Differential Involvement of the Locus Coeruleus in Early- and Late-Onset Alzheimer’s Disease: A Potential Mechanism of Clinical Differences?

Abstract

Early-onset Alzheimers disease (EOAD) has been associated with an increased likelihood of atypical clinical manifestations such as attentional impairment, yet the cause of this heterogeneity remains unclear. The locus coeruleus (LC) is implicated early in Alzheimers disease pathology and is associated with attentional functioning. This study investigated post-mortem atrophy of the LC in EOAD and late-onset Alzheimers disease (LOAD) in a large, well-characterized sample. Results show nearly four times greater likelihood of higher LC atrophy in EOAD as compared to LOAD after controlling for other measures of pathological progression (p < .005). Follow-up analyses within the EOAD group revealed that compared to those who displayed mild or no LC atrophy at autopsy, those with moderate-severe atrophy of the LC displayed significantly worse performance on various baseline measures of attentional functioning (p < .05), despite similar overall cognition (p = .25). These findings suggest the LC is an important potential driver of clinical and pathological heterogeneity in EOAD.

Alzheimer's disease phenotypes show different sleep architecture

“…12 LC degeneration is associated with higher odds for presenting with symptomatic sleep disruption as well as other neuropsychiatric symptoms in early stages, even before tau spread reaches cortical areas (i.e., hippocampus) and leads to cognitive dysfunction. 10,36 Further, the LC is one of the first sites of tau-related neurodegeneration in AD (from Braak I-II already) compared to other tauopathies, suggesting a selective vulnerability pattern of the LC wake-promoting neurons. 9,12,35 Our results showing a pattern of sleep disruption (higher awakenings, N1 and lower sleep maintenance) in a cohort enriched with early-onset presentations, suggests a dysfunctional arousal system driven by LC wake-promoting neurons.…”

“…Indeed, the fact that EOAD manifests with a higher burden of behavioral and sleep disturbances in addition to the higher LC degeneration found on post mortem AD brain tissue, could indicate that vulnerability of the LC is even higher in early-than late-onset presentations. 9,18,36 Greater neuronal count within TMN is associated with less REM sleep and greater neuronal population in LC is associated with prolonged latency to REM sleep. 12 N3-SWS generator.…”

“…Comparison of nighttime sleep metrics and wake‐promoting nuclei in humans (orexinergic lateral hypothalamic area [LHA], the histaminergic tuberomammillary nucleus [TMN], and the noradrenergic LC), found that wake‐promoting nuclei were associated with increased sleep disruption 12 . LC degeneration is associated with higher odds for presenting with symptomatic sleep disruption as well as other neuropsychiatric symptoms in early stages, even before tau spread reaches cortical areas (i.e., hippocampus) and leads to cognitive dysfunction 10,36 . Further, the LC is one of the first sites of tau‐related neurodegeneration in AD (from Braak I–II already) compared to other tauopathies, suggesting a selective vulnerability pattern of the LC wake‐promoting neurons 9,12,35 .…”

“…Our results showing a pattern of sleep disruption (higher awakenings, N1 and lower sleep maintenance) in a cohort enriched with early‐onset presentations, suggests a dysfunctional arousal system driven by LC wake‐promoting neurons. Indeed, the fact that EOAD manifests with a higher burden of behavioral and sleep disturbances in addition to the higher LC degeneration found on post mortem AD brain tissue, could indicate that vulnerability of the LC is even higher in early‐ than late‐onset presentations 9,18,36 . Greater neuronal count within TMN is associated with less REM sleep and greater neuronal population in LC is associated with prolonged latency to REM sleep 12 .…”