Basic Science and Pathogenesis.

Area of Science:

• Neurogenetics
• Psychiatric Genetics
• Alzheimer's Disease Research

Background:

• Neuropsychiatric symptoms (NPS) affect 85% of Alzheimer's Disease (AD) patients, worsening decline and patient/caregiver suffering.
• Current NPS treatments lack efficacy and have adverse effects, partly due to poor understanding of shared genetics with primary psychiatric disorders.

Purpose of the Study:

• To investigate the genetic overlap between Alzheimer's Disease (AD) and major psychiatric disorders (depression, schizophrenia, bipolar disorder, anxiety).
• To identify shared biological processes and genetic drivers underlying AD-associated NPS.

Main Methods:

• Utilized local genetic covariance analyses (MiXeR, LAVA) on large-scale GWAS summary statistics for AD and psychiatric disorders.
• Performed fine mapping, in silico functional analyses, and sequence data analysis on identified overlapping genomic loci.

Main Results:

• Identified significant genetic loci shared between AD and depression (4), schizophrenia (5), bipolar disorder (3), and anxiety (4).
• Pinpointed specific variants: a TMEM106B missense variant (shared with depression/anxiety), an ACE regulatory variant (shared with schizophrenia), and ERC2 variants (shared with AD/anxiety).
• Highlighted gene functions: TMEM106B (lysosomal trafficking), ACE (neuropeptide cleavage), ERC2 (neurotransmitter release).

Conclusions:

• Confirmed pleiotropic genetic overlap between AD and major psychiatric disorders.
• Identified TMEM106B, ACE, and ERC2 as critical shared genetic drivers for AD-associated NPS.
• Emphasized the need for further functional studies to elucidate underlying biological mechanisms.