Sexual dimorphism in the association of APOE ε4 genotype with cognitive decline and dementia progression in mild‐to‐moderate Alzheimer disease

Dear Editor, The Apolipoprotein E (APOE) ε4 allele remains the strongest genetic risk factor for sporadic Alzheimer disease (AD). Previous work has suggested that the risk conferred by APOE genotype is greater in females than males. Female APOE ε4 carriers may be at greater risk of developing mild cognitive impairment (MCI), and also greater likelihood of clinical progression in those with established MCI. These APOE-by-sex interactions have been poorly explored in established AD. We sought to investigate the potential impact of APOE-by-sex interactions on cognitive decline and AD progression in those with established AD. We addressed this question reviewing longitudinal data from NILVAD, a randomised controlled trial of Nilvadipine in mild-tomoderate AD, negative for its primary endpoint of change in ADASCog (Alzheimer Disease Assessment Scale, Cognitive Subsection) score at 18 months. We assessed the impact of APOE-by-gender interactions on cognitive decline (ADAS-Cog) and dementia progression (CDR-Sb, Clinical Dementia Rating, Sum of Boxes and DAD, Disability Assessment for Dementia) over the 18-month study duration with participants assessed at 13, 52 and 78 weeks. Mixed-effects linear regression models were used, with “country” considered a random effect, and adjustment made for variables either significantly differing between APOE/sex groups at baseline, or with an important impact on cognitive function. We used an additive model (carriers of either 0, 1, or 2 APOE ε4 risk alleles) in the first instance, and in later analysis used an ε4 carriers vs non-carriers model to capture associations not seen using the additive model. The change from baseline in ADAS-Cog/CDR-Sb/DAD was the dependent variable in all models and the APOE-by-gender interaction tested using a APOE ε4 × Sex × Visit interaction term, to analyse gene-by-sex interactions over time. Genotype data was available for 334 participants (72.5 ± 8.3 years; 62.0% female). Median baseline scores on the ADAS-Cog/CDR-Sb/DAD were 34.8 (±10.8), 5.3 (±2.7) and 29.4 (±8.0), respectively. Thirty-one participants (9.3%) who withdrew from the study over 18-months did not differ in gender (χ = 0.16, P = .69) or APOE genotype (χ = 2.17, P = .34) from the overall study population. Overall, 59.3% (n = 198/334) carried at least one APOE ε4 allele. At baseline, male carriers of two ε4 alleles had lower ADAS-Cog scores than female non-carriers (F = 2.57, P = .03, ANOVA; Tukey's Honestly Significant Difference = 8.83, P = .03) and groups differed in terms of years of formal education (χ = 16.48, P < .01), necessitating inclusion of these variables in regression models. There were no other baseline differences across the cohort in APOE/sex subgroups. Over 18 months, mean ADAS-Cog score increased by 9.4 ± 9.2 as did CDR-Sb scores (+3.7 ± 3.9), while DAD scores decreased (−8.2 ± 8.3), all indicating greater cognitive decline/AD progression. Using mixed-effects linear models, there were no significant gene-by-sex interaction observed on change in ADAS-Cog in females with one (β: −2.04, −4.87-0.80, P = .16) or two (β: −0.23, −4.16-3.69, P = .91) APOE ε4 alleles (Table 1). Similarly, there were no sex-specific effects of APOE ε4 allele status on dementia progression on either the CDRSb (β: −0.47, −1.66-0.33, P = .19; β: 0.92, −0.45-2.30, P = .19 for 1/2 allele(s) respectively) or DAD (β: −3.05, −15.29-9.18, P = .63; β: −1.28, −18.24-15.69, P = .88) (Table 1). Adjustment for age, baseline score and years of formal education did not reveal any association, nor did additional adjustment for study group (Nilvadipine vs placebo) or use of a cholinesterase inhibitor. Re-running regressions using a carrier vs non-carrier model did not reveal any APOE-by-sex interactions on the above measures. While these results are interesting given previous evidence for sexual dimorphism in the association of APOE ε4 genotype with MCI and AD, they echo previous reports suggesting that the APOE ε4 allele may be more deleterious in females during a certain “susceptibility period. ” This means that while APOE ε4 may expose females to greater risk of developing AD during a certain time-window, these gene-by-sex interactions appear less significant once AD symptoms are established. Future studies are required to identify the key susceptibility periods by which APOE risk alleles may exhibit sexual dimorphism, and any concurrent biological causal interplay, with the aim of early identification of those at greatest risk of cognitive decline.