For reasons that are not entirely clear, Alzheimer’s disease, the most common form of dementia, is twice as common in women as in men. A possible explanation was presented in an article published in the journal Molecular Psychiatry in January. In the study, an international group of researchers that included several Brazilians analyzed the cognitive performance of 125 men and women from Brazil and the USA, as well as compounds found in their blood and the fluid that surrounds the brain and spinal cord. The results suggested two molecules that are likely a factor behind the uneven rates of the condition: carnitine and one of its modified forms, acetyl-L-carnitine (ALC), levels of which are lower in the blood of people with dementia than in healthy people.
Carnitine, formed of a combination of two amino acids (basic protein components), is obtained by eating meat, fish, and dairy products, as well as being produced in smaller quantities by the body. Most of it is stored in the muscles, while a small proportion that circulates in the blood—free carnitine—serves as a reserve.
Some carnitine is converted to ALC inside cells and performs several important functions. One is to transport a specific type of fat—long-chain fatty acids like omega-3, found in fish, and omega-9, found in olive oil—into the mitochondria (the powerhouse of the cell), where it is converted into cellular fuel. Another function of ALC is that it regulates the activity of genes that encode proteins associated with the formation of connections (synapses) between neurons, especially in the hippocampus (the region of the brain linked to memory formation, which is compromised in people with Alzheimer’s). It is also part of the composition of acetylcholine, a chemical messenger (neurotransmitter) that is fundamental for memory and learning, and it helps mitochondria get rid of toxic compounds.
Measurements of ALC and carnitine levels in the participants’ blood showed that both fall as cognitive decline progresses. The average ALC concentration was 9.5 micromoles per liter of blood (µmol/L) in men and women with no cognitive loss, 8.4 µmol/L in people with mild cognitive decline, and 7.9 µmol/L in people diagnosed with Alzheimer’s.
Carnitine, which is recycled in the mitochondria and returns to the blood after transforming fat into energy, behaved differently. Among women, the average level fell from 39.3 µmol/L in the healthy to 36 µmol/L in those with mild cognitive decline and 31.3 µmol/L in those with Alzheimer’s. Men had lower carnitine levels across the board, but there was no difference between the levels measured in healthy individuals and those with cognitive impairment. According to the authors, this finding suggests that women at risk of developing dementia present a more advanced stage of mitochondrial dysfunction than men in the same situation.
Hormonal changes after menopause can disrupt the metabolism and affect the brain
The results found for the 75 Brazilians were similar to those observed among the 50 Americans participating in the study, led by neuroscientist Carla Nasca of New York University, USA, and Brazilian neuroscientists Mychael Lourenço of the Federal University of Rio de Janeiro (UFRJ) and Fernanda De Felice of UFRJ, the D’Or Institute for Research and Education (IDOR), and Queen’s University, Canada.
“These changes in free carnitine and ALC may reflect changes in mitochondrial metabolism throughout the body,” says De Felice, who was first convinced to investigate the role of these molecules in Alzheimer’s by neuroscientist Bruce McEwen (1938–2020), who was studying their effect on depression at Rockefeller University.
At the time, tests on rodents and monkeys showed that changes in mitochondrial function could be associated with the damage observed in Alzheimer’s disease. In parallel, previous studies by Nasca’s team indicated that increasing ALC levels improved the performance of mice in cognitive tests by activating genes that promoted the formation of new synapses. Rodents with decreased ALC levels in their brains and blood performed worse on the tests. “The role of ALC in epigenetic changes [which change gene expression but do not alter DNA] is of special interest to synapse health,” says Lourenço.
“This evidence could guide studies on metabolic changes in women, such as those that occur after menopause,” says biomedical scientist Ricardo Lima-Filho, coauthor of the Molecular Psychiatry article. The women in both groups were 55 or older, and all but one had already gone through menopause. “There has been little research into whether certain pathologies affect women differently than men. There are several hypotheses about how metabolic changes may be one of the factors behind these differences in Alzheimer’s,” adds the researcher, who is doing a postdoctorate at UFRJ under Lourenço’s supervision.
The group suspects that hormonal changes after menopause lead to dysregulated fat metabolism and carnitine and ALC availability, possibly impacting the brain. “We want to explore the mechanism behind this by doing animal experiments,” says Lourenço.
Paulo Bertolucci, a neurologist from the Federal University of São Paulo (UNIFESP), believes that a better understanding of how metabolism impacts the disease could pave the way for new prevention and treatment strategies. “These compounds act in different ways, having a greater or lesser specific effect on Alzheimer’s. The most viable option is therefore not to think about ALC supplements, but to encourage a diet that provides these nutrients naturally,” he explains.
The story above was published with the title “Alzheimer’s and women” in issue in issue 349 of march/2025.
Scientific article
BIGIO, B. et al. Sex differences in mitochondrial free-carnitine levels in subjects at-risk and with Alzheimer’s disease in two independent study cohorts. Molecular Psychiatry. Jan. 7, 2025.
