Synergistic Neurodegeneration in Alzheimer's Disease with Lewy Body Co‐Pathology: Insights from Deep Learning and CSF α‐Synuclein Seed Amplification Assays

BACKGROUND: Alzheimer's disease (AD) and Lewy body (LB) pathology frequently co-occur. While α-synuclein accumulation characterizes LB pathology, its impact on brain aging, atrophy, and function when combined with AD remains poorly understood. Advances in α-synuclein seed amplification assays (SAA) enable in vivo detection of LB, offering new insights into its interplay with AD. METHOD: ratio to define AD positivity, classifying participants into four pathology subgroups: AD-LB-, AD-LB+, AD+LB-, and AD+LB+. We then employed our trained DL model and longitudinal mixed-effects analyses to comprehensively investigate their brain age gaps (a proxy for neurodegeneration), region-specific atrophy, and multiple cognitive measures. RESULT: As shown in Figure 1, the trained DL model robustly captured normal aging trajectories in cognitively unimpaired individuals in ADNI (average brain age gap 0.31 ± 0.11 years; r ≈ 0.93). Among the four pathology subgroups, AD+LB+ displayed the greatest deviation in brain age gap, significantly surpassing either pathology alone (both p < 0.001), reflecting a further acceleration of brain aging. Sex-stratified analyses revealed that males in AD- subgroups had higher brain age gaps than females, whereas in AD+ subgroups, females showed higher brain age gaps than males, suggesting sex-dependent vulnerability. Figure 2 illustrates the DL-driven saliency maps, highlighting more pronounced neurodegeneration in AD+LB+, aligning with its steeper longitudinal brain age gap progression (Figure 3A). Specifically, the maps show heightened saliency in the medial temporal, occipital, and basal ganglia regions for AD+LB+, corresponding to its more pronounced longitudinal atrophy in these regions (Figure 3B). Cognitively, AD+LB+ showed the most severe deficits in global and domain-specific tests, following accelerated declines that outpaced single-pathology subgroups (Figure 3C and D). CONCLUSION: These findings underscore α-synuclein's synergistic role in amplifying AD-related neurodegeneration, highlighting the importance of combined biomarker assays and targeted interventions for individuals harboring co-existing AD and LB pathology.