What is the pathophysiology of Alzheimer's disease?

From the Guidelines

Alzheimer's disease is characterized by a complex pathophysiological process involving the accumulation of beta-amyloid plaques and neurofibrillary tangles in the brain, leading to progressive neurodegeneration and cognitive decline. The process begins with abnormal processing of amyloid precursor protein, leading to beta-amyloid peptide deposition outside neurons, as noted in studies such as 1. Simultaneously, hyperphosphorylation of tau protein causes it to form neurofibrillary tangles inside neurons, disrupting cellular transport systems. These pathological changes trigger neuroinflammation as microglia and astrocytes attempt to clear the protein aggregates, inadvertently causing further damage through inflammatory cytokine release, as discussed in 1. Neurotransmitter systems become dysregulated, particularly acetylcholine, which is crucial for memory and learning. Synaptic connections between neurons deteriorate, and neuronal death occurs progressively, starting in the hippocampus and entorhinal cortex before spreading to other brain regions. This explains why memory impairment is typically the first clinical manifestation. Vascular factors, oxidative stress, and mitochondrial dysfunction further contribute to neuronal damage, as highlighted in 1. Genetic factors like APOE ε4 allele increase susceptibility, while environmental and lifestyle factors may accelerate the disease process. This cascade of events ultimately leads to the characteristic symptoms of progressive memory loss, cognitive decline, and behavioral changes seen in Alzheimer's disease.

Some key points to consider in the pathophysiology of Alzheimer's disease include:

• The accumulation of beta-amyloid plaques and neurofibrillary tangles in the brain
• The role of abnormal processing of amyloid precursor protein and hyperphosphorylation of tau protein
• The impact of neuroinflammation and dysregulation of neurotransmitter systems
• The contribution of vascular factors, oxidative stress, and mitochondrial dysfunction to neuronal damage
• The influence of genetic factors, such as APOE ε4 allele, and environmental and lifestyle factors on disease susceptibility and progression.

It is essential to recognize that the pathophysiological process of Alzheimer's disease is complex and multifactorial, and further research is needed to fully understand the underlying mechanisms and to develop effective therapeutic strategies, as emphasized in studies such as 1.

From the FDA Drug Label

Persistent activation of central nervous system N-methyl-D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer’s disease Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer’s disease attribute some of them to a deficiency of cholinergic neurotransmission.

The pathophysiology of Alzheimer's disease is thought to involve persistent activation of NMDA receptors by glutamate, leading to excitotoxicity and contributing to the symptomatology of the disease. Additionally, deficiency of cholinergic neurotransmission is also believed to play a role in the cognitive signs and symptoms of Alzheimer's disease. These two mechanisms are thought to be separate but related, with glutamate excitotoxicity and cholinergic deficiency both contributing to the overall pathophysiology of the disease 2 3.

• Key factors involved in the pathophysiology of Alzheimer's disease include:
  • Glutamate excitotoxicity
  • Cholinergic deficiency
  • NMDA receptor activation It is essential to note that the exact mechanisms underlying Alzheimer's disease are not fully understood and are the subject of ongoing research.

From the Research

Pathophysiology of Alzheimer's Disease

The pathophysiology of Alzheimer's disease (AD) is a complex process characterized by the accumulation of amyloid beta plaques and tau protein tangles in the brain, along with neuroinflammation and synaptic dysfunction 4. The disease is marked by cognitive decline, memory loss, and impaired daily functioning. Key features of the pathophysiology of AD include:

• Accumulation of amyloid beta plaques and tau protein tangles in the brain
• Neuroinflammation and synaptic dysfunction
• Cognitive decline, memory loss, and impaired daily functioning
• Genetic factors, such as mutations in APP, PSEN1, and PSEN2 genes, as well as the APOE ε4 allele, contribute to increased risk of acquiring AD 4

Underlying Mechanisms

The underlying mechanisms of AD involve the accumulation of amyloid-beta, which increases and leads to the formation of phosphorylated tau (P-tau) protein, a key feature of the disease 5. The mechanisms leading to the accumulation of plaques and tangles are unknown, and removing amyloid-β has not halted neurodegeneration 6. Current treatments provide symptomatic relief but do not halt disease progression, and research efforts are focused on developing disease-modifying therapies that target the underlying pathological mechanisms of AD 4.

Biomarkers and Diagnosis

Biomarkers such as amyloid beta peptides, Tau proteins, and phosphorylated Tau protein are used for the diagnosis of AD, and their detection in body fluids such as cerebrospinal fluid (CSF), blood, or saliva is being implemented 7. Early diagnosis is important for disease-modifying treatment, and the search for a molecular signature of AD in a body fluid that can be collected in a minimally invasive way offers hope 7. Non-pharmacologic interventions, such as psychosocial approaches, and pharmacologic management, such as acetylcholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist memantine, are used to manage symptoms and target symptom relief and disease progression 8.