New approaches for the quantification and targeting of noradrenergic dysfunction in Alzheimer's disease

Abstract

There is clear, early noradrenergic dysfunction in Alzheimer's disease. This is likely secondary to pathological tau deposition in the locus coeruleus, the pontine nucleus that produces and releases noradrenaline, prior to involvement of cortical brain regions. Disruption of noradrenergic pathways affects cognition, especially attention, impacting memory and broader functioning. Additionally, it leads to autonomic and neuropsychiatric symptoms. Despite the strong evidence of noradrenergic involvement in Alzheimer's, there are no clear trial data supporting the clinical use of any noradrenergic treatments. Several approaches have been tried, including proof‐of‐principle studies and (mostly small scale) randomised controlled trials. Treatments have included pharmacotherapies as well as stimulation. The lack of clear positive findings is likely secondary to limitations in gauging locus coeruleus integrity and dysfunction at an individual level. However, the recent development of several novel biomarkers holds potential and should allow quantification of dysfunction. This may then inform inclusion criteria and stratification for future trials. Imaging approaches have improved greatly following the development of neuromelanin‐sensitive sequences, enabling the use of structural MRI to estimate locus coeruleus integrity. Additionally, functional MRI scanning has the potential to quantify network dysfunction. As well as neuroimaging, EEG, fluid biomarkers and pupillometry techniques may prove useful in assessing noradrenergic tone. Here, we review the development of these biomarkers and how they might augment clinical studies, particularly randomised trials, through identification of patients most likely to benefit from treatment. We outline the biomarkers with most potential, and how they may transform symptomatic therapy for people living with Alzheimer's disease.

Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer’s disease: systematic review and meta-analysis

“…Such overactivity might lead to agitation and anxiety, or worsening of cognition. 27 56 For example, atomoxetine does not merely produce a general increase in synaptic NA levels, 54 but increases the likelihood that patients will be at an ‘engaged’, intermediate state of noradrenergic tone. In promoting this state, LC neurons are rendered less tonically active with heightened neural gain.…”

“…Such baseline-dependency may apply in Alzheimer’s disease too, calling for stratification tools in clinical trials and practice. 27 58 …”

“…Therefore, it is likely that noradrenergic treatments are maximally effective only at a specific dose; or only in patients with a sufficient degree of LC-NA dysfunction so as to not to induce a state of over-activity of the LC-NA system. Such overactivity might lead to agitation and anxiety, or worsening of cognition 27 56. For example, atomoxetine does not merely produce a general increase in synaptic NA levels,54 but increases the likelihood that patients will be at an ‘engaged’, intermediate state of noradrenergic tone.…”

“…However, after a series of small studies failed to provide convincing evidence for treatment benefits in Alzheimer’s disease, interest waned. Recently, recognition of early LC-NA involvement in Alzheimer’s disease has increased alongside new tools to assay the system in vivo,26 27 and new drug options.…”

Targeting the cannabinoid system to counteract the deleterious effects of stress in Alzheimer’s disease

“…NE is responsible for maintaining a plethora of functions: agitation, aggression, arousal, attention, cognition, autonomic processes, and sleep-wake cycles ( Berridge and Waterhouse, 2003 ; David and Malhotra, 2022 ). The LC is uniquely poised to coordinate endocrine, emotional, and cognitive aspects of the central response to stress.…”