Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by a decline in cognitive function, ultimately leading to dementia. The brain constantly works to maintain a stable internal environment, a process known as homeostasis. This biological balance involves the tight regulation of temperature, pH, energy, and molecular cleanup within its billions of nerve cells. AD mechanisms fundamentally destabilize this balance, transforming a finely tuned system into a state of chronic cellular stress. The pathology of AD, driven by abnormal protein accumulation, sets off a cascade of homeostatic failures that overwhelm the neuron’s ability to survive and communicate.
Impaired Protein Stability
Cellular health relies on proteostasis, the continuous management of protein synthesis, folding, and degradation. Neurons maintain this balance using sophisticated waste disposal systems to clear damaged or misfolded proteins. Alzheimer’s disease directly compromises this stability by causing the accumulation of two problematic proteins: amyloid-beta (A-beta) and hyperphosphorylated tau (p-tau).
The accumulation of these proteins overwhelms the cell’s primary clearance mechanisms, the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP). The UPS becomes dysfunctional when faced with the large, insoluble aggregates formed by A-beta and p-tau. Autophagy, the process of recycling cellular components, also falters, leading to the buildup of toxic clumps within the neuron. This failure of protein homeostasis is an early and foundational stressor, creating an internal environment where structural integrity is constantly undermined.
Disruption of Cellular Energy Production
Maintaining the brain’s internal stability requires a constant and massive supply of energy, which neurons depend upon more than any other cell type. This energy comes almost entirely from adenosine triphosphate (ATP), generated by mitochondria through oxidative phosphorylation. In AD, the accumulation of A-beta and p-tau directly interferes with mitochondrial function, triggering a widespread energy crisis.
Mitochondria become structurally and functionally damaged early in the disease process, transforming them into inefficient powerhouses. They begin to produce significantly less ATP, which starves the neuron of the energy needed for basic functions like maintaining ion gradients and synaptic transmission. Simultaneously, these dysfunctional mitochondria become a major source of reactive oxygen species (ROS), unstable molecules that damage cellular components. This imbalance between ROS production and the cell’s antioxidant defenses leads to a state of oxidative stress.
Breakdown of Neuronal Signaling
Precise control of ion concentrations is paramount for neuronal communication, with calcium (Ca2+) homeostasis being particularly sensitive. Ca2+ acts as a versatile intracellular messenger, regulating everything from neurotransmitter release to gene expression and synaptic plasticity. In a healthy neuron, intracellular Ca2+ levels are tightly controlled, with the endoplasmic reticulum (ER) serving as the main internal storage and buffering system.
AD pathology profoundly disrupts this delicate balance, causing chronic elevation of Ca2+ within the neuron. A-beta oligomers and mutations in presenilin proteins (PS1 and PS2) compromise the ER’s ability to store and release Ca2+ in a controlled manner. This dysregulation affects key channels (IP3R and RyR), leading to an excessive and prolonged release of Ca2+ into the cytoplasm. Chronically high intracellular Ca2+ levels cause excitotoxicity, which overstimulates and ultimately destroys the neuron.
Chronic Inflammatory State
The brain’s immune system, composed primarily of microglia and astrocytes, normally maintains immune homeostasis by constantly surveying the environment and clearing debris. Microglia, the resident immune cells, are initially activated to phagocytose A-beta plaques and other toxic material in a protective response. Astrocytes also respond to injury by becoming reactive and helping to clear misfolded proteins.
In AD, however, this immune response transitions from acute and beneficial to chronic and detrimental. Microglia and astrocytes become persistently activated, transforming into a neurotoxic state. Instead of resolving the pathology, these chronically activated glial cells release pro-inflammatory cytokines, such as TNF-alpha and IL-1 beta, that injure surrounding healthy neurons and synapses. This sustained neuroinflammation creates a toxic local environment that accelerates the accumulation of protein aggregates.