A major feature of Alzheimer's disease (AD) is the loss of noradrenergic locus coeruleus (LC) projection neurons that mediate attention, memory, and arousal. However, the extent to which the LC projection system degenerates during the initial stages of AD is still under investigation. To address this question, we performed tyrosine hydroxylase (TH) immunohistochemistry and unbiased stereology of noradrenergic LC neurons in tissue harvested postmortem from subjects who died with a clinical diagnosis of no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI, a putative prodromal AD stage), or mild/moderate AD. Stereologic estimates of total LC neuron number revealed a 30% loss during the transition from NCI to aMCI, with an additional 25% loss of LC neurons in AD. Decreases in noradrenergic LC neuron number were significantly associated with worsening antemortem global cognitive function as well as poorer performance on neuropsychological tests of episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. Reduced LC neuron numbers were also associated with increased postmortem neuropathology. To examine the cellular and molecular pathogenic processes underlying LC neurodegeneration in aMCI, we performed single population microarray analysis. These studies revealed significant reductions in select functional classes of mRNAs regulating mitochondrial respiration, redox homeostasis, and neuritic structural plasticity in neurons accessed from both aMCI and AD subjects compared to NCI. Specific gene expression levels within these functional classes were also associated with global cognitive deterioration and neuropathological burden. Taken together, these observations suggest that noradrenergic LC cellular and molecular pathology is a prominent feature of prodromal disease that contributes to cognitive dysfunction. Moreover, they lend support to a rational basis for targeting LC neuroprotection as a disease modifying strategy.
Keywords: Alzheimer’s disease; Gene expression; Locus coeruleus; Mild cognitive impairment; Neurodegeneration; Norepinephrine.