Invited Perspective: Blue Skies and Alzheimer’s Disease

If a fresh brain is cut in half, two blue spots can be observed in the brainstem: the locus coeruleus (LC), or “sky-blue place.” This bilateral nucleus was first described by Félix Vicq d’Azyr in 1786¹ but received its name in 1812,² incidentally 7 years after the pigment cerulean blue was invented.³ The pigment was popularized in the 1860s by the Impressionists, with the bright cerulean puffs of smoke spewing from the engine in Claude Monet’s La Gare Saint-Lazare a prime example (Figure 1).

Figure 1.

La Gare Saint-Lazare, 1877. Claude Monet (1840–1926).

The LC is the principle brain site of noradrenaline synthesis, and it is one of the first regions to be impacted by Alzheimer’s disease.^4,5 The potential effects of Monet’s blue smoke on the nucleus has now been demonstrated by Puckett et al.⁶ in this issue of Environmental Health Perspectives. In 381 older twin brothers, higher levels of residential air pollution exposure was related to lower signal-to-noise ratio—a hazier magnetic resonance image (MRI)—of the LC.

Air pollution is a well-established risk factor for cardiopulmonary and lung cancer mortality,^7,8 and accumulating evidence indicates that air pollutants increase the risk of developing dementia.⁹ Exposure to particles smaller than 2.5 μm (${\mathrm{PM}}_{2.5}$) is epidemiologically linked to Alzheimer’s disease, age-associated brain atrophy,¹⁰ and decreased cognitive function in middle-aged and older adults.¹¹ ${\mathrm{PM}}_{2.5}$ may reach the brain via a leaky blood–brain barrier and/or the nasal olfactory pathway to the trigeminal nerves, brainstem, hippocampus, and striatum.^12–14 Once there, particles may induce microglial activation,¹⁵ tau phosphorylation,¹⁶ and neuronal death.¹⁷ The LC innervates the majority of the brain’s microvasculature, and no other brain region has as much contact with circulating blood.¹⁸ Indeed, the neuromelanin that pigments the LC is formed from monoamine metabolites, heavy metals, protein aggregates, and rancid fats,¹⁹ where paramagnetic metals might contribute to changes in MRI contrast.^20,21 As such, the sky-blue place may be particularly vulnerable to skies that are … not.²²

As in all good studies, Puckett et al. open the door to more specific questions: First, they demonstrate that the integrity of the LC is related to exposure to ${\mathrm{PM}}_{2.5}$ in individuals without cognitive decline. These study participants should be tracked longitudinally to determine if the observed reduced LC integrity is indeed a precursor to developing Alzheimer’s disease. Second, by utilizing the between-brother variability in this sample of twins, genetic effects on LC integrity were minimized. But some of these brothers, all Vietnam Era veterans, were likely exposed to other toxicants during their military service, including Agent Orange, another known risk factor in Alzheimer’s disease.²³

Although studying brothers is an excellent strategy, it neglects half the world’s population. If one pathway to develop Alzheimer’s disease is via toxicants such as ${\mathrm{PM}}_{2.5}$ entering the LC through a leaky blood–brain barrier, then women may be more susceptible to this process; declining estrogen levels after menopause render the blood–brain barrier more leaky.^24,25 Indeed, the risk of Alzheimer’s disease from air pollution exposures may be somewhat higher in women,²⁶ whereas the association of LC integrity and cognitive reserve in healthy aging appears similar in men and women.²⁷

Monet loved smoke, and many of his Paris and London cityscapes depict the haze of the nascent industrial revolution.²⁸ But Monet was no fan of city life, and he spent the latter half of his life in the countryside at Giverny.²⁹ He died in 1926 at the respectable age of 86, 30 years above the average life expectancy at the time in France.³⁰ He died from lung cancer, with no known accounts of dementia or mental decline. Indeed, both access to greenspace and engaging in artistic activities reduce risk of Alzheimer’s disease.^31,32 We might all follow Monet’s example and spend more of our time en plein air.

Conclusions and opinions are those of the individual authors and do not necessarily reflect the policies or views of EHP Publishing or the National Institute of Environmental Health Sciences.

Refers to https://doi.org/10.1289/EHP14344