Alzheimer Disease Pathology May Manifest Differently in Women


Findings from a cross-sectional exploration have suggested that biological differences between men and women may explain the higher risk for Alzheimer faced by women.

Dr Rachel Buckley

Rachel F. Buckley, PhD, BSc, a postdoctoral research fellow in neurology at Harvard Medical School

Rachel F. Buckley, PhD, BSc

Clinically normal women, predominately in those with higher amyloid beta (Aß) burden, have been shown to exhibit higher regional accumulations of tau than men with higher Aß burden, suggesting that there may be differences in Alzheimer disease pathology trajectory between the sexes.

Previous research has shown that elevated levels of cerebrospinal fluid (CSF) tau in women compared to men as a function of apolipoprotein E (APOE) 4 status and Aß, though the association of sex with tau deposition in individuals who are clinically normal. The study consisted of 2 cross-sectional cohorts including 296 clinically normal adults to determine the differences with positron emission tomography (PET).

“This study is prompted by epidemiological research showing that women have a risk for being diagnosed with Alzheimer disease dementia,” first author Rachel F. Buckley, PhD, BSc, a postdoctoral research fellow in neurology at Harvard Medical School, told NeurologyLive. “Although we find that there is a higher risk for new diagnoses of Alzheimer dementia in women compared with men in the community, it is still unclear whether there is a difference in the level of biological risk for Alzheimer.”

Buckley explained that several post-mortem studies have been suggestive that there are differences in the pathology of Alzheimer, while others using cerebrospinal fluid have found differences in levels of tau, specifically. “Our study would be the first to examine the levels and location of both amyloid and tau in the living brains of healthy older men and women from 2 large independent cohort studies,” she said.

The study took 2 cross-sectional, convenience-sampled cohorts of clinically normal adults who had received tau and Aß PET scans, collected from the Harvard Aging Brain Study and the Alzheimer’s Disease Neuroimaging Initiative. The main outcome measure was the association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, defined as a composite of regions in the temporal lobe.

The investigators, including Reisa A. Sperling, MD, MMSc, the director of the Center for Alzheimer Research and Treatment and professor of neurology at Harvard Medical School, and Buckley, found that in both cohorts, clinically normal women showed higher entorhinal cortical tau than men (meta-analytic estimate: ß male, -0.11 [standard deviation (SD), 0.05]; 95% CI, —0.21 to –0.02; P = .02), which was linked to those with higher Aß burden.

Although, interaction between APOE4 and sex was not associated with regional tau (meta-analytic estimate: β male, APOE4+, −0.15 [SD, 0.09]; 95% CI, —0.32 to 0.01; P = .07).

“What we did find interesting was the magnitude of the effect,” Buckley said. “While we see a sex difference in the level of tau in those at risk of Alzheimer, the difference is relatively subtle. How we interpret this is that while females may show a greater biological susceptibility, this is not the whole story that explains greater female risk for Alzheimer. There are clearly other factors at play which we are yet to tie together [such as] hormones, vascular risk, longevity, etcetera.”

Buckley explained that at this point in the research, it’s still too early to tell if these findings will impact drug development. Although, she noted that if there is this biological difference between men and women, this should be taken into account when conducting clinical trials, as the differing levels of pathology between men and women could produce different levels of therapeutic efficacy with treatments targeting pathology.

“It is important to maintain awareness of signs of Alzheimer disease in both sexes,” she explained. “Our findings do not speak to how regularly checkups should occur, but it is important for family and friends to speak up if they have concerns. Clinicians may already be aware that women are at greater risk of Alzheimer dementia, however, we do not recommend differential clinical strategies based on sex at this stage.”


Buckley RF, Mormino EC, Rabin JS, et al. Sex differences in the association of global amyloid and regional tau deposition measured by positron emission tomography in clinically normal older adults. JAMA Neurol. Published online February 4, 2019. doi:10.1001/jamaneurol.2018.4693.

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