Sex-driven modifiers of Alzheimer risk: A multimodality brain imaging study

Area of Science:

• Neuroscience
• Biomarkers
• Alzheimer's Disease Research

Background:

• Late-onset Alzheimer's disease (AD) risk factors and sex differences are not fully understood.
• Investigating early-stage AD biomarkers in cognitively normal individuals is crucial for timely intervention.
• Multimodality brain imaging offers a comprehensive approach to assess AD pathology.

Purpose of the Study:

• To investigate sex differences in Alzheimer's disease (AD) risk using multimodality brain biomarkers.
• To compare β-amyloid load (PiB PET), glucose metabolism (FDG PET), and brain structure (MRI) between men and women.
• To identify sex-specific risk factors associated with AD biomarker differences in middle-aged adults.

Main Methods:

• 121 cognitively normal participants (85 women, 36 men, aged 40-65) underwent clinical, cognitive, and neuroimaging assessments.
• Assessed clinical, medical, hormonal, and lifestyle risk factors for AD.
• Utilized statistical parametric mapping and LASSO regression to analyze sex differences in AD biomarkers and risk factors.

Main Results:

• Women exhibited higher β-amyloid deposition, lower glucose metabolism, and reduced gray/white matter volumes than men.
• These sex differences in brain biomarkers remained significant after adjusting for confounders and age.
• Menopausal status, hormone therapy, hysterectomy, and thyroid disease were strongly associated with observed biomarker differences in women.

Conclusions:

• Hormonal factors, particularly menopause, predict the Alzheimer's disease endophenotype in middle-aged women.
• These findings highlight the importance of early intervention for AD prevention in women during endocrine aging.
• Sex-specific differences in AD biomarkers emerge in midlife, suggesting a critical window for preventive strategies.