Biomarkers

Area of Science:

• Neuroscience
• Biomarkers
• Neuroimaging

Background:

• Alzheimer's disease (AD) and Lewy body (LB) pathology often coexist, but their combined impact on brain aging, atrophy, and function is not well understood.
• Advances in α-synuclein seed amplification assays (SAA) allow for in vivo detection of LB pathology, providing new avenues to study its interaction with AD.

Purpose of the Study:

• To investigate the synergistic effects of co-occurring AD and LB pathology on brain aging, atrophy, and cognitive function.
• To utilize deep learning (DL) models and seed amplification assays (SAA) to quantify neurodegeneration in individuals with distinct AD and LB pathology profiles.

Main Methods:

• A 3D-DenseNet deep learning model was trained on structural MRI data from 4,355 cognitively unimpaired individuals to estimate brain age.
• In 803 cognitively impaired participants, α-synuclein positivity was determined by CSF SAA, and AD positivity by the p-tau₁₈₁/Aβ₄₂ ratio, classifying them into AD-LB-, AD-LB+, AD+LB-, and AD+LB+ subgroups.
• Brain age gaps, region-specific atrophy, and cognitive performance were analyzed longitudinally across the four pathology subgroups.

Main Results:

• The AD+LB+ subgroup exhibited the largest brain age gap, significantly exceeding that of single-pathology groups, indicating accelerated brain aging.
• Sex-stratified analyses revealed sex-dependent vulnerabilities, with males showing higher brain age gaps in AD- subgroups and females in AD+ subgroups.
• DL-driven saliency maps highlighted pronounced neurodegeneration in medial temporal, occipital, and basal ganglia regions for AD+LB+, correlating with accelerated atrophy and the most severe cognitive deficits.

Conclusions:

• Co-occurring AD and LB pathology synergistically amplify neurodegeneration and accelerate brain aging.
• The findings emphasize the critical importance of combined biomarker assays for diagnosing and managing individuals with co-existing AD and LB pathology.
• Targeted interventions are crucial for addressing the amplified neurodegenerative effects observed in individuals with combined AD and LB pathology.