Leucine-Rich Repeat Kinase 2 Relates to Neuroaxonal Degeneration via Tau Pathology and Microglial Activation in Alzheimer's Disease.

Leucine-rich repeat kinase 2 (LRRK2), a key contributor to Parkinson's disease (PD). However, its potential role in Alzheimer's disease (AD) progression remains unclear. This study analyzed baseline and 5-year follow-up data from 716 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 87 participants in the Parkinson's Progression Markers Initiative (PPMI). Participants had cerebrospinal fluid (CSF) LRRK2 or LRRK2 (rs34637584 and rs76904798) genotypes, CSF biomarkers for AD core pathology, microglial activation and synaptic function, and underwent cognitive assessments. The mean age was 72.62 ± 7.34 years for the ADNI and 62.32 ± 9.66 years for the PPMI. The associations between LRRK2 and AD biomarkers were tested in CN, MCI and AD groups. In both ADNI and PPMI, CSF LRRK2 levels were correlated with CSF P-tau, T-tau, NfL, and α-syn. In ADNI, CSF LRRK2 showed correlations with sTREM2, PGRN, TREM2, TREML2, TRML1.ITIM, and Ng. Longitudinally, CSF LRRK2 was only correlated with the MOCA score in PPMI. Across CN, MCI, and AD groups, CSF LRRK2 levels exhibited correlations with sTREM2, PGRN, TREM2, TREML2, TREML1.ITIM, and NfL. The association between CSF LRRK2 and T-tau and P-tau was most pronounced in the MCI stage. Conversely, no significant association was observed between CSF LRRK2 and Aβ42 levels. Additionally, significant indirect effects were found in the TREM2-dependent mediation pathway in ADNI. This study suggests that CSF LRRK2 promotes tau-associated synaptic neurodegeneration, and TREM2-related microglial activation may play an important role.