GRN Mutations Are Associated with Lewy Body Dementia

Area of Science:

• Neurogenetics
• Neurodegenerative Diseases

Background:

• Loss-of-function mutations in the GRN gene cause familial frontotemporal dementia.
• GRN variants are linked to increased risk for Alzheimer's and Parkinson's diseases.
• TDP-43 inclusions characterize GRN-related neurodegeneration, but Lewy body pathology is also seen in GRN mutation carriers.

Purpose of the Study:

• To investigate pathogenic GRN variants in a Lewy body dementia (LBD) cohort.
• To determine if damaging GRN mutations are enriched in LBD patients.

Main Methods:

• Whole-genome sequencing of 2591 LBD cases and 4032 healthy controls.
• Analysis of GRN gene for pathogenic variants.
• Immunohistochemistry in LBD cases with confirmed pathology.

Main Results:

• Six heterozygous exonic GRN mutations were identified in seven participants (6 cases, 1 control).
• All identified GRN variants were predicted pathogenic or likely pathogenic.
• Significant enrichment of GRN loss-of-function mutations was found in LBD patients versus controls (P=0.0162).
• Immunohistochemistry confirmed Lewy body pathology and TDP-43 inclusions in three LBD cases.

Conclusions:

• Deleterious GRN mutations represent a rare genetic cause of familial LBD.
• This finding highlights the role of GRN in LBD pathogenesis.