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Quartet of Papers Provide a Fresh Look at Sex Differences in Dementia

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Four new research papers presented at the Alzheimer’s Association International Conference (AAIC), hosted in Los Angeles this week, have highlighted the disparities between the sexes in onset and disease course of Alzheimer’s disease (AD). The new studies include a link between employment and slower memory decline in women, and sex-specific AD risk genes.

The research has exposed gaps in our knowledge of how AD and other forms of dementia affect sub-populations of society, despite women making up two-thirds of AD cases.

Working women keep their memory sharp

Elizabeth Mayeda, an assistant professor at the UCLA Fielding School of Public Health, wanted to explore how female employment status, something which has changed drastically in the last 60 years in the USA alone, affects women’s chance of experiencing memory decline.

Their large cohort (n=6,386) of women were born between 1935 and 1956. Mayeda and her team collected reported data on their employment, marital, and parenthood status between the ages of 16 to 50.

The group are part of the Health and Retirement study, an NIH-funded project that has tested the word recall memory of the cohort every two years since their 50th birthday. 

The study’s findings, which Mayeda presented yesterday (16th of July) suggested that women who were never in waged employment saw their average memory performance decline 61% between the ages of 60 and 70 compared to working married mothers. Single non-employed mothers saw an even faster decline: 83% faster than their married, working peers.

Dr Jana Voigt, Head of Research at charity Alzheimer’s Research UK, commented on the findings in a press release: “These preliminary results suggest that paid employment may play an important role in [preventing] later-life memory decline, but we can’t tell from this study whether the link is causal. The study looked at age-related memory decline, so we don’t know what effect work has on the number of women developing dementia. Unraveling the link between employment and memory decline will help grow our understanding of brain health and the best ways to maintain it”.

Sex differences in tau spread

Neurofibrillary tau is one of the key pathological proteins in AD. Research presented at AAIC by Vanderbilt University Assistant Professor Sepi Shokouhi has shown that tau’s spread through the brain may be markedly different in males and females.

Shokouhi’s team examined the brains of healthy volunteers (178 women and 123 men) and in individuals (60 women and 101 men) with mild cognitive impairment (MCI) which is often considered a precursor to AD. The team used positive emission tomography (PET) scans to assess how networks of tau protein, which fulfils a vital role in the brain besides its pathological function in AD, varied between the groups. Women with MCI had tau networks quite different to the other groups. This group had a denser tau network and higher tau burden. The team’s analysis of healthy female tau networks suggested that their brains had a stronger network of tau protein connections, which Shokouhi thinks might explain the higher tau burden seen in the brains of women with MCI. 

“The differences that we observed indicate the strong possibility that there are sex differences in the structural and functional connections in the brain, which may contribute to women’s increased risk for Alzheimer’s disease,” said Shokouhi. “This study has implications for the possibility of creating sex-specific risk-reduction strategies and preventive interventions.”

Brain energy use gives female AD patients a verbal advantage

In both healthy and AD-affected women, verbal memory outperforms that of men with similar brain health. UC San Diego’s Eric Sundermann decided to investigate this difference by analyzing brain metabolism of glucose, often used as a measure of brain function, to see whether any differences might explain the verbal memory variation.

Improved verbal memory might seem a positive thing, but it often means women with AD are not diagnosed until later in the disease course. Early intervention is key to slowing the progression of AD.

Sundermann’s team looked at a cohort of over 1,000 older adults from the Alzheimer’s Disease Neuroimaging Initiative, a data resource that has been used in hundreds of studies. Their group were tested on their verbal memory, whilst their brains were imaged to assess glucose metabolism and burden of amyloid plaques, another key protein hallmark of AD.

Sundermann’s findings were summed up by Voigt, “Despite having similar levels of toxic protein build-up to men, women’s brains showed higher brain activity and better verbal memory. These new findings suggest that women’s brains may be able to compensate for the early damage of Alzheimer’s disease.”

Sex-specific genes for AD

A final study looked at the genetics of AD, a topic that has produced much interest among the research community. The University of Miami’s Brian Kunkle, in collaboration with geneticists from other institutions, looked at the exome of over 5,500 AD patients and nearly 5,000 controls from the Alzheimer’s Disease Sequencing Project, which aims to understand the genomic variants underlying AD risk using genome sequencing.

The project identified 11 genes with sex-specific associations, including the immune gene CD1E, which was tied to risk in women, and the endocytosis gene MCOLN3, which was related to risk in men.

These four studies are part of a new body of research that can help make treatments for AD work better for individual patients. Sundermann sums this approach up: “As the field moves towards using brain changes and biomarkers to measure Alzheimer’s risk, this research is important in understanding how these changes differ by sex. By doing so we can develop more personalized dementia risk measurements and interventions.”