Do Metabolic Changes Impact Cognition Post-Menopause?

Forgetfulness and cognitive decline after menopause might be explained by changes in the metabolic cycle, a researcher reported.

In both peri- and postmenopausal women, markers of efficient mitochondrial function — including higher baseline respiratory rate and maximal respiratory rate — were associated with better performance on verbal learning and memory tests, according to Rachel Schroeder, BS, of the University of Illinois in Chicago.

But some methods of energy production considered inefficient, such as non-mitochondrial oxygen consumption and basal glycolytic rate, were also associated with good cognitive function, Schroeder reported at the North American Menopause Society 2020 virtual meeting.

Schroeder and colleagues also found that higher mitochondrial function in peri- and postmenopausal women was consistently associated with dependence on executive, prefrontal cognitive strategies.

Schroeder told MedPage Today that this research provides further evidence that declining estrogen levels may affect the ability of mitochondria to perform efficient forms of energy production. But what was surprising was that inefficient forms of energy production were still associated with higher measures of verbal learning and memory, she noted.

“We saw that some energy markers that are typically seen as ‘bad’ in animal models were actually related to good cognitive performance,” Schroeder said. She added that this association might be a compensatory shift in the short-term, but “potentially in the long-term, these types of energy production are still harmful.”

Previous research has hypothesized that declining estrogen levels during the transition to menopause could reduce efficiency of energy production. When estrogen levels are high, glucose is converted to energy via glycolysis. But when these hormones decrease during and after the transition to menopause, cells shift to ketogenesis and other inefficient forms of production, which in turn may affect memory and verbal learning abilities.

Paul Newhouse, MD, director of the center for cognitive medicine at Vanderbilt University in Nashville, told MedPage Today that it was interesting to see these biomarkers examined in humans, versus cellular and animal models, where most of the previous research exists.

Newhouse, who has conducted research on cognitive decline in menopausal women, added that understanding these blood-based markers might help predict risks of neurologic diseases later in life.

“What’s exciting about this work is that these additional markers could also be related to early changes that might indicate risk of Alzheimer’s,” said Newhouse, who was not involved in the study.

Schroeder and colleagues analyzed data from the MsBrain study, which investigates brain health in a cohort of peri- and postmenopausal women. The researchers assessed mitochondrial function by measuring baseline respiratory rate, maximal respiratory capacity, basal glycolytic rate, proton leak, mitochondrial oxidation production, and ATP-linked respiration in circulating platelets.

Participants (n=110, average age 58, 77.3% white) then completed a series of cognitive tests to correlate to measure against the biomarkers, including assessments for verbal learning, memory and verbal recall, global cognition, spatial reasoning, and working memory. The researchers used the California Verbal Learning Test-2 (CVLT) to assess verbal learning, memory, and organizational strategies, card rotations to test spatial reasoning, a letter-number sequencing (LNS) subtest for working memory, and the Montreal Cognitive Assessment (MOCA) for global cognition. The authors controlled for age, race, education, and BMI.

Women who had higher levels of non-mitochondrial oxygen consumption, baseline respiratory rate, maximal respiratory capacity, basal glycolytic rate, proton leak, ATP-linked respiration in circulating platelets, and mitochondrial oxidant production scored better on verbal learning (total CVLT: β=0.14, standard error [SE]=0.05, P<0.01) and memory (MOCA: β=0.03, SE=0.01, P<0.05) as well as on organizational strategies to enhance learning:

  • CVLT total cluster weighted: β=0.17, SE=0.18, P<0.05
  • CVLT short delay: β=0.04, SE=0.02, P<0.05
  • LNS: β=0.04, SE=0.02, P<0.05
  • Card rotations: β=0.44, SE=0.18, P<0.05

None of the participants had hormone therapy, and all had both their ovaries and uteruses intact.

Schroeder’s group concluded that in peri- and postmenopausal women, markers of mitochondrial function were associated with improved cognition.

She said her group has plans to conduct a longer-term follow-up study, which may answer questions about the relationship between inefficient forms of energy production and cognitive function.

  • Amanda D’Ambrosio is a reporter on MedPage Today’s enterprise & investigative team. She covers obstetrics-gynecology and other clinical news, and writes features about the U.S. healthcare system. Follow

Disclosures

The study was supported by the National Institutes of Health and the National Science Foundation Graduate Research Fellowship Program.

Schroeder and co-authors disclosed no relevant relationships with industry.

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