Gout’s Protective Effect Against AD May Be Linked to Purines

Well over 100 years ago, psychiatrist Carl Lange suggested that depression, much like gout, was linked to high levels of uric acid in the blood. He proposed that substances that could dissolve uric acid crystals, such as lithium, could be an effective treatment for depressed individuals.

This notion of “brain gout” fell quickly out of favor, but perhaps Lange was simply ahead of his time, for as the years have passed, evidence for a connection between uric acid and mental health has been steadily growing.

The latest association comes courtesy of a study appearing in the Annals of Rheumatic Diseases, which provides the first population-based evidence that gout can reduce the risk of Alzheimer’s disease (AD).

A team led by Hyon Choi, M.D., director of clinical epidemiology at Massachusetts General Hospital, monitored nearly 60,000 adults who developed gout and 240,000 matched controls using data from a United Kingdom medical records database.

They found that the people with a history of gout had a 24 percent lower risk of developing AD. As a comparison, people with osteoarthritis did not show any differences in AD risk, indicating that the protective effect is likely specific to gout and not a general feature of arthritis or inflammation.

The authors believe the results support a neuroprotective role for uric acid, which is a natural antioxidant.

While it’s a biologically plausible notion, and a concept worth pursuing, it’s not so cut and dry, noted Carlos Zarate, M.D., chief of the Experimental Therapeutics and Pathophysiology Branch at the National Institute of Mental Health.

“It’s not like adding motor oil to a car, in that more uric acid will make the brain run better,” he told Psychiatric News. As a prime example, multiple studies have shown that people with bipolar disorder have higher levels of uric acid than normal.

“Uric acid and related purines interact with a wide range of circuits and synapses in the brain,” he said. “But different areas require different amounts at different times. So in psychiatry at least, therapy with purines will require finely tuned modulation, which can be difficult to pull off.”

He noted that several controlled clinical studies have demonstrated that the common gout medication allopurinol can improve both depression and mania, though it can cause hypersensitivity reactions in patients, which has limited its widespread use. (Some clinicians have been prescribing allopurinol for patients who have been resistant to other drugs.)

Zarate’s group has been active in this area, using imaging approaches like positron emission tomography or functional magnetic resonance imaging to identify which receptors turn on or off in response to different conditions. He hopes that the studies may help identify specific purine receptors that can be drug targets rather than the metabolites themselves.

Specificity is important, as the purinergic system has receptors located throughout the body, so any drugs targeting this system could have far-reaching effects. In the case of the new study from Choi and colleagues, the authors did acknowledge that since they focused specifically on AD risk, the protection offered by uric acid might be partially offset by the cardiovascular risks, which include vascular dementia. However, in older people with low cardiovascular risks, some sort of uric acid supplementation might be a viable preventive strategy.

Multiple risks might also mean multiple rewards, however. “So frequently, we see mental disorders go hand in hand with heart problems or diabetes, and the diverse targets of purinergic molecules may explain part of that,” Zarate said (see story on page 17). “That raises the possibility that we can find novel therapies that tackle multiple aspects of a disorder.”

At the least, a study like this one connecting gout and AD should make researchers appreciate that every disease has systemic consequences; many consequences just haven’t been clarified yet.

Choi’s study was supported by grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. ■