A new review of the literature suggests that a breakdown in the integrity of the locus coeruleus (LC), the small region of the brain that releases the key neurotransmitter norepinephrine (NE), may figure more prominently in late-onset Alzheimer’s than previously suspected.  

The analysis further suggests that, conversely, norepinephrine released by the LC earlier in life during cognitively stimulating episodes helps protect the LC’s neurons against damage.

The latter observation may help explain why continuing education and engaging work prevent cognitive decline in later years, according to the authors of the study, published online Feb. 16 in the journal Trends in Cognitive Sciences.

In introducing their observations, Mara Mather, PhD, University of Southern California-Davis School of Gerontology, and Carolyn Harley, PhD, MSc, Memorial University of Newfoundland, point out that the LC is known to be vulnerable to toxins as well as infection, and it is often the first place Alzheimer’s-related pathology appears. In fact, they note, most people show at least some tau pathology by their mid-20s.

Given the association between the integrity of the LC-NE system and the maintenance of cognitive function late in life, a natural next question is whether specific interventions might be indicated to help the aging stay cognitively fit, the authors suggest.

To date, there has been little research in humans investigating whether pharmacologically increasing NE levels could benefit cognition, Mather and Harley write.

Among the several projects they cite is a six-month, double-blind study of patients with mild-to-moderate Alzheimer’s disease in which researchers found that adding atomoxetine, an NE reuptake inhibitor, to ongoing cholinesterase-inhibitor therapy did not significantly improve cognitive function.  

“The lack of effectiveness may relate to the Alzheimer’s disease in the patients,” write Mather and Harley, “because animal research suggests that NE reuptake inhibitors lack effectiveness when NE levels are already reduced as a result of disease.”  

Understanding the role of the LC in cognitive aging “is not merely of theoretical importance,” the authors conclude, emphasizing that their literature review outlines evidence suggesting that age-related change in the LC structure and NE function “plays more of role in cognitive aging than has been previously appreciated.”

Going forward, they add, “one exciting prospect is that, by stimulating the LC and NE release, cognitive challenges and physical exercise may be effective interventions throughout life that harness the anti-inflammatory and cell-protective qualities of NE to help to forestall cognitive decline and dementia.”

In a USC-Davis news post spotlighting the research for a consumer audience, Mather says education and engaging careers “produce late-life ‘cognitive reserve,’ or effective brain performance, despite encroaching pathology. Activation of the locus coeruleus-norepinephrine system by novelty and mental challenge throughout one’s life may contribute to cognitive reserve.”