Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that represents the most common cause of dementia worldwide. It is characterised by the gradual decline in cognitive function, particularly affecting memory and executive function. As of now, millions of people globally are affected by AD, and with an ageing population, the number of cases is projected to rise significantly by 2050. Understanding the underlying pathophysiology of AD is essential for developing effective therapeutic strategies and for pharmacy students to understand the implications for patient care and treatment.

Hallmarks of Alzheimer’s Disease

The pathological hallmarks of AD are characterised by specific changes in the brain, including the accumulation of protein aggregates and widespread neuronal loss.

1. Extracellular Amyloid Beta (Aβ) Plaques:

   • Aβ plaques are composed of misfolded amyloid-beta peptides, which aggregate outside neurons. These plaques are believed to disrupt cell-to-cell communication and activate immune cells, leading to inflammation and neuronal damage.

2. Intracellular Neurofibrillary Tangles (NFTs):

   • NFTs are aggregates of hyperphosphorylated tau protein, a microtubule-associated protein, found inside neurons. The tangles disrupt the microtubule network, impairing cellular transport and contributing to neuronal death.

3. Glial Dysfunction:

   • Glial cells, including microglia and astrocytes, play critical roles in maintaining homeostasis in the brain. In AD, their function is compromised, contributing to neuroinflammation and impaired clearance of Aβ.

4. Neuronal Loss:

   • A progressive loss of neurons, particularly in brain regions critical for memory and cognition (e.g., hippocampus and cortex), leads to the clinical manifestations of AD.

5. Synaptic Dysfunction:

   • Disruption in synaptic communication between neurons is an early feature of AD, contributing to the cognitive deficits seen in patients.

Amyloid Beta (Aβ) Hypothesis

The amyloid beta hypothesis is one of the most widely studied theories in AD research and suggests that the accumulation of Aβ peptides is a primary event in AD pathogenesis.

• APP Processing:
  • Amyloid precursor protein (APP) is a transmembrane protein that, when cleaved by β-secretase and γ-secretase, produces Aβ peptides.
• Aβ Oligomerisation and Aggregation:
  • Aβ peptides can misfold and aggregate, forming soluble oligomers that are neurotoxic. These oligomers further aggregate into insoluble fibrils and plaques, disrupting neuronal function and triggering inflammatory responses.

Tau Hypothesis

The tau hypothesis proposes that abnormalities in tau protein, rather than Aβ, are the primary drivers of AD pathology.

• Tau Phosphorylation:
  • Tau protein normally stabilises microtubules in neurons. In AD, tau becomes abnormally hyperphosphorylated, leading to its detachment from microtubules and subsequent aggregation into NFTs.
• Synaptic and Neuronal Dysfunction:
  • NFTs disrupt axonal transport, impair synaptic function, and ultimately contribute to neuronal death and cognitive decline.

Glial Cell Involvement

Glial cells, which include microglia and astrocytes, play significant roles in the pathogenesis of AD.

• Microglia:

  • Microglia are the brain’s resident immune cells. In AD, they become activated and contribute to chronic neuroinflammation. However, their ability to clear Aβ declines with disease progression.

• Astrocytes:

  • Astrocytes support neuronal function and maintain the blood-brain barrier. In AD, astrocytes become reactive, contributing to neuroinflammation and exacerbating neuronal dysfunction.

Other Factors Contributing to AD Pathogenesis

AD is a multifactorial disease influenced by a combination of genetic, environmental, and lifestyle factors.

1. Genetics:

   • Early-onset familial AD is associated with mutations in APP, PSEN1, and PSEN2 genes. The apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for late-onset AD.

2. Ageing:

   • Age is the most significant risk factor for AD, with the prevalence increasing exponentially with age.

3. Environmental Factors:

   • Chronic exposure to environmental toxins, such as heavy metals and air pollution, has been linked to an increased risk of developing AD.

4. Lifestyle Factors:

   • Factors such as diet, exercise, cognitive activity, and social engagement have been shown to influence AD risk.

5. Infection and Inflammation:

   • Chronic inflammation and infections, such as periodontal disease, have been implicated in AD pathogenesis, potentially accelerating the progression of the disease.

6. Sleep Disturbances:

   • Poor sleep quality and sleep disorders have been associated with increased Aβ accumulation and a higher risk of cognitive decline.

Therapeutic Strategies

While there is currently no cure for AD, several therapeutic strategies are being explored:

1. Amyloid-Targeting Therapies:

   • These therapies aim to reduce Aβ production, prevent its aggregation, or enhance its clearance from the brain. Examples include monoclonal antibodies targeting Aβ.

2. Tau-Targeting Therapies:

   • These therapies focus on inhibiting tau phosphorylation, preventing its aggregation, or enhancing its clearance to prevent NFT formation.

3. Anti-inflammatory Therapies:

   • Targeting neuroinflammation through various mechanisms is a promising approach to modifying disease progression.

4. Lifestyle Interventions:

   • Encouraging a healthy lifestyle, including a balanced diet, regular physical activity, and cognitive stimulation, may help reduce the risk or delay the onset of AD.

Conclusion

Alzheimer’s disease is a complex and multifactorial neurodegenerative disorder with significant global health implications. Understanding its pathophysiological mechanisms, including the roles of Aβ plaques, NFTs, glial cell dysfunction, and various genetic and environmental factors, is crucial for developing effective therapeutic strategies.

References

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4. Malpetti, M., Jones, P. S., & O’Brien, J. T. (2020). The role of tau in the pathophysiology of Alzheimer’s disease. Molecular Neurodegeneration, 15(1), 40. Retrieved from Molecular Neurodegeneration.