39. Alzheimer's disease - etiology, pathogenesis, clinical manifestations.

Alzheimer's disease – etiology, pathogenesis, and clinical manifestations.

Alzheimer’s disease is a progressive neurodegenerative disorder and the most common cause of dementia, characterized by progressive memory loss, cognitive

dysfunction, and behavioral changes.

Etiology (Causes)

1. 1 Genetic factors

• Familial (early-onset) AD: ~1–5% of cases, onset before 65 years.
• Mutations in:
• APP (amyloid precursor protein) gene (chromosome 21).
• Presenilin 1 (PSEN1)gene (chromosome 14).
• Presenilin 2 (PSEN2) gene (chromosome 1).
• Sporadic (late-onset) AD: most common.
• Strongly associated with APOE ε4 allele (Apolipoprotein E gene).

1. 2 Environmental factors

• Age (most significant risk factor).
• Head trauma.
• Low educational attainment (possibly related to lower cognitive reserve).

Pathogenesis

1. 1 Accumulation of β-amyloid plaques

• Abnormal cleavage of APP → generation of Aβ peptide (especially Aβ42).
• Aβ peptides aggregate extracellularly → form senile (neuritic) plaques.
• Plaques disrupt neuronal function and promote inflammation.

1. 2 Neurofibrillary tangles (NFTs)

• Hyperphosphorylated tau protein accumulates intracellularly → forms paired helical filaments → neurofibrillary tangles.
• Leads to microtubule destabilization and neuronal death.

1. 3 Neuroinflammation and oxidative stress

• Activation of microglia and astrocytes → release of cytokines and reactive oxygen species.
• Further neuronal injury and synaptic dysfunction.

1. 4 Neurotransmitter deficits

• Significant loss of cholinergic neurons in basal forebrain (especially nucleus basalis of Meynert) → decreased acetylcholine levels → contributes to cognitive deficits.

Affected brain regions

• Early: hippocampus and entorhinal cortex (memory-related areas).
• Later: widespread cortical atrophy, including parietal and frontal lobes.

Clinical Manifestations

1. 1 Early stage

• Subtle short-term memory loss (difficulty recalling recent events).
• Word-finding difficulty (anomia).
• Mild disorientation (losing objects, getting lost in familiar places).

1. 2 Progressive stage

• Severe memory impairment (both short-term and eventually long-term).
• Impaired judgment and problem-solving.
• Difficulty with language (aphasia), visuospatial skills, and executive function.
• Behavioral and personality changes:
• Apathy.
• Agitation, aggression.
• Depression or anxiety.
• Wandering behavior.

1. 3 Late stage

• Profound cognitive decline.
• Inability to perform activities of daily living.
• Incontinence.
• Motor dysfunction (rigidity, spasticity).
• Eventually bedridden; complications like infections lead to death.

Other features

• Seizures in some patients.
• Sleep disturbances.