10 August 2012. After recent reinforcement of the amyloid hypothesis (see ARF related news story) paled in the light of yet another disappointing amyloid-based therapy (see ARF related news story; ARF related news story), some Alzheimer’s disease researchers may find solace in a promising Phase 2 clinical trial that seems entirely unrelated to Aβ. In the August 6 Archives of Neurology, researchers report that 20 weeks of treatment with growth hormone-releasing hormone (GHRH) improved some measures of cognition in healthy seniors and in people with mild cognitive impairment (MCI). Though the sample size was small and effects modest, experts say the findings show proof of concept and warrant follow-up with a larger, longer trial. First author Laura Baker at the University of Washington School of Medicine and Veterans Affairs Puget Sound Health Care System, Seattle, led the work with senior author Michael Vitiello of UW.
Hints that GHRH might help the brain came fortuitously in a previous trial that Vitiello and colleagues designed to test the hormone’s effects on sleep, measuring brain function as a secondary outcome. “Lo and behold, it did not affect sleep at all, but it did improve cognition,” Baker told Alzforum. In that 2006 study of 89 older adults, six months of daily GHRH treatment provided a brain boost. The strongest effects emerged in tests involving executive control and in subjects with lower baseline Mini-Mental State Examination (MMSE) cognitive scores (Vitiello et al., 2006).
In follow-up, Baker and colleagues conducted the Phase 2 trial to see if GHRH could slow mental decline in people already somewhat impaired. They studied 137 older adults ranging in age from 55 to 87 years (mean age 68); 61 had MCI. Participants received subcutaneous injections of tesamorelin (a human GHRH analogue) or placebo once a day for 20 weeks. Three times during the study—at baseline, 10 weeks, and 20 weeks—and 10 weeks after treatment ended, they gave blood samples and took a battery of cognitive tests. GHRH seemed to improve executive function. Relative to placebo-treated controls, healthy elderly received a 200 percent boost, while MCI patients deteriorated about half as much, over the 20-week treatment. The numbers reflect a composite score based on computerized tests of task switching, visual working memory, word fluency, and Stroop color-word interference reaction time. Among other cognitive domains analyzed, verbal memory showed a trend toward improvement—though not as robust as executive function. Visual memory did not change with GHRH treatment.
Since hormones turn on a slew of signaling pathways, it is tricky to pinpoint which of GHRH’s many effects underlie the cognitive gains. Normally, GHRH signals the pituitary to release growth hormone (GH), which triggers secretion of insulin-like growth factor 1 (IGF-1) from the liver. IGF-1 then goes back to suppress the pituitary’s release of GH—in essence, enhancing GH production but shutting down the system when it makes too much. “This is different from other approaches where you take GH directly, with no inherent autoregulation,” Baker said. Moreover, GH supplements confer a sustained boost, whereas GHRH stimulates the pituitary to release small amounts of GH intermittently. “We get pulses of GH activity at night, then more during the day. Our bodies are programmed to respond this way,” Baker said.
In the present study, serum IGF-1 levels rose 117 percent in treated participants (while staying within the normal physiological range) during the 20-week intervention and returned to baseline 10 weeks later. In addition, GHRH increased fasting insulin levels by 35 percent in subjects with MCI, and reduced body fat by 7.4 percent in all treated participants. However, when the researchers adjusted their model to examine each of these GHRH-related changes, serum IGF-1 was the only factor that could account for the improved cognition in the treatment group. “This tells us that change in IGF-1 is somehow related to change in cognition,” Baker said. “But it could be indirect.”
That is likely the case, said Craig Atwood of the University of Wisconsin, Madison. He cited two lines of evidence, the first being a huge literature linking increased IGF-1 signaling with shorter lifespan and accelerated development of age-related disease. In contrast, the present study found that increasing IGF-1 in the elderly improved cognition. “That goes against two decades of work indicating the opposite, which suggests to me that the GHRH is probably not working through IGF-1,” Atwood told Alzforum. However, Baker noted, much of the research on IGF-1 effects in aging was done in animals, not people. Human studies have found unusually low levels of serum IGF-1 in AD patients (Alvarez et al., 2007; Luppi et al., 2009), and have linked lower IGF-1 with poorer cognition in seniors (Rollero et al., 1998).
However, other trial data discount IGF-1 as a critical player. In a 12-month trial of 416 seniors with mild to moderate AD, a Merck compound that enhanced IGF-1 secretion (MK-677) showed no clinical benefit (ARF related news story on Sevigny et al., 2008). “That was a well-run study, and the drug did what we expected—eliciting a 73 percent increase in blood IGF-1 at month 12. But the results were completely negative,” said Jeff Sevigny, who led the trial. Sevigny now works at Biogen Idec in Cambridge, Massachusetts.
Baker thinks timing could explain the Merck trial data. “Once you’ve got AD dementia, it may be too late (to intervene),” she said. Baker and colleagues have applied for National Institute on Aging (NIA) funding for a 12-month trial of GHRH in amnestic MCI patients and cognitively normal seniors with first-degree family history of dementia. They hope to enroll 160 participants, about half with aMCI.
Christian Hölscher of the University of Ulster in Coleraine, U.K., found the present data “very encouraging,” and said, “it is definitely worth continuing this line of research.” However, one issue the study did not address is how well GHRH gets into the brain, he said. “If you tailor the compound to get better brain uptake, you might see a bigger effect.”
Whereas the current study focuses on growth hormone and insulin-like growth factor 1, Hölscher and others are turning their attention toward agents that directly boost insulin. Buoyed by recent work demonstrating insulin signaling defects in the brains of AD patients (Talbot et al., 2012; see also Bomfim et al., 2012 and ARF related conference story), the scientists are exploring whether AD could be treated with glucagon-like peptide 1 (GLP-1) analogues—drugs already approved for type 2 diabetes. These compounds reach the brain and show activity there, giving them a leg up on nerve growth factor (NGF) and other growth factors with poor brain penetrance that are being pursued as AD targets, Hölscher said. Plus, GLP-1 receptor analogues have a proven safety record in diabetes patients. Likewise, the GHRH in the current study has been used safely for up to three years to treat lipodystrophy in HIV patients, Baker said.—Esther Landhuis.
Baker LD, Barsness SM, Borson S, Merriam GR, Friedman SD, Craft S, Vitiello MV. Effects of Growth Hormone-Releasing Hormone on Cognitive Function in Adults with Mild Cognitive Impairment and Healthy Older Adults. Arch Neurol. 6 Aug 2012. Abstract