Alzheimer's Disease Mechanisms

Alzheimer's Mechanism

• Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid plaques and neurofibrillary tangles.
• These plaques, primarily composed of amyloid-beta (Aβ) peptides, aggregate extracellularly disrupting neuronal communication and function.
• Neurofibrillary tangles result from hyperphosphorylation of tau proteins, leading to their aggregation within neurons and disrupting intracellular transport.
• The exact mechanisms linking Aβ, tau, and neuronal dysfunction are still under investigation.

Aβ Formation and Aggregation

• Amyloid precursor protein (APP) is a transmembrane protein.
• APP is cleaved by enzymes, including β- and γ-secretases, to produce Aβ peptides.
• Aβ peptides are prone to aggregation, forming oligomers, fibrils, and plaques.
• The formation of toxic Aβ oligomers may precede deposition of amyloid plaques.
• Genetic variations in APP, presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes increase the risk of AD, likely by influencing Aβ production or aggregation.
• Impaired clearance of Aβ contributes to plaque formation in AD.

Tau Protein and Neurofibrillary Tangles

• Tau is a microtubule-associated protein found in neurons, crucial for axonal transport.
• Hyperphosphorylation of tau disrupts its normal function, leading to the formation of insoluble neurofibrillary tangles.
• These tangles are found inside neurons in AD brains.
• Genetic mutations and enhanced phosphorylation lead to tau pathology, contributing to progressive neurodegeneration.

Mutations and Genetic Predisposition

• Specific mutations in APP, PSEN1, and PSEN2 increase the risk of early-onset familial AD.
• These mutations increase the production of Aβ peptides, particularly those prone to aggregation.
• APOE gene variants: the APOE ε4 allele is the strongest genetic risk factor for late-onset AD.
• The APOE ε4 allele may influence Aβ clearance mechanisms or accelerate tau hyperphosphorylation.

Brain Aging and AD Risk

• Age is the primary risk factor for AD.
• Brain aging is associated with changes in neuronal structure, synaptic plasticity, and neuroinflammation, potentially making neurons sensitive to toxic impacts of Aβ and tau.

Underlying Mechanisms of AD

• Inflammatory processes and glial activation play a critical role in AD progression.
• Oxidative stress from free radicals can damage neurons and contribute to Aβ aggregation.
• Impaired neuronal function and synaptic dysfunction occur early in the disease process and affect various brain areas, leading to cognitive impairment.
• Neurotransmission dysregulation, primarily involving cholinergic systems, is a significant feature in AD.

Clinical Features of AD

• Progressive decline in memory, thinking, and behavior.
• Difficulties with language, problem-solving, and performing daily tasks.
• Changes in personality and behavior.