Almost two-thirds of the people diagnosed with Alzheimer's disease (AD) are women. The reasons why women are so disproportionately affected by this chronic neuro-degenerative disease are the focus of a recent study that suggests some ways interventions could reduce degenerative effects even before the disease is clinically apparent.

Hormonal changes, particularly the decrease in estrogen, that occur during and after menopause, were suspected as being behind women's vulnerability. The researchers wanted to see if the decrease in estrogen changes the way the brain uses glucose, its primary and most efficient source of energy during the perimenopause. This change in the metabolic state of the brain tissue causes a cascade of effects that may increase the risk of Alzheimer disease later on.

The endocrine changes of menopause accelerate the chronologic aging of the female brain, and this aging precedes the emergence of clinical signs of Alzheimer's disease.

Brain tissue contains numerous estrogen receptors, and many of the symptoms of perimenopause — such as temperature regulation, sleep regulation, depression and decease in cognitive skills — are neurologic in nature. So researchers examined ways that estrogen deprivation might affect the central nervous system.

They used brain imaging to look at glucose metabolism and the amyloid beta deposits (shown in red in the image of a mouse brain above), a hallmark of Alzheimer's disease, in 42 women who were between 40 and 60 years old. All were cognitively normal and were in pre-, peri- and post-menopause. They found that the women had reduced glucose metabolism in the frontal cortex of their brains and increased uptake of amyloid compared to age-matched men.

The biomarkers for AD — amyloid and tau proteins — were most pronounced in post-menopausal women, moderate in perimenopausal women and lowest in premenopausal women.

The menopausal and perimenopausal women also showed lower levels of the metabolic enzyme, mitochondrial cytochrome oxidase.

When glucose metabolism is disrupted, the brain is forced to change to a starvation mode of obtaining its energy, ketone metabolism. In order to produce ketones, the brain must metabolically destroy white matter — the brain tissue itself. This leads to the loss of important neural tissue and the increased risk of cognitive decline.

The endocrine changes of menopause accelerate the chronologic aging of the female brain, and this aging precedes the emergence of clinical signs of AD. This preclinical period may offer a potential for early intervention, the researchers suggest.

“...[T]here may be a critical window of opportunity, when women are in their 40s and 50s to detect metabolic signs of higher Alzheimer's risk and apply strategies to reduce that risk,” lead author, Lisa Mosconi, said in a statement. One possibility is the use of estrogen-based therapies to prevent the changes in the energy metabolism of brain tissue during perimenopause. “Our work indicates that women may need antioxidants to protect their brain activity and [structure] in combination with strategies to maintain estrogen levels.”

More studies on more diverse demographic and medical populations are needed to develop appropriate screening and intervention. Though limited by its small size, this research suggests the possibility of intervening long before AD symptoms are apparent.

The study is published in PLOS One.