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

Artikel i vetenskaplig tidskrift
Författare Timothy J Hohman
Logan Dumitrescu
Lisa L Barnes
Madhav Thambisetty
Gary Beecham
Brian Kunkle
Katherine A Gifford
William S Bush
Lori B Chibnik
Shubhabrata Mukherjee
Philip L De Jager
Walter Kukull
Paul K Crane
Susan M Resnick
C Dirk Keene
Thomas J Montine
Gerard D Schellenberg
Jonathan L Haines
Henrik Zetterberg
Kaj Blennow
Eric B Larson
Sterling C Johnson
Marilyn Albert
David A Bennett
Julie A Schneider
Angela L Jefferson
Publicerad i JAMA neurology
Volym 75
Nummer/häfte 8
ISSN 2168-6157
Publiceringsår 2018
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
Språk en
Länkar dx.doi.org/10.1001/jamaneurol.2018....
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Neurokemi

Sammanfattning

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.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.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.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.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.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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