One marker of Alzheimer’s in the brain is bad news, but two spell real trouble in cognitively normal older adults, according to a paper in the September 15 JAMA Neurology. Scientists led by Reisa Sperling, Harvard Medical School, Boston, found that people with both brain amyloid and neurodegeneration performed worse on neuropsychological tests over the next three years. People who had neither biomarker improved over this time period due to practice, and people with only one biomarker improved a little—evidence of a weaker practice effect.
“This study shows that both neurodegeneration and amyloid deposition independently have an impact on global cognition, and that together they have a synergistic effect,” Gaël Chételat, INSERM-EPHE-University of Caen, France, wrote to Alzforum in an email (see full comment below). The findings also imply that practice effects could be useful for detecting subtle deterioration in people who otherwise appear healthy, wrote the authors. To Sperling, the findings suggest that people with amyloid deposition plus neurodegeneration might decline fast enough for a treatment effect on cognition to be measurable within the time span of a secondary prevention trial, but people with only amyloid deposition might not.
It is known that cognitively healthy people with brain amyloid deposition or evidence of neurodegeneration—be it hippocampal shrinkage, low glucose metabolism in certain areas, or high amounts of phosphorylated tau in the cerebrospinal fluid—are likelier to decline cognitively than people with just one biomarker (see Knopman et al., 2012; Desikan et al., 2012; Vos et al., 2013). Researchers disagree about whether these markers act independently (see Chetelat, 2013; Knopman et al., 2013). Sperling and colleagues wanted to probe this question in cognitively normal people. They also wanted to test whether they could pick up evidence of cognitive decline over two to three years. Secondary prevention trials for Alzheimer’s disease, such as A4 (see Sep 2013 news story) may be too short to use clinical progression as an endpoint, first author Beth Mormino explained.
The researchers enrolled 166 cognitively normal participants from the Harvard Aging Brain Study. Their median age was 74. All scored in the normal range on neuropsychological tests such as the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale, and Geriatric Depression Scale. To distinguish those who were positive or negative for amyloid deposition, the researchers used positron emission tomography with Pittsburgh Compound B. To identify neurodegeneration, they measured reduced glucose metabolism with FDG-PET, and hippocampal atrophy by volumetric MRI. Participants with either were deemed positive for neurodegeneration.
The cohort fell into four groups: 81 participants with neither amyloid nor neurodegeneration; 19 with amyloid only; 28 with both; and 38 for neurodegeneration without amyloid. These groups correspond to the proposed new staging method for preclinical AD, and represent Stages 0, 1, 2, and what some scientists call “suspected non-AD pathophysiology,” aka SNAP (see Sperling et al., 2011; Jack et al., 2012). Over the following two to four years, everyone completed annual cognitive tests, including the Logical Memory delayed recall, Selective Reminding Test delayed recall, Face-Name Associative Memory Exam, Trail Making Tests A and B, Digit Symbol Substitution Test, and the MMSE. Scores were rolled into a global composite.
Improvement from year to year, or lack thereof, best distinguished the groups. These practice effects arise on repeat testing as a person becomes familiar with the questions, grows more comfortable taking the test, or remembers information from previously sittings. Stage 2 participants did worse as time went on, while stage 1 participants improved somewhat, but less than stage 0 participants.
The study “support[s] the hypothesis that evidence of both fibrillar amyloid deposition and neurodegeneration is associated with an even greater rate of subsequent cognitive decline,” Eric Reiman, Banner Alzheimer's Institute, Phoenix, wrote to Alzforum in an email (see full comment below). He said that larger cohorts should be followed for longer periods to further clarify how well these biomarkers predict deterioration and clinical progression.
As clinical trials move toward treating asymptomatic Alzheimer’s disease, researchers are looking for ways to detect subtle cognitive changes (see Jun 2014 news story). The current study suggests a way to do that, said Mormino. “People often see practice effects as sources of noise in their sample, but the lack of them might be a sensitive way to pick up cognitive decline in clinically normal samples,” she told Alzforum. “It’s reassuring that we can detect differences in just two years, since prevention trials may last only three,” she added.
The standardized uptake value cutoff Mormino used in the PiB-PET imaging—1.196— is lower than the 1.4 or 1.5 used in other studies (see Mormino et al., 2014). Sylvia Villeneuve, University of California, Berkeley, recently reported that lower SUVRs better capture people who are at the earliest stages of amyloid deposition (see Jul 2014 conference story). “That almost identical ‘early thresholds’ were found in two independent cohorts supports the idea that amyloid can be detected long before individuals reach widely used SUVR cutoffs,” she wrote to Alzforum in an email. Mormino expected that even if she had used a higher threshold, the main result would hold. “The strongest decline occurred in those with the highest PiB values,” Mormino wrote.
Interestingly, among people whose amyloid deposition was below the threshold, those with the highest values were likelier to exhibit smaller practice effects over time and test positive for neurodegeneration. This could mean that even a little Aβ build-up could be biologically meaningful, the authors wrote. David Wolk, University of Pennsylvania, Philadelphia, agreed. “Some of the SNAP group may represent individuals with cerebral amyloid at levels lower than typically constitutes a positive amyloid scan,” he wrote to Alzforum in an email. “This could reflect that these individuals—mostly non-ApoE4 carriers—have a lower threshold of amyloid required for neurodegenerative changes to occur.”
The findings will not change how researchers recruit for the ongoing A4 trial. A4 selects based on Aβ status, not whether or not people have neurodegeneration. A4 will test whether the monoclonal antibody solanezumab delays Alzheimer’s disease. Investigators will assess post hoc whether the presence of neurodegeneration affected the response to treatment, Mormino said. They will also investigate whether certain cognitive domains are more sensitive to changes in practice effects than others. “If we understood where the practice effects are coming from, we could try to exaggerate them to our advantage,” she said.
“It is helpful that we are building up datasets in this preclinical window,” said Nick Fox, University College London. “As we investigate earlier periods of disease, we will need to understand not just the predictive value of these cross-sectional and longitudinal changes, but figure out how they vary and if they can be used as outcome measures for trials,” he said. He noted that a drop in practice effects constitutes one of the earliest cognitive changes he sees in people who carry mutations for familial Alzheimer’s.
The findings “highlight the importance of examining continuous cognitive outcomes in cognitively normal individuals” to detect practice effects, wrote Susan Resnick, National Institute on Aging, Baltimore, in an accompanying editorial.—Gwyneth Dickey Zakaib