Clinical trials for Alzheimer’s disease are moving toward earlier and earlier intervention, based on the assumption that this may prevent or slow cognitive decline before Alzheimer’s damage occurs. But how early can we detect the cognitive changes associated with Alzheimer’s disease?
Ron Petersen, MD, of the Mayo Clinic in Rochester, Minn., said in an interview with MedPage today. “Something like cdr [Clinical Dementia Rating] The sum of squares is probably not very useful because most people in those stages will be zero in the CDR. Thus, there is not a lot of movement on a scale like this.”
Several Alzheimer’s disease researchers are studying whether certain aspects of cognition are more sensitive to emerging amyloid and tau diseases.
“If amyloid is an important player in this process and we’ve shown some movement in the symptomatic stage, shouldn’t we go early in the preclinical stage?” Petersen noted. “Even then, it might not be a home run but we might have an effect that flattens that curve. And then we step in with other compounds to get the tau, etc., and the complexity of the disease is taken off, piece by piece.”
Emerging pathology and early changes
In March, an analysis was published in Neurology Led by Risa Sperling, MD, of Brigham and Women’s Hospital in Boston, showed that emerging Alzheimer’s disease in older, non-disabled people was associated with two components of cognition: decreased processing speed and memory retrieval, with processing speed showing changes first.
“What we saw in this study is that measures of processing speed and executive function were actually associated with early amyloid deposits,” co-author Michelle Farrell, Ph.D., also of Brigham and Women and Harvard, said in an interview with MedPage today. “It’s definitely very subtle changes.”
Researchers evaluated 112 cognitively normal participants in the Harvard Aging Brain Study who underwent PET scans for amyloid and tau. Cognitive testing was performed annually in the study. Measures of processing speed/executive function included the Number Code Substitution Test (DSST) and the Pathway Configuration Test, Parts A and B (paths A and B).
The researchers categorized participants based on their amyloid PET (CL) values into those who were negative for amyloid (CL less than 20) and those who were mildly amyloid positivity (range 20-40 CL), and then correlated these levels with cognitive measures. Farrell noted that in the general population, people in the 20-40 CL range are rare—the study sample included only 10 of these people—but that range may represent an ideal window for intervention.
The study showed an early and concurrent association between amyloid accumulation and measures of processing speed, stronger with DSST scores. The DSST and Trails A and B scores showed contemporary changes in amyloid-beta and cognitive decline.
“I’m not sure these results would be very useful in a clinical setting because they are such a small change,” Farrell noted. “But from a clinical trial perspective – this is where I hope information like this will help us better monitor cognitive changes at this early stage, when people have little to no amyloid.”
Overall, a combined measure of processing speed and memory retrieval tasks was the strongest predictor of cognitive decline in people with CL under 40. In a separate analysis of people with CL above 40, the preclinical Alzheimer’s disease cognitive complex (PACC) remained optimal.
The sample size was small, and “it’s hard to go to the bank with that,” noted Petersen, who was not involved in the study. “But the suggestion was that measures of executive function might actually move, even in the early amyloid deposition stage when PET scans go from negative to positive,” he noted. “And then, as the disease progresses and in particular tau involvement, measures of memory may be a little more sensitive.”
“So it’s supposed to be executive function first, then memory, and then we get into some combination procedures like PACC, which were thought to be very good for preclinical stages that might be a little bit late,” Petersen said.
amyloid accumulation and executive function
The findings echo what researchers in Sweden reported earlier this year. at Neurology, Oscar Hanson, MD, PhD from Lund University, and co-authors evaluated 316 non-cognitively impaired participants in the Swedish BioFINDER-2 study who had cerebrospinal fluid (CSF) measurements, imaging, and cognitive tests. The researchers used the difference in scores for Trails B and Trails A to measure executive function.
Hanson and colleagues note that executive function is an umbrella term for a range of different abilities. “In this study, we used the delta score [Trails B minus Trails A] which reduce the requirements for working memory and sensory memory for the task. Depending on the scale used in this study, the results suggest that neuropsychological tests that exploit more complex divided attention and cognitive flexibility may be more sensitive to beta-amyloid accumulation. “
The study found that amyloid pathology, measured with CSF or PET, was specifically associated with performance on the executive scale. Tau pathology has been independently associated with memory.
To see relationships in preclinical stage I Alzheimer’s disease, the researchers also looked at a subset of participants with normal tau biomarkers and neurodegeneration and found that amyloid status correlated with executive function, but not with other cognitive domains. The aggregate findings were replicated in a sample from the North American Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.
Although the associations between amyloid pathology and the degree of executive function were modest, this finding could shed light on how cognitive deficits present in asymptomatic individuals with early amyloid buildup, Hanson and co-authors note. “More sensitive measures of this cognitive ability may be useful in screening for beta-amyloid pathology or used as an outcome measure in clinical trials targeting beta-amyloid.”