Higher Tau May Explain Greater Frequency of Alzheimer's in Women

Batya Swift Yasgur, MA, LSW

February 21, 2019

Women are at higher risk of the tau-related neurologic changes associated with Alzheimer's disease (AD), possibly explaining why more women than men develop the disorder, new research shows.

Investigators studied close to 300 clinically normal individuals between the ages of 55 and 94 years, with an average age of 74, drawn from 2 studies —the Harvard Aging Brain Study (HABS) and the Alzheimer's Disease Neuroimaging Initiative. Subjects were required to have received tau and beta-amyloid (Aβ) positron emission tomography (PET) scans.

Women with higher amyloid burden displayed more tau pathology, specifically in the entorhinal cortex (EC) — an area strongly implicated in early AD changes — as compared with men who had similar amyloid burden.

"Our findings suggest that women show higher levels of tau in neurofibrillary tangles, as estimated with tau PET imaging, particularly apparent in women with elevated levels of amyloid at high risk for memory decline," senior author Reisa Sperling, MD, professor of neurology at Harvard Medical School and director of the Center for Alzheimer Research and Treatment at Brigham and Women's Hospital in Boston, Massachusetts, told Medscape Medical News.

"This sex difference was most apparent in the entorhinal cortex, where tangles are accumulating as we age, and then begin to spread throughout the cortex as memory impairment becomes manifest," she said.

The study was published online February 4 in JAMA Neurology.

Tau's Role Needs More Investigation

"Mounting evidence suggests that women are at heightened risk for developing AD pathophysiology," the authors write. However, "sex differences in Aβ alone have not been reported in older adults."

"Our previous work has suggested that women and men have similar levels of amyloid plaque, assessed with amyloid PET imaging, in the presymptomatic stages of AD," Sperling said.

Women tend to demonstrate a "more rapid cognitive decline, for a given amount of amyloid," Sperling noted, stating that the study was designed to investigate one of the potential mechanisms for this difference — levels of tau in neurofibrillary tangles.

Little attention has been paid to elucidating sex differences in regional tau deposition in the context of Aβ burden at APOE ε4, the authors point out.

They therefore set out to examine "the influence of sex to modify the well-characterized cross-sectional association between regional tau PET and global Aβ PET."

Additionally, they sought to investigate the degree to which sex and APOE ε4 might interact to influence regional tau PET.

To investigate the question, the researchers used data from two cross-sectional convenience samples (the HABS study and the ADNI database) of participants who received both tau and Aβ PET scans between January 2016 and February 2018.

Both sets of participants were clinically normal at the time of their first tau scan.

Of the 193 participants in HABS (global clinical dementia rating score, 0; mean [SD] age 74.3 [8.0] years), 118 (61%) were female.

The ADNI cohort consisted of 103 individuals (global clinical dementia rating score, 0; mean age, 75.6 [6.3] years), of whom 55 (53%) were female.

Both studies used the [18F]flortaucipir tau PET tracer. Additionally, HABS patients underwent  [11C]PiB PET scanning, while ADNI patients underwent florbetapir PET scanning.

Greater Susceptibility to Amyloid?

HABS individuals performed significantly better on logical memory (delayed recall), compared to their ADNI counterparts (t = −5.56, P < .001) but otherwise did not differ by age, sex, Aβ+ status, or APOE ε4 status. 

In both the HABS and the ADNI cohorts, women with higher Aβ burden exhibited higher EC tau, compared to men with similar Aβ (β = −0.17; 95% confidence interval [CI], −0.32 to −0.01; P = .04 and β = −0.23; 95% CI, −0.42 to −0.04, respectively).

In the HABS group, however, the findings became attenuated after using "robust" regression analysis, in contrast to the ADNI group, in which the findings remained significant.

Sex and APOE did not interact to influence tau retention in the HABS group, while in the ADNI group, the association between APOE ε4 and tau retention was stronger among women than among men.

The researchers found no sex differences in the precuneus region of interest (ROI) in either cohort.

However, women in both cohorts showed elevated signal in the superior parietal ROI compared with men, after adjusting for age.

In a meta-analytic model comprising participants in both cohorts who had a higher Aβ burden, women exhibited higher EC tau, as compared to men (meta-analytic estimate: β [male] = −0.11 [0.05]; 95% CI, −0.21 to −0.02; P = .02).

The interactive effect of sex and APOE on EC tau was not significant; however, the interaction between sex and Aβ on EC tau was significant: β (male, Aβ+) = −0.19 (0.06) [95%CI, −0.32 to −0.07], P = .002.

An exploratory examination of a 3-way interaction between sex, APOE, and Aβ found no significant interaction.

"We don't yet know why women might have greater levels of tau overall, but this study suggests that women might be more susceptible to the effects of amyloid, with greater neurodegeneration and more tangle pathology," Sperling commented.

Important Puzzle Piece

Commenting on the study for Medscape Medical News, Keith Fargo, PhD, Director of Scientific Programs & Outreach at the Alzheimer's Association, who was not involved with the study, called it a "very good" and "important" study conducted by a "world class group of researchers."

He described women as being at the "epicenter of AD," noting that the "traditional wisdom has been that women outlive men and since age is the greatest risk factor [for AD], more women are affected than men."

However, "more recent research is putting that idea to the test, including this study," he noted.

The findings "get us a step closer to figuring out the question of why more women than men are affected by AD, and contributes to closing the gap," he said.

Fargo cautioned that "no single study will be the golden study that answers all questions, and this study isn't the be-all and end-all, but it is definitely an important piece in the puzzle."

He noted that the Alzheimer's Association has a grant program, the Sex and Gender in Alzheimer's (SAGA), which is "designed specifically for researchers trying to answer the question not only of whether sex and gender are associated with increased risk of AD, but also how and why."

Answering those questions will "provide important clues to how to attack AD so that in the future, maybe we can design better treatment regimens for women and men, rather than one-size-fits-all approaches," Fargo said.

Study coauthor Sperling agreed: "This study suggests one mechanism [for women's increased risk] that may help us develop personalized medicine to prevent cognitive decline in the future," she said.

The study was supported by the National Institutes of Health, the Center for Functional Neuroimaging Technologies, and the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. Other sources of funding are listed on the original paper.

Sperling reports serving as a paid consultant for AbbVie, Biogen, Bracket, Genentech, Lundbeck, Roche, and Sanofi; has served as a coinvestigator for Avid Radiopharmaceuticals, Eli Lilly, and Janssen Alzheimer Immunotherapy clinical trials; has spoken at symposia sponsored by Eli Lilly, Biogen, and Janssen Pharmaceuticals; receives research support from Janssen Pharmaceuticals and Eli Lilly (unrelated to this study), and also receives research support from Fidelity Biosciences, Harvard NeuroDiscovery Center, and the Alzheimer's Association. The other authors' disclosures are listed on the original paper. Fargo has disclosed no relevant financial relationships.

JAMA Neurology. Published online February 4, 2019. Abstract

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