Sex modifies the APOE-related risk of developing Alzheimer disease
- PMID: 24623176
- PMCID: PMC4117990
- DOI: 10.1002/ana.24135
Sex modifies the APOE-related risk of developing Alzheimer disease
Abstract
Objective: The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Case-control studies suggest the APOE4 link to AD is stronger in women. We examined the APOE4-by-sex interaction in conversion risk (from healthy aging to mild cognitive impairment (MCI)/AD or from MCI to AD) and cerebrospinal fluid (CSF) biomarker levels.
Methods: Cox proportional hazards analysis was used to compute hazard ratios (HRs) for an APOE-by-sex interaction on conversion in controls (n = 5,496) and MCI patients (n = 2,588). The interaction was also tested in CSF biomarker levels of 980 subjects from the Alzheimer's Disease Neuroimaging Initiative.
Results: Among controls, male and female carriers were more likely to convert to MCI/AD, but the effect was stronger in women (HR = 1.81 for women; HR = 1.27 for men; interaction: p = 0.011). The interaction remained significant in a predefined subanalysis restricted to APOE3/3 and APOE3/4 genotypes. Among MCI patients, both male and female APOE4 carriers were more likely to convert to AD (HR = 2.16 for women; HR = 1.64 for men); the interaction was not significant (p = 0.14). In the subanalysis restricted to APOE3/3 and APOE3/4 genotypes, the interaction was significant (p = 0.02; HR = 2.17 for women; HR = 1.51 for men). The APOE4-by-sex interaction on biomarker levels was significant for MCI patients for total tau and the tau-to-Aβ ratio (p = 0.009 and p = 0.02, respectively; more AD-like in women).
Interpretation: APOE4 confers greater AD risk in women. Biomarker results suggest that increased APOE-related risk in women may be associated with tau pathology. These findings have important clinical implications and suggest novel research approaches into AD pathogenesis.
© 2014 American Neurological Association.
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References
-
- Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921–3. - PubMed
-
- Ward A, Crean S, Mercaldi CJ, et al. Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer's disease: a systematic review and meta–analysis. Neuroepidemiology. 2012;38(1):1–17. - PubMed
-
- Huang Y. Abeta–independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease. Trends in molecular medicine. 2010 Jun;16(6):287–94. - PubMed
-
- Sunderland T, Mirza N, Putnam KT, et al. Cerebrospinal fluid beta-amyloid1–42 and tau in control subjects at risk for Alzheimer's disease: the effect of APOE epsilon4 allele. Biological psychiatry. 2004 Nov 1;56(9):670–6. - PubMed
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