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Sex modifies the APOE-related risk of developing Alzheimer disease.

ABSTRACT: 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.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.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-A? ratio (p = 0.009 and p = 0.02, respectively; more AD-like in women).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.

SUBMITTER: Altmann A

PROVIDER: S-EPMC4117990 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Sex modifies the APOE-related risk of developing Alzheimer disease.

Altmann Andre A Tian Lu L Henderson Victor W VW Greicius Michael D MD

Annals of neurology 20140414 4

<h4>Objective</h4>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.<h4>Methods</h4>Cox proportional hazards analysis was used to compute hazard ratios (HRs) for an APOE-by-sex interaction on conversion ...[more]

PMID: 24623176

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Project description:The ApoE ?4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ?4, however, differs across populations, with populations of African ancestry showing lower ?4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations. Exploring these hypotheses may lead to novel, population-specific therapeutics and risk predictions. To test these hypotheses, we analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study. We first assessed average ancestry across the genome ("global" ancestry) and then tested it for interaction with ApoE genotypes. Next, we assessed the ancestral background of ApoE alleles ("local" ancestry) and tested if ancestry local to ApoE influenced Alzheimer disease risk while controlling for global ancestry. Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE ?4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ?4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene ?4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors.

Project description:Importance:There are conflicting results claiming that Alzheimer disease signature neurodegeneration may be more, less, or similarly advanced in individuals with ?-amyloid peptide (A?)-negative (A?-) suspected non-Alzheimer disease pathophysiology (SNAP) than in A?-positive (A?+) counterparts. Objective:To examine patterns of neurodegeneration in individuals with SNAP compared with their A?+ counterparts. Design, Setting, and Participants:A longitudinal cohort study was conducted among individuals with mild cognitive impairment (MCI) and cognitively normal individuals receiving care at Alzheimer's Disease Neuroimaging Initiative sites in the United States and Canada for a mean follow-up period of 30.5 months from August 1, 2005, to June 30, 2015. Several neurodegeneration biomarkers and longitudinal cognitive function were compared between patients with distinct SNAP (A?- and neurodegeneration-positive [A?-N+]) subtypes and their A?+N+ counterparts. Main Outcomes and Measures:Participants were classified according to the results of their florbetapir F-18 (A?) positron emission tomography and their Alzheimer disease-associated neurodegeneration status (temporoparietal glucose metabolism determined by fluorodeoxyglucose F 18 [FDG]-labeled positron emission tomography and/or hippocampal volume [HV] determined by magnetic resonance imaging: participants with subthreshold HV values were regarded as exhibiting hippocampal volume atrophy [HV+], while subthreshold mean FDG values were considered as FDG hypometabolism [FDG+]). Results:The study comprised 265 cognitively normal individuals (135 women and 130 men; mean [SD] age, 75.5 [6.7] years) and 522 patients with MCI (225 women and 297 men; mean [SD] age, 72.6 [7.8] years). A total of 469 individuals with MCI had data on neurodegeneration biomarkers; of these patients, 107 were A?-N+ (22.8%; 63 FDG+, 82 HV+, and 38 FDG+HV+) and 187 were A?+N+ (39.9%; 135 FDG+, 147 HV+, and 95 FDG+HV+ cases). A total of 209 cognitively normal participants had data on neurodegeneration biomarkers; of these, 52 were A?-N+ (24.9%; 30 FDG+, 33 HV+, and 11 FDG+HV+) and 37 were A?+N+ (17.7%; 22 FDG+, 26 HV+, and 11 FDG+HV+). Compared with their A?+ counterparts, all patients with MCI SNAP subtypes displayed better preservation of temporoparietal FDG metabolism (mean [SD] FDG: A?-N+, 1.25 [0.11] vs A?+N+, 1.19 [0.11]), less severe atrophy of the lateral temporal lobe, and lower mean (SD) cerebrospinal fluid levels of tau (59.2 [32.8] vs 111.3 [56.4]). In MCI with SNAP, sustained glucose metabolism and gray matter volume were associated with disproportionately low APOE ?4 (A?-N+, 18.7% vs A?+N+, 70.6%) and disproportionately high APOE ?2 (18.7% vs 4.8%) carrier prevalence. Slower cognitive decline and lower rates of progression to Alzheimer disease (A?-N+, 6.5% vs A?+N+, 32.6%) were also seen in patients with MCI with SNAP subtypes compared with their A?+ counterparts. In cognitively normal individuals, neurodegeneration biomarkers did not differ between A?-N+ and A?+N+ cases. Conclusions and Relevance:In MCI with SNAP, low APOE ?4 and high APOE ?2 carrier prevalence may account for differences in neurodegeneration patterns between A?-N+ and A?+N+ cases independent from the neuroimaging biomarker modality used to define neurodegeneration associated with Alzheimer disease.

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Sex modifies the APOE-related risk of developing Alzheimer disease.

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Sex modifies the APOE-related risk of developing Alzheimer disease.

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