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Large intracranial volume accelerates conversion to dementia in males and APOE4 non-carriers with mild cognitive impairment

ABSTRACT Background: It is unclear how brain reserve interacts with gender and apolipoprotein E4 (APOE4) genotype, and how this influences the progression of Alzheimer's disease (AD). The association between intracranial volume (ICV) and progression to AD in subjects with mild cognitive impairment (MCI), and differences according to gender and APOE4 genotype, was investigated. Methods: Data from subjects initially diagnosed with MCI and at least two visits were downloaded from the ADNI database. Those who progressed to AD were defined as converters. The longitudinal influence of ICV was determined by survival analysis. The time of conversion from MCI to AD was set as a fiducial point, as all converters would be at a similar disease stage then, and longitudinal trajectories of brain atrophy and cognitive decline around that point were compared using linear mixed models. Results: Large ICV increased the risk of conversion to AD in males (HR: 4.24, 95% confidence interval (CI): 1.17–15.40) and APOE4 non-carriers (HR: 10.00, 95% CI: 1.34–74.53), but not in females or APOE4 carriers. Cognitive decline and brain atrophy progressed at a faster rate in males with large ICV than in those with small ICV during the two years before and after the time of conversion. Conclusions: Large ICV increased the risk of conversion to AD in males and APOE4 non-carriers with MCI. This may be due to its influence on disease trajectory, which shortens the duration of the MCI stage. A longitudinal model of progression trajectory is proposed.