Summary: Cognitive test performance can help predict which individuals with normal amyloid-beta levels are likely to progress to abnormal, Alzheimer’s-associated amyloid accumulation.
Source: UCSD
Researchers at the University of California San Diego School of Medicine report that subtle differences in cognitive performance—such as recalling fewer words on a memory test—can indicate early, clinically meaningful accumulation of Alzheimer’s-related proteins in the brain, even when protein levels remain below the usual threshold for diagnosis. The study was published online February 14, 2020 in Biological Psychiatry.
Alzheimer’s disease (AD) is marked pathologically by the gradual buildup of beta-amyloid (Aβ) plaques outside neurons and abnormal tau protein inside neurons. These protein accumulations interfere with neural function and eventually lead to neuron loss and progressive cognitive decline. Although Aβ pathology begins many years before overt dementia, identifying who will progress from normal to abnormal Aβ levels is critical for early intervention.
New diagnostic frameworks from the National Institute on Aging and the Alzheimer’s Association define an early stage of AD as individuals who are Aβ-positive but still cognitively normal. However, the UC San Diego team led by first author Jeremy A. Elman, PhD, and senior author William S. Kremen, PhD, investigated whether subtle cognitive weaknesses could predict which Aβ-negative people will later become Aβ-positive.
“AD pathology, and Aβ in particular, appear long before severe cognitive deficits,” said Elman, “but recent evidence suggests that more subtle cognitive changes may appear earlier than commonly appreciated.” Kremen added that detecting at-risk individuals before they develop substantial amyloid burden would improve the chances of effective treatment and of slowing progression to dementia.
The researchers analyzed data from 292 nondemented, Aβ-negative participants enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Each participant completed standardized, noninvasive cognitive assessments at baseline; over the study and follow-up period, 40 of these participants converted to Aβ-positivity.
The study found that poorer cognitive performance at baseline significantly increased the odds of progressing to Aβ-positivity. In other words, lower scores on well-established cognitive composites pointed to rising amyloid levels that had not yet reached diagnostic thresholds but were on a trajectory toward pathology.
Analyses also showed that more abnormal cerebrospinal fluid (CSF) markers—higher phosphorylated tau and subthreshold increases in Aβ—were associated with greater risk of later Aβ-positivity. Importantly, baseline cognitive measures remained predictive of progression even after accounting for these subthreshold biomarker levels and APOE genotype, demonstrating that inexpensive cognitive screening can add valuable predictive information beyond biomarker assays alone.
Survival analyses examining time to conversion were consistent with these findings: performance on cognitive composites predicted earlier progression to Aβ-positivity after controlling for baseline biomarker status. The results indicate that subtle cognitive decline and incipient biomarker changes can co-occur, and that simple cognitive testing can identify people most likely to develop measurable amyloid pathology.
These findings have direct implications for early detection strategies and clinical trial recruitment. Because cognitive tests are low-cost, noninvasive, and widely available, they could be used to screen and prioritize individuals for biomarker testing, monitoring, and preventive interventions aimed at delaying or preventing progression to Alzheimer’s dementia.
Source:
UCSD
Media Contact:
Scott Lafee – UCSD
Image Source:
The image is credited to NIH/NIA.
Original Research: Closed access
“Amyloid-β Positivity Predicts Cognitive Decline but Cognition Predicts Progression to Amyloid-β Positivity.” Jeremy A. Elman et al. Biological Psychiatry. doi: 10.1016/j.biopsych.2019.12.021.
Abstract (summary)
Stage 1 of the proposed Alzheimer’s disease continuum is defined as amyloid-β positive but cognitively normal. Identifying individuals before Aβ reaches pathological levels could enable earlier interventions. This study examined whether baseline cognitive performance predicted progression from normal to abnormal Aβ levels in 292 nondemented, Aβ-negative participants from ADNI. Forty participants progressed to Aβ-positivity. Poorer baseline performance on cognitive composites was significantly associated with increased odds of progression. Abnormal CSF phosphorylated tau and subthreshold Aβ also increased odds of progression, but cognitive performance remained predictive after accounting for biomarkers and APOE genotype. These results support the use of low-cost cognitive screening to identify people likely to progress to Aβ-positivity for research and early intervention.