“When it comes to stress hormones, we all think of circulating glucocorticoid levels, high or low. This work shows differences between people are also a matter of one’s receptors. The receptor can determine the actual consequences a person sustains in their tissues from a given level of cortisol,” Van Rossum said.

First, a little background. Both biorhythms and stress drive the production of glucocorticoids. Those who remember their Biology 101 will recall the hypothalamic-pituitary-adrenal axis, which hosts the cycle leading from CRH via ACTH to the release of cortisol. This hormone exerts a wide range of effects on target tissues in the body and the brain, and then throttles its own production in a negative feedback loop. Brain consequences of cortisol are less well established than peripheral ones, but they include effects on dendritic branching, synapse formation, norepinephrine uptake, and glucose utilization. What’s important is that acute cortisol exposure enhances memory performance, but chronically elevated levels have been blamed for cognitive impairment, shrunken hippocampuses, and an increased risk of cerebrovascular problems (for a review, see Belanoff et al., 2001).

Glucocorticoids act through their receptors, and humans have two basic kinds. The type1 or mineraloreceptor (MR) regulates basal and circadian cortisol release, and the type2 (or GR) receptor regulates stress-dependent functions. Both occur in the hippocampus and other brain regions, though their distribution is not identical. When the receptor, which belongs to the nuclear receptor family, binds cortisol, it comes off its chaperone, dimerizes, enters the nucleus, and turns transcription of certain target genes on, of other genes off.

While studying this receptor, Van Rossum came across a variant in its second exon. This ER22/23EK polymorphism resides in the GR receptor, and 7 percent of the population carry at least one allele of it. Otherwise, the glucocorticoid receptor gene is largely terra incognita in AD research (see Alzgene). Carriers of this new polymorphism seem to enjoy benefits across the cardiovascular/metabolic range. They have more muscle and less fat than the rest of the population (in fact, the sole homozygous carrier Van Rossum knows is an avid triathlete), lower blood pressure, lower total and LDL cholesterol levels, lower C-reactive protein levels (this inflammatory marker is implicated in both heart disease and cognitive dysfunction), and increased insulin sensitivity.

“Since carriers are protected against harmful glucocorticoid effects in the body, we asked whether that held true in the brain,” said Van Rossum. To answer this question, Van Rossum studied two elderly populations. By screening 6,034 community elderly from the long-standing Rotterdam study, she found that the prevalence of dementia in this group was a whopping 86 percent lower among ER22/23EK carriers than non-carriers. When she excluded all subjects who were impaired at baseline and looked forward in time at the incidence of further cases of dementia over the course of the study, she again found carriers were less likely to develop dementia. Among a separate 1,011 people in the Rotterdam Scan Study, ER22/23EK carriers were less likely to have cerebral white matter lesions and brain infarctions than non-carriers. Those carriers who did had progressed less in a second scan 3 years later than non-carriers. Atrophy of the medial temporal lobe, or hippocampus, showed no association with glucocorticoid receptor variant, however. Finally, in a cognitive test battery, carriers had no better memory or overall cognitive function than non-carriers. However, they aced tests of coordination and psychomotor speed—the kind of reaction skills that fast-acting videogames train and that may reflect the integrity of white matter tracts.

Van Rossum does not know whether the effect of the gene variant is direct—that is, by dampening a direct toxic effect of glucocorticoids in neurons—or represents an indirect benefit of the carriers’ favorable metabolic and cardiovascular profile. Certainly, she said, small vessel disease can induce white matter lesions. What’s clear is that carriers express more of a longer form of the receptor that is relatively indolent when it comes to transactivating target genes. That means carriers sense the cortisol and react to it, but some of the downstream tissue consequences are softened. In the brain, this change occurs not so much in the hippocampus, but mostly in white matter. In essence, people carrying the variant may experience as many stressful episodes in their lives as anyone, but their bodies suffer the physical consequences less intensely, Van Rossum said.—Gabrielle Strobel.