Genetic correlates of corticobasal degeneration: a systematic review and meta-analysis

Corticobasal degeneration (CBD) is a primary 4-repeat tauopathy marked by progressive motor, cognitive, and behavioral decline, substantial clinicopathologic heterogeneity, and few disease-modifying therapeutic options. Although MAPT variation has long been implicated in CBD susceptibility, the full genetic architecture of CBD has remained highly fragmented and poorly synthesized.

This systematic review and meta-analysis was conducted in accordance with the PRISMA guidelines to identify studies evaluating genetic associations with CBD through August 2026. Eligible studies reported effect estimates for MAPT haplotypes, MAPT subhaplotypes, MAPT SNPs, or non-MAPT candidate loci. Risk of bias was assessed using ROBINS-E, and pooled associations were calculated using inverse-variance meta-analysis. Twenty-two studies published between 2001 and 2025 were included.

The most consistent associations involved MAPT haplotype architecture, with H1 and H1/H1 showing increased CBD susceptibility and H2 showing a protective association. Among MAPT H1 subhaplotypes, H1c, H1d, and H1q demonstrated significant risk associations, whereas other subhaplotypes showed less significant effects. MAPT SNP-level associations were generally modest, though several variants showed small yet significant protective or risk-related effects. Among non-MAPT loci, C9orf72, MOBP, and KIF13B were associated with CBD risk.

These results indicate that genetic susceptibility to CBD is dominated by MAPT architecture; however, significant heterogeneity within and beyond MAPT exists, with significant contributions from select subhaplotypes, SNPs, and non-MAPT loci. Overall, these findings support tau-centered genetic vulnerability while highlighting candidate pathways relevant to CBD pathogenesis, glial biology, and broader neurodegenerative vulnerability, providing a foundation for future biomarker, mechanistic, and precision-medicine studies.