Alzheimer's Imaging Consortium

Area of Science:

• Neuroscience
• Genetics
• Medical Imaging

Background:

• Excessive neural hyperexcitation is linked to early cognitive decline and Alzheimer's disease (AD) progression.
• The APOE-ε4 genotype and female sex may increase vulnerability to hyperexcitation, but longitudinal data are scarce.
• Restoring excitation-inhibition (E/I) balance is a potential therapeutic target for AD.

Purpose of the Study:

• To investigate longitudinal changes in the brain's excitation-inhibition ratio (EIR) based on sex and APOE-ε4 status in cognitively unimpaired older adults.
• To determine if E/I dysregulation trajectories differ between female and male APOE-ε4 carriers and non-carriers.
• To explore the relationship between E/I balance and early cognitive decline indicators.

Main Methods:

• Analysis of multimodal MRI data (resting-state fMRI, DTI) from 106 older adults with longitudinal scans.
• Application of an inverse Ising model with structural connectivity regularization to calculate whole-brain EIR.
• Linear mixed modeling to assess the impact of sex, APOE-ε4 status, age, and time on EIR trajectory.

Main Results:

• A significant three-way interaction revealed an elevated, hyperexcitable EIR trajectory in female APOE-ε4 carriers (p=0.018).
• Female ε4 carriers exhibited steeper EIR slopes compared to female non-carriers (p=0.042), even after adjusting for age, time, and amyloid status.
• Higher baseline excitatory tone was observed in females within default mode and limbic networks (p=0.02).

Conclusions:

• Longitudinal data support heightened hyperexcitability susceptibility in female APOE-ε4 carriers, emphasizing sex and genetic risk factors in AD.
• E/I balance is a potential biomarker and therapeutic target for AD, with interventions like levetiracetam showing promise.
• Further research with larger cohorts is needed to confirm sex- and genotype-specific E/I dysregulation effects on dementia risk and treatment efficacy.