There is a direct and linear association between plasma beta-amyloid (Aβ) levels and multiple aspects of cognitive decline over time, including cognitive changes that constitute conversion to Alzheimer's disease, according to new findings from a population-based, ethnically diverse longitudinal sample of older adults.
Stephanie Cosentino, PhD, from the Taub Institute for Research in Alzheimer's Disease and the Aging Brain at Columbia University Medical Center, New York City, and multicenter colleagues found that in their overall sample of 880 adults, individuals in the top 3 quartiles of Aβ42 at baseline had faster declines in cognitive function during 4.5 years of follow-up than those in the lowest quartile. The same observation held largely true for individuals who remained cognitively healthy during the same study interval.
"Individuals in the top 3 Aβ40 quartiles also declined faster than those in the lowest quartile," investigators add, "[whereas] in the healthy elderly individuals, only the highest quartile declined faster than those in the lowest."
Looking at the rate of global cognitive change by change in Aβ, investigators noted that in both the overall cohort and the healthy elderly, individuals with relatively stable or decreasing Aβ42 values had faster cognitive decline than those with increasing Aβ42 values.
In contrast, change in Aβ40 was not associated with cognitive change in either the overall cohort or the healthy elderly.
"What we tend to see in healthy elders is a steady increase in Aβ42 levels over time, so what we are trying to characterize here is the absence of an increase," Dr. Cosentino told Medscape Medical News.
She also noted that previous studies have shown that high initial plasma levels of Aβ and declining levels of Aβ over time are risk factors for Alzheimer's disease, "so changes in Aβ levels provide information about disease risk." In this particular study, changes in the same plasma Aβ levels predicted the rate of cognitive decline in patients who eventually developed dementia.
"This linear association between plasma Aβ and cognitive change increases our ability to use plasma Aβ as a marker of impending cognitive decline and Alzheimer's disease," Dr. Cosentino said, adding that interestingly enough, the same Aβ profile predicted cognitive decline even in those individuals who remained healthy over time.
The study was published online August 9 and will appear in the December issue of the Archives of Neurology.
Aging Project
The amyloid cascade hypothesis suggests that Alzheimer's disease develops subsequent to aberrant metabolism of glycoproteins, the precursors to amyloid, the authors write. Aβ40 and Aβ42 then accumulate, and this accumulation is considered the primary trigger for the development of Alzheimer's disease. Previous research indicates that plasma Aβ levels decrease as brain levels increase, suggesting that plasma Aβ level may be used as a biomarker of disease risk.
In this study, participants were drawn from the Washington Heights and Inwood Columbia Aging Project and represented 3 broadly defined ethnic groups: Caribbean Hispanic, black, and white. All participants were free of dementia at the time of the first Aβ sample; at follow-up, 481 patients remained cognitively healthy, 329 were cognitively or functionally impaired but not demented at any point, and 70 developed Alzheimer's disease.
Investigators then determined whether Aβ levels could be linked to either specific cognitive changes that constitute conversion to Alzheimer's disease or whether they corresponded to cognitive change independent of dementia. Cognitive change consisted of a composite score and memory, language, and visuospatial indices.
When researchers examined cognitive change in specific domains by Aβ, they determined that baseline Aβ42 predicted cognitive change in all 3 domains in the overall sample, with those in the highest Aβ quartile "consistently declining faster" than those in the lowest. "Baseline Aβ40 quartile predicted change in memory," the authors add, with those in the second and third quartiles declining faster than those in the lowest quartile.
Baseline Aβ40 quartiles also predicted change in language, with individuals in the highest quartile declining faster than those in the lowest. "Finally, change in Aβ42 predicted change in memory and visuospatial scores, with relatively stable or decreasing Aβ42 predicting faster decline," the researchers add. Among the group who remained cognitively healthy during the study interval, baseline Aβ42 predicted change primarily in memory, with higher baseline levels generally predicting faster decline.
In contrast, baseline Aβ40 was generally unrelated to cognitive change in the same healthy elderly group, and change in Aβ42 was not associated with change in any domain. Finally, change in Aβ40 over time was not related to cognitive change in either the overall sample or the cognitively healthy.
Relatively Rapid Decline
As the authors point out, the relatively rapid cognitive decline seen as a function of high baseline plasma Aβ levels and stable or decreasing Aβ42 in the entire sample is not surprising given that a similar plasma Aβ profile predicted conversion to Alzheimer's disease in the same sample in an earlier study — cognitive decline in more than one domain is a prerequisite for incident Alzheimer's disease.
"We need to further validate these Aβ levels, and we also need to understand how plasma Aβ levels relate to brain levels," Dr. Cosentino cautioned. "But once we have a better understanding of this, testing patients for plasma Aβ levels is an inexpensive and noninvasive way to identify people at greater risk for cognitive decline and Alzheimer's disease, and ultimately, this would be very important in terms of being able to provide preventive treatment when we have such a treatment."
The study was supported by grants from the National Institutes of Health. The authors have disclosed no relevant financial relationships.
Arch Neurol. Published online August 9, 2010.
