Affiliations: [a] Lab for Clinical & Integrative Neuroscience, School of Psychology, Trinity College Dublin, Dublin, Ireland
| [b]
Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland
| [c] Trinity College Institute for Neuroscience, Trinity College Dublin, Dublin, Ireland
Correspondence:
[*]
Correspondence to: Sven Vanneste, Lab for Clinical & Integrative Neuroscience, School of Psychology, Trinity College Dublin, College Green 2, Dublin, Ireland. E-mail: sven.vanneste@tcd.ie.; website: http://www.lab-clint.org
Abstract: This article aims to reevaluate our approach to female vulnerability to Alzheimer’s disease (AD) and put forth a new hypothesis considering how sex differences in the locus coeruleus-noradrenaline (LC-NA) structure and function could account for why females are more likely to develop AD. We specifically focus our attention on locus coeruleus (LC) morphology, the paucity of estrogens, neuroinflammation, blood-brain barrier permeability, apolipoprotein ɛ4 polymorphism (APOE ɛ4), and cognitive reserve. The role of the LC-NA system and sex differences are two of the most rapidly emerging topics in AD research. Current literature either investigates the LC due to it being one of the first brain areas to develop AD pathology or acknowledges the neuroprotective effects of estrogens and how the loss of these female hormones have the capacity to contribute to the sex differences seen in AD; however, existing research has neglected to concurrently examine these two rationales and therefore leaving our hypothesis undetermined. Collectively, this article should assist in alleviating current challenges surrounding female AD by providing thought-provoking connections into the interrelationship between the disruption of the female LC-NA system, the decline of estrogens, and AD vulnerability. It is therefore likely that treatment for this heterogeneous disease may need to be distinctly developed for females and males separately, and may require a precision medicine approach.
Keywords: Blood-brain barrier, cognitive reserve, dementia, estrogen, locus coeruleus-noradrenaline, neuroinflammation
