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Basic Science and Pathogenesis.

Ajneesh Kumar1, Nicholas R Ray1, Jiji T Kurup1

  • 1Columbia University Irving Medical Center, New York, NY, USA.

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Summary
This summary is machine-generated.

Neuropsychiatric symptoms in Alzheimer's disease (AD) share genetic links with depression, schizophrenia, and anxiety. Key genes like TMEM106B, ACE, and ERC2 may drive these overlapping conditions.

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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.