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Study Provides Robust Evidence of Sex Differences with Alzheimer’s Gene

Summary: According to researchers, Alzheimer’s disease may be more prevalent in women, not simply because they live longer on average, but due to the APOE E4 gene. Researchers found the APOE association was greater for women in the Tau pathway than in men. However, there was no difference between APOE expression in the amyloid pathway in women compared to men.

Source: Vanderbilt University.

The APOE gene, the strongest genetic risk factor for Alzheimer’s disease, may play a more prominent role in disease development among women than men, according to new research from the Vanderbilt Memory and Alzheimer’s Center.

The research confirmed recent studies that carrying the APOE ε4 allele has a greater association with Alzheimer’s disease among women compared to men, and went one step further by evaluating its association with amyloid and tau levels.

The study published May 7 in JAMA Neurology adds to mounting evidence that the higher prevalence of Alzheimer’s disease among women may not simply be a consequence of longer longevity. Almost two-thirds of Americans with Alzheimer’s are women. The research, based on a meta-analysis of both cerebral spinal fluid (CSF) samples from study volunteers from four datasets and autopsy findings from six datasets of Alzheimer-diseased brains, is the most robust evidence to date that the APOE gene may play a greater role in women than men in developing Alzheimer’s pathology, said Timothy J. Hohman, PhD, assistant professor of Neurology and the study’s lead author.

“In Alzheimer’s disease, we have not done enough to evaluate whether or not sex is a contributing factor to the neuropathology,” Hohman said. “We haven’t fully evaluated sex as a biological variable. But there is good reason to expect in older adulthood that there would be hormonal differences between the sexes that could impact disease.”

The study looked at whether APOE in men and women was primarily associated with the amyloid pathway — the proteins that form plaques in the brain — or with the tau pathway — the proteins that form tangles in the brain.

The association with the amyloid pathway was the same in men and women. However, the APOE association was much greater for women with the tau pathway. This is opposite of what researchers expected because of APOE’s established role in amyloid processing.

“The prevailing hypothesis of disease in Alzheimer’s is that amyloid comes online first and downstream is where we see tau changes that ultimately drive neurodegenerative changes,” Hohman said.

Further analysis revealed that the sex difference with tau levels was present in amyloid-positive individuals — those with higher levels of amyloid plaque as determined by their CSF amyloid levels. The research suggests that APOE may modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis.

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The study looked at whether APOE in men and women was primarily associated with the amyloid pathway — the proteins that form plaques in the brain — or with the tau pathway — the proteins that form tangles in the brain.NeuroscienceNews.com image is in the public domain.

The greater association with tau occurred in CSF samples, but not with the autopsy datasets.

The reason for the contradiction between CSF samples and autopsy datasets could be because Braak staging — the method for quantifying the degree of tau tangle pathology at autopsy — measures a different aspect of tau pathology than what is measured in CSF.

“The way Braak staging works is you are actually looking at where in the cortex you see tangles at autopsy,” Hohman explained. “So it is not a measure of how many tangles are there. It is a measure of where those tangles are located.


Video: The APOE gene, the strongest genetic risk factor for Alzheimer’s disease, may play a more prominent role in disease development among women than men, according to new research from the Vanderbilt Memory and Alzheimer’s Center.

Another possibility is that CSF tau may be an indicator of a more general neurodegenerative process that is not specific to tangle pathology.

“This study is at least moving toward bringing sex as a biological variable into our analyses and thinking about sex differences. Do we see differences in disease that could tell us something about the biology of the disease and could help both sexes in terms of coming up with treatment approaches? I think that the right treatment approach for a female above the age of 65 may end up being different than what it is for a male. Really the only way to find out is to look.”

About this neuroscience research article

Funding: The research was supported by the National Institutes of Health, the Alzheimer’s Disease Genetics Consortium (funded by the National Institute on Aging) and the Vanderbilt Memory and Alzheimer’s Center.

Source: Craig Boerner – Vanderbilt University
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Video Source: Video credited to Vanderbilt University.
Original Research: Abstract for “Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau” by Timothy J. Hohman, PhD; Logan Dumitrescu, PhD; Lisa L. Barnes, PhD; Madhav Thambisetty, MD, PhD; Gary Beecham, PhD; Brian Kunkle, PhD, MPH; Katherine A. Gifford, PsyD; William S. Bush, PhD; Lori B. Chibnik, PhD; Shubhabrata Mukherjee, PhD; Philip L. De Jager, MD, PhD; Walter Kukull, PhD; Paul K. Crane, MD; Susan M. Resnick, PhD; C. Dirk Keene, MD, PhD; Thomas J. Montine, MD, PhD; Gerard D. Schellenberg, PhD; Jonathan L. Haines, PhD; Henrik Zetterberg, MD, PhD; Kaj Blennow, MD, PhD; Eric B. Larson, MD, MPH; Sterling C. Johnson, PhD; Marilyn Albert, PhD; David A. Bennett, MD; Julie A. Schneider, MD; Angela L. Jefferson, PhD; for the Alzheimer’s Disease Genetics Consortium and the Alzheimer’s Disease Neuroimaging Initiative in JAMA Neurology. Published May 7 2018.
doi:10.1001/jamaneurol.2018.0821

Cite This NeuroscienceNews.com Article
Vanderbilt University “Study Provides Robust Evidence of Sex Differences with Alzheimer’s Gene.” NeuroscienceNews. NeuroscienceNews, 9 May 2018.
<http://neurosciencenews.com/apoe-sex-differences-9014/>.
Vanderbilt University (2018, May 9). Study Provides Robust Evidence of Sex Differences with Alzheimer’s Gene. NeuroscienceNews. Retrieved May 9, 2018 from http://neurosciencenews.com/apoe-sex-differences-9014/
Vanderbilt University “Study Provides Robust Evidence of Sex Differences with Alzheimer’s Gene.” http://neurosciencenews.com/apoe-sex-differences-9014/ (accessed May 9, 2018).

Abstract

Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau

Importance The strongest genetic risk factor for Alzheimer disease (AD), the apolipoprotein E (APOE) gene, has a stronger association among women compared with men. Yet limited work has evaluated the association between APOE alleles and markers of AD neuropathology in a sex-specific manner.

Objective To evaluate sex differences in the association between APOE and markers of AD neuropathology measured in cerebrospinal fluid (CSF) during life or in brain tissue at autopsy.

Design, Setting, and Participants This multicohort study selected data from 10 longitudinal cohort studies of normal aging and AD. Cohorts had variable recruitment criteria and follow-up intervals and included population-based and clinic-based samples. Inclusion in our analysis required APOE genotype data and either CSF data available for analysis. Analyses began on November 6, 2017, and were completed on December 20, 2017.

Main Outcomes and Measures Biomarker analyses included levels of β-amyloid 42, total tau, and phosphorylated tau measured in CSF. Autopsy analyses included Consortium to Establish a Registry for Alzheimer’s Disease staging for neuritic plaques and Braak staging for neurofibrillary tangles.

Results Of the 1798 patients in the CSF biomarker cohort, 862 were women, 226 had AD, 1690 were white, and the mean (SD) age was 70 [9] years. Of the 5109 patients in the autopsy cohort, 2813 were women, 4953 were white, and the mean (SD) age was 84 (9) years. After correcting for multiple comparisons using the Bonferroni procedure, we observed a statistically significant interaction between APOE-ε4 and sex on CSF total tau (β = 0.41; 95% CI, 0.27-0.55; P < .001) and phosphorylated tau (β = 0.24; 95% CI, 0.09-0.38; P = .001), whereby APOE showed a stronger association among women compared with men. Post hoc analyses suggested this sex difference was present in amyloid-positive individuals (β = 0.41; 95% CI, 0.20-0.62; P < .001) but not among amyloid-negative individuals (β = 0.06; 95% CI, −0.18 to 0.31; P = .62). We did not observe sex differences in the association between APOE and β-amyloid 42, neuritic plaque burden, or neurofibrillary tangle burden.

Conclusions and Relevance We provide robust evidence of a stronger association between APOE-ε4 and CSF tau levels among women compared with men across multiple independent data sets. Interestingly, APOE-ε4 is not differentially associated with autopsy measures of neurofibrillary tangles. Together, the sex difference in the association between APOE and CSF measures of tau and the lack of a sex difference in the association with neurofibrillary tangles at autopsy suggest that APOE may modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis.

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