Longitudinal Cognitive Associates of the ATN Model in Down Syndrome
Jamie C Peven- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Individuals with Down syndrome (DS) are genetically at risk of Alzheimer’s disease (AD) due to the triplication of the amyloid precursor protein, resulting in overproduction of amyloid‐beta. In autosomal dominant AD (ADAD) and late‐onset AD (LOAD), the cascade of pathology begins with amyloid‐beta (A) accumulation, followed by tau (T) accumulation, and finally neurodegeneration (N), known as the ‘ATN model.’ The goal of this study was to understand the relationship between ATN and cognitive functioning in DS.
Method
Data on two time points (16 months apart) from a subset of adults with DS (N = 93) in the Alzheimer’s Biomarkers Consortium for Down Syndrome were analyzed. Participants completed a cognitive battery at both time points including the modified Cued Recall Test (mCRT) to measure episodic memory. Change scores were calculated subtracting baseline from cycle 2 performance. Baseline PET imaging assessed A+ and T+ defined by previously published regional cutoffs. Baseline hippocampal volume was extracted from structural MRI and N+ was defined as one standard deviation below the mean controlling for intracranial volume. General linear models examined follow‐up cognitive performance and total change by baseline ATN group controlling for age, premorbid intellectual disability, and, when appropriate, baseline scores using Bonferroni correction.
Result
Participants were 39.15 years old (SD = 8.99) and 55.9% male. Participants were classified as: A‐T‐N‐ (65; 69.9%), A+T‐N‐ (15; 16.1%), A+T+N‐ (8; 8.6%), A+T+N+ (5, 5.4%). At follow‐up, the A‐T‐N‐ and A+T‐N‐ groups produced significantly fewer mCRT intrusions than the A+T+N‐ and A+T+N+ groups (F(3,86) = 4.41, p = .006). ATN status was not associated with any other follow‐up or change score. However, patterns of change reflect greater decline with conversion to T+ for recall, switching, visual construction, and overall cognitive ability.
Conclusion
Adults with DS with greater AD biomarkers, and particularly the presence of T+, show poorer memory functioning compared with those who have lower neuropathological burden. At follow‐up, only intrusions were significantly associated with baseline ATN status. Adults with DS show similar trends of neuropathology and related cognitive decrements as have been reported in both ADAD and LOAD, although individuals with DS may require greater accumulation of neuropathology to detect more subtle impairments.