# Molecular mechanism of Alzheimer’s disease using integrated multi-omics

## TL;DR

This paper reviews how genetic, immune, and metabolic factors interact to cause Alzheimer’s disease, focusing on mechanisms like neuroinflammation and protein aggregation.

## Contribution

The paper integrates multi-omics data to clarify the interconnected molecular mechanisms underlying Alzheimer’s disease pathogenesis.

## Key findings

- Genetic risk genes like APOE, TREM2, and CR1 are linked to immune and metabolic pathways in Alzheimer’s disease.
- Neuroinflammation, chronic cytokine signaling, and HPA-axis dysregulation contribute to neuronal damage and cognitive decline.
- Impaired autophagy worsens amyloid-β and tau aggregation, accelerating synaptic loss in Alzheimer’s disease.

## Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder driven by complex interactions between neuroinflammation, immune dysregulation, metabolic impairment, and disrupted synaptic plasticity. Emerging evidence highlights maladaptive microglial activation, chronic cytokine signaling (including IL-1β, TNF-α, and IL-6), and hypothalamic–pituitary–adrenal (HPA) axis hyperactivity as pivotal contributors to neuronal damage and cognitive decline. Genetic studies further underscore the importance of immune and metabolic pathways, implicating key risk genes such as APOE, TREM2, and CR1, while deficits in autophagy exacerbate pathological protein aggregation, including amyloid-β and tau, ultimately accelerating synaptic loss. In this review, we synthesize molecular, genetic, and cellular evidence to clarify the mechanisms driving AD pathogenesis. We discuss genome-wide association study (GWAS) findings that define the genetic architecture of the disease, the neuroimmune crosstalk affecting memory-related brain regions, the link between chronic stress and amyloid pathology through HPA-axis dysregulation, and metabolic reprogramming in neurons, astrocytes, and microglia. Together, these interconnected processes highlight how dysregulated immunity and impaired protein clearance contribute to neuronal dysfunction and the progressive cognitive decline characteristic of AD.

Diagram illustrating the links between genetic risk factors in Alzheimer’s disease and major depressive disorder, molecular dysfunctions such as neuroinflammation, metabolic collapse, and HPA-axis dysregulation, and resulting disease phenotypes like amyloid plaques, brain atrophy, autophagy dysregulation, and synaptic loss.