Sex-Specific Heterogeneity of Mild Cognitive Impairment Identified Based on Multi-Modal Data Analysis

Abstract

Background: Mild cognitive impairment (MCI), a prodromal phase of Alzheimer’s disease (AD), is heterogeneous with different rates and risks of progression to AD. There are significant gender disparities in the susceptibility, prognosis, and outcomes in patients with MCI, with female being disproportionately negatively impacted. Objective: The aim of this study was to identify sex-specific heterogeneity of MCI using multi-modality data and examine the differences in the respective MCI subtypes with different prognostic outcomes or different risks for MCI to AD conversion. Methods: A total of 325 MCI subjects (146 women, 179 men) and 30 relevant features were considered. Mixed-data clustering was applied to women and men separately to discover gender-specific MCI subtypes. Gender differences were compared in the respective subtypes of MCI by examining their MCI to AD disease prognosis, descriptive statistics, and conversion rates. Results: We identified three MCI subtypes: poor-, good-, and best-prognosis for women and for men, separately. The subtype-wise comparison (for example, poor-prognosis subtype in women versus poor-prognosis subtype in men) showed significantly different means for brain volumetric, cognitive test-related, also for the proportion of comorbidities. Also, there were substantial gender differences in the proportions of participants who reverted to normal function, remained stable, or converted to AD. Conclusion: Analyzing sex-specific heterogeneity of MCI offers the opportunity to advance the understanding of the pathophysiology of both MCI and AD, allows stratification of risk in clinical trials of interventions, and suggests gender-based early intervention with targeted treatment for patients at risk of developing AD.

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022

“…A clustering study of MCI participants based on multimodal factors identified sex‐specific groups of differing prognoses. 289 In the worst prognosis group, there were almost twice as many female than male APOE ε4 carriers, suggesting that the ε4 allele has a disproportionately detrimental effect in women. Women had a greater association between whole brain atrophy and functional decline than men, and female ε4 carriers had the greatest functional decline for a given level of whole brain atrophy.…”

“…A clustering study of MCI participants based on multimodal factors identified sex‐specific groups of differing prognoses 289 . In the worst prognosis group, there were almost twice as many female than male APOE ε4 carriers, suggesting that the ε4 allele has a disproportionately detrimental effect in women.…”

The role of sex differences in depression in pathologically defined Alzheimer’s disease

“…AD is associated with progressive decline in memory, executive, and other cognitive functions leading to functional decline and can manifest with diverse clinical presentations and heterogeneity ( Murray et al, 2011 ; Atri, 2019 ; Knopman et al, 2021 ). Sex differences in AD have been shown to contribute to this heterogeneity and affect prevalence, risks factors, disease trajectories, and outcomes ( Nebel et al, 2018 ; Katabathula et al, 2022 ). Depression is a frequent neuropsychiatric symptom that affects many patients with AD and has been shown to be more prevalent in women in the general population as well as in dementia ( Lovheim et al, 2009 ; Chi et al, 2015 ).…”