Clinical Challenges: How Early Can We Spot Alzheimer’s?

Alzheimer’s disease clinical trials 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?

“Some of our current clinical instruments are kind of blunt, especially in the preclinical stages of the disease,” said Ron Petersen, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, in an interview with MedPage Today. “Something like the CDR [Clinical Dementia Rating] sum of boxes is probably not very useful since most people in those stages would be a CDR zero. Consequently, there’s not a lot of movement on a scale like that.”

Whether specific aspects of cognition are more sensitive to emerging amyloid and tau pathology is something several Alzheimer’s researchers are investigating.

“If amyloid is an important player in the process and we’ve demonstrated some movement at the symptomatic stage of the disease, shouldn’t we go earlier in the preclinical stage?” Petersen noted. “Even then, it might not be a home run but we may have an impact flattening that curve. And then we intervene with other compounds to get at tau, etc., and the complexity of the disease gets chipped away, piece by piece.”

Emerging Pathology and Early Changes

In March, an analysis published in Neurology led by Reisa Sperling, MD, of Brigham and Women’s Hospital in Boston, showed that emerging Alzheimer’s pathology in unimpaired older adults was associated with two components of cognition: declining processing speed and memory retrieval, with processing speed showing changes first.

“What we saw in this study was that measures of processing speed and executive function were associated with really early deposits of amyloid,” co-author Michelle Farrell, PhD, also of Brigham and Women’s and Harvard, said in an interview with MedPage Today. “They’re definitely very subtle changes.”

The researchers evaluated 112 cognitively normal participants in the Harvard Aging Brain Study who had PET imaging for amyloid and tau. Cognitive testing was done annually in the study. Measures of processing speed/executive function included the Digit Symbol Substitution Test (DSST) and the Trail Making Test, parts A and B (Trails A and B).

The researchers categorized participants based on amyloid PET centiloid values (CL) into those who were negative for amyloid (CL under 20) and those who had mild amyloid positivity (20-40 CL range), then correlated these levels with cognitive measures. In the general population, people in the 20-40 CL range typically are scarce — the study sample included only 10 such people — but this range may represent an optimal window for intervention, Farrell noted.

The study demonstrated an early and concurrent association between accumulating amyloid and measures of processing speed, most robustly with DSST scores. DSST and Trails A and B scores showed contemporaneous changes in amyloid beta and cognitive decline.

“I’m not sure these findings would be super useful in a clinical setting because it’s such a small change,” Farrell noted. “But from the perspective of clinical trials — that’s where I’m hopeful that information like this will help us better monitor cognitive changes at this early stage, when people have just a little bit of 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 Cognitive Composite (PACC) remained optimal.

The sample size was small, and “it’s hard to go to the bank with this,” noted Petersen, who wasn’t involved with the study. “But the suggestion was that the measures of executive function may in fact be moving, even in the early amyloid deposition stage when PET scans are transitioning from negative to positive,” he observed. “And then, as the disease progresses and in particular tau becomes involved, memory measures may be a bit more sensitive.”

“So, presumably executive function first, then memory, and then we get into some of the composite measures like the PACC, which was thought to be pretty good for preclinical stages that may be a bit later,” Petersen said.

Amyloid Accumulation and Executive Function

The findings echoed what researchers in Sweden had reported earlier in the year. In Neurology, Oskar Hansson, MD, PhD, of Lund University, and co-authors evaluated 316 cognitively unimpaired participants in the Swedish BioFINDER-2 study who had cerebrospinal fluid (CSF) measures, imaging, and cognitive tests. The researchers used the difference in Trails B and Trails A scores to measure executive function.

Executive function is an umbrella term that encompasses a set of different abilities, Hansson and colleagues noted. “In this study, we utilized a delta score [Trails B minus Trails A] that reduces visuoperceptual and working memory demands for the task. Based on the measure used in this study, the results suggest that neuropsychological tests tapping more complex divided attention and cognitive flexibility are perhaps more sensitive to amyloid beta accumulation.”

The study found that amyloid pathology, measured using either CSF or PET, was specifically associated with performance on the executive measure. Tau pathology was independently associated with memory.

To see the relationships in the earliest stage of preclinical Alzheimer’s, the researchers also looked at a subset of participants who had normal biomarkers of tau and neurodegeneration and found that amyloid status was associated with executive function, but not with other cognitive domains. The overall results were replicated in a sample from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort in North America.

Although the associations between amyloid pathology and the executive function score were modest, this finding could shed light on how cognitive deficits are manifested in asymptomatic individuals with early amyloid accumulation, Hansson and co-authors noted. “More sensitive measures of this cognitive ability might be useful for screening for amyloid beta pathology or used as an outcome measure in clinical trials targeting amyloid beta.”