Lecture Notes on Alzheimer Disease and Dementia

Understanding Dementia

• Dementia is not a disease but a description of symptoms:
  • Poor memory
  • Difficulty learning new information
  • Impairment in independent functioning
• Usually caused by damage to brain cells from various diseases.

Alzheimer Disease

• Most common cause of dementia.
• Classified as a neurodegenerative disease.
• Key symptoms: Characteristic of dementia due to the loss of neurons, particularly in the cortex.
• Causes: Not completely understood, but major contributors are plaques and tangles.

Key Components: Plaques and Tangles

• Amyloid Precursor Protein (APP):
  • Located in the neuron cell membrane.
  • Involved in neuron growth and repair.
• Enzymes:
  • Normal breakdown by alpha and gamma secretase leads to soluble peptides.
  • Problematic breakdown by beta secretase with gamma secretase leads to amyloid beta monomers.
  • Monomers aggregate to form beta-amyloid plaques.

Impact of Plaques:

• Interference with neuron signaling.
• Can initiate immune responses causing inflammation and damage to surrounding neurons.
• Plaques can deposit around blood vessels (amyloid angiopathy) increasing hemorrhage risk.

Histology of Plaques:

• Clumps of beta-amyloid observed outside the cells.

Neurofibrillary Tangles

• Found inside the neuron, formed from tau protein.
• Tau maintains microtubules necessary for nutrient transport.
• Beta-amyloid plaques may activate kinase, leading to abnormal phosphorylation of tau, resulting in tangles.
• Tangles disrupt neuron signaling and can lead to apoptosis (cell death).

Histology of Tangles:

• Neurofibrillary tangles shown inside neurons.

Brain Changes Over Time

• Neuronal death leads to brain atrophy:
  • Narrowing of gyri (ridges) and widening of sulci (grooves).
  • Enlarged ventricles (fluid-filled cavities).

Types of Alzheimer Disease

• Sporadic Alzheimer Disease:
  • Late-onset, most common form.
  • Risk increases significantly with age:
    • 1% of patients aged 60-65.
    • 50% of patients over age 85.
  • Influenced by genetic (e.g., APOE-e4 allele) and environmental factors.
• Familial Alzheimer Disease:
  • Early-onset, accounts for 5-10% of cases.
  • Caused by mutations in genes like PSEN-1 or PSEN-2 affecting gamma-secretase function.
  • Also linked to trisomy 21 (Down syndrome) due to extra APP gene.

Symptoms Progression

• Symptoms worsen as plaques and tangles build up:
  • Early stages: Short-term memory loss (e.g., forgetting recent meals).
  • Progression leads to loss of motor skills and language difficulties.
  • Late stages: Loss of long-term memory, disorientation, and bedridden state.
• Common cause of death: Infection (e.g., pneumonia).

Diagnosis and Treatment

• Diagnosis is challenging.
  • Definitive diagnosis is made post-mortem via brain biopsy.
  • Clinicians diagnose by excluding other dementia causes.
• No known cure for Alzheimer Disease.
  • Existing medications provide small benefits, no definitive treatments halt progression.