# Cortical asymmetry in autosomal dominant Alzheimer’s disease progression

## TL;DR

This study shows that brain asymmetry can help detect early signs of Alzheimer’s disease in people with genetic mutations, even before symptoms appear.

## Contribution

The study introduces cortical asymmetry as a potential early biomarker for autosomal dominant Alzheimer’s disease progression.

## Key findings

- Cortical asymmetry distinguished asymptomatic and symptomatic mutation carriers from healthy controls.
- Higher asymmetry correlated with cognitive decline, proximity to symptom onset, and elevated neurofilament light levels.
- Longitudinal analysis showed increased asymmetry over time in symptomatic mutation carriers.

## Abstract

The cortical asymmetry index evaluates the cortical thickness asymmetry between hemispheres. We investigated cortical asymmetry index in asymptomatic and symptomatic mutation carriers of autosomal dominant Alzheimer’s disease to explore the brain asymmetry within the Alzheimer’s disease continuum. Sixty baseline T1-weighted MRI scans were obtained from the Clinic Barcelona cohort. Baseline and longitudinal MRI data from 564 participants within the dominantly inherited Alzheimer network observational study were used as an independent, confirmatory cohort. Cerebrospinal fluid and plasma neurofilament light chain levels were included when available. Cortical thickness was calculated using Freesurfer and cortical asymmetry index was calculated via an open-source pipeline. Cross-sectional analyses examined cortical asymmetry index differences based on clinical classification and APOE ε4 status, adjusting for age, sex and estimated years from onset, while correlations were assessed with age, estimated years from onset, mini-mental state examination scores, and neurofilament light. Longitudinal cortical asymmetry index evolution was modelled using generalized additive models in the dominantly inherited Alzheimer network observational study cohort, incorporating age, sex, and the interaction between group and estimated years from onset. The cortical asymmetry index successfully distinguished asymptomatic mutation carrier and symptomatic mutation carriers from healthy controls in the Clinic Barcelona cohort and symptomatic mutation carriers from controls in dominantly inherited Alzheimer network observational study. Higher cortical asymmetry index in mutation carriers (asymptomatic mutation carrier and symptomatic mutation carriers combined) and in symptomatic mutation carriers were associated with higher plasma neurofilament light levels, a closer proximity to symptom onset, and lower mini-mental state examination in the Clinic Barcelona cohort. In the dominantly inherited Alzheimer network observational study cohort, mutation carriers exhibited increased cortical asymmetry index compared to controls and correlated with elevated neurofilament light (plasma and Cerebrospinal fluid), lower mini-mental state examination, and a closer proximity to symptom onset. APOE3/3 carriers showed greater asymmetry than other APOE genotypes and significant cortical asymmetry index differences between asymptomatic mutation carrier and symptomatic mutation carriers. Longitudinally, cortical asymmetry index increased over time significantly in symptomatic mutation carriers. These findings underscore brain asymmetry as a potential biomarker for early Alzheimer’s disease progression in autosomal dominant Alzheimer’s disease, with implications for detection and monitoring tracking disease-related neuroanatomical changes.

Pérez-Millan et al. report that cortical asymmetry distinguishes mutation carriers of autosomal dominant Alzheimer’s disease from healthy controls and differentiates asymptomatic carriers. Higher asymmetry was correlated with neurofilament light chain, cognitive decline, and proximity to symptom onset. Longitudinal analyses showed progression in symptomatic carriers, supporting asymmetry as an early biomarker.

Graphical Abstract