Genetic colocalization of cathepsins H, D, and L1 with Alzheimer's disease: Implications for biomarker and therapeutic target discovery

BackgroundCathepsins, a family of lysosomal proteases, have been implicated in Alzheimer's disease (AD) pathogenesis through their involvement in amyloid-β protein precursor processing and neuroinflammation. However, the specific roles of different cathepsins in AD remain unclear.ObjectiveThis study aimed to investigate the genetic associations and potential causal relationships between cathepsins and AD, using Mendelian randomization (MR) to explore their roles as biomarkers and therapeutic targets.MethodsA two-sample MR analysis was conducted using genome-wide association study data for AD and cathepsins. Genetic variants associated with cathepsin expression were used as instrumental variables. Forward MR assessed the causal effect of cathepsins on AD, while reverse MR explored the impact of AD on cathepsin levels. Colocalization analysis was performed to identify shared genetic variants between cathepsins and AD.ResultsCathepsin H was significantly associated with an increased risk of AD (p = 0.0034, OR = 1.04), with consistent results across multiple MR methods. Colocalization analysis revealed a significant genetic overlap between Cathepsin L1 and AD (PP.H4 = 100%), suggesting a shared genetic basis.ConclusionsCathepsin H may be a potential risk factor for AD, while Cathepsin L1 shows promise as a therapeutic target and biomarker due to its genetic overlap with AD. Further research is needed to explore the mechanisms by which these cathepsins influence AD progression and to assess their therapeutic potential in diverse populations.