### PSEN1 Gene Overview

**Gene Symbol:** PSEN1  
**Full Name:** Presenilin 1  
**Location:** Chromosome 14q24.3  
**Function:** It is an essential component of the gamma-secretase complex with critical involvement in the processing of amyloid precursor protein (APP) and Notch receptors, facilitating cell signaling and adhesion.

### 1. Associated Genes
In addition to **APP** and **PSEN2**, other genes closely associated with **PSEN1** include:
- **APOE**: Variants (particularly the ε4 allele) are significant risk factors for Alzheimer's disease.
- **MAPT**: While primarily linked to tauopathies, polymorphisms have been studied in relation to Alzheimer’s pathology.
- **SORL1**: Variants may influence APP processing and have been implicated in sporadic Alzheimer's disease risk.

### 2. Aging and Age-Related Diseases
**PSEN1** mutations are notorious for their association with early-onset familial Alzheimer's disease (EOFAD), typically manifesting in individuals aged 30-60. The gene's involvement in the processing of APP relegates it to a crucial role in age-related cognitive decline. Other aspects include:
- **Cognitive decline**: Alterations in gamma-secretase activity with age can contribute to amyloid-beta accumulation.
- **Neurodegeneration**: Aging can exacerbate the effects of PSEN1 mutations, leading to increased deposition of amyloid plaques, a hallmark of Alzheimer’s pathology.

### 3. Drug Interactions
Several drugs have been studied for their interaction with the PSEN1 gene and its associated gamma-secretase activity:
- **Gamma-secretase inhibitors**: These include compounds like semagacestat and avagacestat, which aim to reduce amyloid-beta production.
- **Nonsteroidal anti-inflammatory drugs (NSAIDs)**: Some studies suggest a possible modulation of gamma-secretase activity, though results on efficacy are mixed.
- **Cholinesterase inhibitors**: Drugs like donepezil and rivastigmine may indirectly affect pathways influenced by PSEN1 through the cholinergic system.

### 4. Pathways and Biological Processes
**PSEN1** is involved in several key biological processes:
- **Gamma-secretase signaling**: Essential in cleavage reactions for Notch signaling and APP processing, leading to amyloid-beta formation.
- **Wnt signaling pathway**: Plays a role in the regulation of beta-catenin levels and may influence cell proliferation and differentiation.
- **Calcium homeostasis**: Functions as a calcium-leak channel, facilitating calcium movements between the endoplasmic reticulum and the cytoplasm, affecting synaptic function.
- **Neuronal development**: Crucial for normal embryogenesis, particularly in brain and skeleton formation.
- **Cell adhesion**: Mediates interactions between cadherins (such as CDH1) and associated proteins, influencing tissue integrity and signaling.

### Conclusion
The PSEN1 gene is pivotal in the pathogenesis of Alzheimer's disease, particularly with mutations leading to dysregulation of amyloid-beta production and disturbances in vital cellular processes such as signaling and calcium homeostasis. Understanding its interactions and pathways is crucial for developing therapeutics targeting Alzheimer's and related neurodegenerative conditions.