed less cognitive decline even with the same b-amyloid levels.
With Alzheimer's disease and other dementias predicted to affect up to 1 in 4 elderly persons, the interest in finding better tests for diagnosis and early detection is enormous. Ever since postmortem studies suggested that pathological b-amyloid brain plaques were associated with Alzheimer's disease, there has been active research to determine how to measure these early in the disease. However, past studies of b-amyloid in plasma have given conflicting reports, and the role of b-amyloid in the brain can vary considerably even in severe cases. To further confuse the association, large amounts of b-amyloid can sometimes be found at autopsy with little previous symptoms of dementia.
"Cognitive reserve" is the concept now thought to explain that variability, used to describe an individual with more developed cognitive function as a result of many factors such as brain size, more flexible neural networks, and more synapses. This has been correlated to higher educational and occupational achievement, so literacy and education are used as measures of cognitive reserve in this research.
These data appear to support the hypothesis that cognitive reserve affects the association between b-amyloid and cognitive impairment. When the plasma ratio was found to be low, more cognitive decline occurred, and the decline was greatest in those with less cognitive reserve. Nonetheless, it's important to note that the plasma result alone was not a measure of the extent of future disease, so at this point it cannot be widely used as a biomarker for detecting disease. Nor is it even clear that b-amyloid is a cause of brain degeneration as opposed to an end result, so we are still left with dementias as complex conditions that need to be assessed using a variety of clinical tools.