Further evidence for a role for the locus coeruleus in the aetiopathogenesis of dementia

We read with great interest the article by Peters et al, which provides a systematic review of changes in blood pressure, body mass index (BMI) and cholesterol levels in individuals that go on to develop all-cause dementia.¹ The authors find that a decrease in BMI and, in turn, blood pressure occurs well before the onset of dementia.¹ This finding, based on 13 longitudinal studies, adds to a confluence of evidence indicating that the locus coeruleus (meaning ‘blue place’ in Latin) plays a key role in the aetiopathogenesis of dementia.

The locus coeruleus serves as the major noradrenaline supplier to the brain. Via a ubiquitous network of projections, the locus coeruleus critically influences cognitive and affective processes together with physiological parameters such as heart rate, blood pressure, pupil size, sleep pattern, inflammation and stress. Neuropathologically, locus coeruleus degeneration is a hallmark of dementia, especially of those subtypes that are characterised by prion-like protein aggregates such as Alzheimer's disease, Down syndrome and Lewy body dementia, but not typically vascular dementia.² Importantly, neurofibrillary degeneration of locus coeruleus neurons seems to be an early event, and is closely linked to mild cognitive impairment and its progression to Alzheimer's disease.³ It is easy to envisage how cytopathology in the locus coeruleus might affect sympathetic output to the cardiovascular system via coeruleo-vasomotor and coeruleo-spinal pathways and, thus, cause a decrease in blood pressure.

Placing the findings of Peters et al¹ in the context of the neuropathology of neurodegenerative diseases raises several interesting issues. If the decrease in blood pressure is a risk factor and/or precursor for dementia, should we monitor blood pressure in our elderly patients more carefully and, in particular, pay more attention to a decline in blood pressure? Furthermore, an exciting study in amyloid precursor protein transgenic mice found that noradrenaline depletion results in microglia dysfunction together with an increase in extracellular β-amyloid deposition, which can be rescued pharmacologically.⁴ It remains to be seen whether this finding can be translated into noradrenaline-based therapies for patients with dementia (for example noradrenaline reuptake inhibitors). Conceivably, the neuroprotective effects of noradrenaline may even extend beyond a single cellular mechanism or disease entity. Understanding the alterations in central noradrenaline signalling preceding overt dementia may create a powerful new window of opportunity for identifying both preclinical dementia stages and developing novel treatments targeting the locus coeruleus circuitry.⁵