Why Females are Twice as Prone to Alzheimer's as Males

How does sex causes these prevalence differences?

Whether you’ve heard this statistic before, or are just tuning in: Alzheimer’s Disease (AD) affects twice as many women as it does men. According to the Alzheimer’s Association, the lifetime risk for AD at age 45 is 1 in 10 for men, and 1 in 5 for women. In this week’s article, I’ll go over the postulated reasons for these differences and how researchers are addressing them in their studies (including in my lab).

A major aspect of my lab’s current study is addressing the synaptic changes in genetically altered mice between males and females. It got me thinking about where these differences stem from, so I wanted to share them.

XX Genes Susceptibility

Humans typically have 46 chromosomes, two of which are sex chromosomes: XY in males and XX in females. When an individual has two X chromosomes, “X-inactivation” occurs, where all but one of the X chromosomes are silenced. This is healthy, acting as a countermeasure to the high X chromosome content, as it prevents overexpression. However, approximately 15% of genes escape this X inactivation mechanism, leading to double the X expression, which can lead to a variety of consequences.

X-linked genes are highly expressed in brain tissue and are believed to be responsible for the amount of white matter and surface area of the brain. On top of that, individuals with additions or deletions of the X or Y chromosome develop changes in brain tissue (Klinefelter syndrome: XXY, Turner Syndrome: X, and XYY syndrome). For example, an additional X-chromosome results in higher gray matter (neuron cell bodies and some axons) volume, and the subtraction of an X-chromosome results in reduced gray matter volume. Individuals with these syndromes are also more susceptible to cognitive and motor impairments, as well as neurological and psychiatric disorders.

The X chromosome is closely tied to brain tissue expression and cognitive function. When certain genes get overexpressed or underexpressed, several biological changes occur that specifically impact the brain. Women’s increased susceptibility to this type of X-linked activation suggests a correlation to neurodegenerative diseases, including Alzheimer’s Disease.

Fluctuating Hormone Levels

The most commonly studied sex-specific hormones are estrogen and progesterone for females, and testosterone for males (although all three hormones are present in both sexes). Sex hormone-induced changes have been linked to changes in seizure susceptibility, movement disorder symptoms, memory performance, neuroplasticity, and more.

Hormonal levels undergo drastic shifts during menstrual cycles, pregnancy, and menopause. These events directly lead to altered brain function and changes in gray matter volume. For example, within the late luteal phase of the menstrual cycle, neuronal connectivity and emotional perception are reduced. Across the different stages of pregnancy, significant changes were seen in white and gray matter regions that are directly correlated with maternal attachment. During menopause, many of the symptoms (such as hot flashes, night sweats, and sleep disruptions) are mediated by key brain regions. Premature loss of ovarian function has even been linked to memory loss, as well as higher dementia risk following menopause.

Women experience several events throughout their lives that lead to hormonal and brain volume changes. These constant fluctuations suggest a strong link to the development of Alzheimer’s Disease.

Alzheimer’s Asymmetry

Studies suggest that females who carry APOEε4, a genetic variation strongly associated with genetic risk for non-familial AD, have an increased risk of developing AD compared to males.

Researchers also believe female brains are more susceptible to AD biomarkers (a-beta and tau), with more cognitive decline and atrophy of the hippocampus compared to males with the same level of AD biomarkers. Females were shown to have greater global pathology of tau tangles, the leading biomarker in AD (read more about them here).

On a cellular level, female mice were found to have lower microglia (the immune cells of the brain) density levels in important brain regions such as the hippocampus. Improper microglia activation may promote tau accumulation, particularly in females. Tau accumulation has even been linked to earlier menopause age onset.

Ongoing Research & Final Thoughts

To prevent and cure neurodegenerative diseases, researchers must deepen their understanding of sex differences. Alzheimer’s Disease (2F:1M) and Multiple Sclerosis (3F:1M) have the opposite prevalence pattern of Parkinson’s Disease (1F:1.5M).

Many labs around the world are doing their part, piece by piece, to unravel this complex puzzle. I could write hundreds of blogs on all the different angles scientists are taking to address this topic, so have faith that the industry is working hard. My lab’s current project aims to identify sex differences in neuroplasticity, intertwined with the role of palmitoylation, a complex cellular process (read about our work here).

Understanding the sex differences among AD and other neurodegenerative diseases may be the key to the puzzle. The sex differences in prevalence rates are too hard to ignore. I will continue to shed light on this subject in future posts, as well as many other key neuroscience topics.

Sources:

https://www.science.org/doi/10.1126/sciadv.adt9243

https://www.alz.org/