Cognitive functioning in relation to brain amyloid-β in healthy adults with Down syndrome

Abstract

Nearly all adults with Down syndrome show neuropathology of Alzheimer's disease, including amyloid-β deposition, by their fifth decade of life. In the current study, we examined the association between brain amyloid-β deposition, assessed via in vivo assessments of neocortical Pittsburgh compound B, and scores on an extensive neuropsychological battery of measures of cognitive functioning in 63 adults (31 male, 32 female) with Down syndrome aged 30-53 years who did not exhibit symptoms of dementia. Twenty-two of the adults with Down syndrome were identified as having elevated neocortical Pittsburgh compound B retention levels. There was a significant positive correlation (r = 0.62, P < 0.0001) between age and neocortical Pittsburgh compound B retention. This robust association makes it difficult to discriminate normative age-related decline in cognitive functioning from any potential effects of amyloid-β deposition. When controlling for chronological age in addition to mental age, there were no significant differences between the adults with Down syndrome who had elevated neocortical Pittsburgh compound B retention levels and those who did not on any of the neuropsychological measures. Similarly, when examining Pittsburgh compound B as a continuous variable, after controlling for mental age and chronological age, only the Rivermead Picture Recognition score was significantly negatively associated with neocortical Pittsburgh compound B retention. Our findings indicate that many adults with Down syndrome can tolerate amyloid-β deposition without deleterious effects on cognitive functioning. However, we may have obscured true effects of amyloid-β deposition by controlling for chronological age in our analyses. Moreover, our sample included adults with Down syndrome who were most 'resistant' to the effects of amyloid-β deposition, as adults already exhibiting clinical symptoms of dementia symptoms were excluded from the study.

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

“…Nonetheless, most individuals with DS have amyloid-positive PET scans by the age of 50 (REFS 45,96,99,100). Amyloid load, as measured by PET, does not correlate well with cognitive function in adults who have DS in cross-sectional studies 45,99 , highlighting the importance of factors other than amyloid in the development of dementia. However, longitudinal imaging studies in this population have yet to be undertaken and may be highly informative 45,99 .…”

“…Amyloid load, as measured by PET, does not correlate well with cognitive function in adults who have DS in cross-sectional studies 45,99 , highlighting the importance of factors other than amyloid in the development of dementia. However, longitudinal imaging studies in this population have yet to be undertaken and may be highly informative 45,99 .No NFTs have been reported in AD-DS in the absence of dense-core plaque pathology, which is consistent with the predictions of the amyloid cascade hypothesis. The density of NFTs triples between the fourth and fifth decade of life in AD-DS 77 , mirroring the onset of dementia, and NFT formation rather than amyloid deposition correlates best with cognitive decline 34 , which is consistent with similar findings in LOAD.…”

“…This discrepancy may be because amyloid imaging recognizes only a subset of Aβ aggregates, thus not all deposition may be detected 98 . Nonetheless, most individuals with DS have amyloid-positive PET scans by the age of 50 (REFS 45,96,99,100). Amyloid load, as measured by PET, does not correlate well with cognitive function in adults who have DS in cross-sectional studies 45,99 , highlighting the importance of factors other than amyloid in the development of dementia.…”

Frontal Lobe Degeneration in Adults with Down Syndrome and Alzheimer's Disease: A Review

“…Neuroimaging studies have identified typical brain atrophy in patients with DS and AD [12], as well as indicators of dementia correlated with structural and functional findings in individuals with DS without clinical signs of AD but at the age of risk for its development [13]. Nevertheless, recent research indicates that many adults with DS can tolerate the deposition of Aβ with no effects on their cognitive functions [14]. …”

Cognitive decline and brain amyloid-β accumulation across 3 years in adults with Down syndrome

“…However, conclusions are limited due to cross-sectional designs (Annus et al, 2016; Handen et al, 2012; Hartley et al, 2014; Nelson et al, 2011), small sample sizes (Handen et al, 2012), and restricted neuropsychological batteries of cognitive functioning (Nelson et al, 2011). In the largest cross-sectional study, and the one with the most extensive battery of directly-administered neuropsychological measures, Hartley et al (2014) found a negative association between neocortical PiB retention and verbal and visual episodic memory, executive functioning, and expressive language in 63 adults with DS (aged 30–50 years) who did not exhibit clinical signs of AD. A handful of studies have also examined neocortical amyloid-β accumulation in the preclinical stages of AD in DS using the PET tracer Florbetapir (Rafii et al, 2015; Sabbagh et al, 2015).…”