Introduction to Alzheimer's Disease

Introduction to Alzheimer's Disease

• Affects approximately 7.5 million Americans of all ages
• Progressive illness
• Loss of cognitive and physical function
• Often accompanied by behavioral symptoms
• Unknown cause

Pathophysiology

• Genetic susceptibility to late-onset AD is primarily linked to the APOE genotype, but environmental factors also play a role

• Young-onset AD is less than 1% of cases and is linked to chromosomal alterations affecting the amyloid precursor protein

• Risk factors include: age, decreased brain reserve, head injury, Down syndrome, depression, mild cognitive impairment, and risk factors for vascular disease (high blood pressure, high cholesterol, obesity, metabolic syndrome, diabetes, and elevated homocysteine)

• Characteristic lesions include: intracellular neurofibrillary tangles (NFTs), extracellular plaques in the cortex and medial temporal lobe, neuron and synapse degeneration, and cortical atrophy

• Proposed mechanisms:

  • beta-amyloid protein aggregation leading to plaques
  • hyperphosphorylation of tau protein leading to NFTs
  • synaptic failure and neurotransmitter depletion
  • mitochondrial dysfunction
  • oxidative stress

• Amyloid cascade hypothesis suggests an imbalance in beta-amyloid production and clearance leading to aggregation and accumulation, which is a possible primary contributor to AD pathology in most cases.

• Cholinergic activity loss is a significant neurotransmitter deficit correlating with AD severity, potentially resulting from AD pathology instead of being a cause.

• Other neurotransmitters affected include serotonin, norepinephrine, glutamate, and excitatory neurotransmitters like glutamate, potentially being neurotoxic.

Clinical Presentation

• Early stages involve changes in learning, memory, planning, organization, and mood
• Progression includes further declines in cognitive domains, personality changes, judgment, speech, and spatial orientation
• Late-stage functional decline leads to inability to walk, speak, feed themselves, incontinence, and behavioral changes, requiring 24/7 care

Diagnosis

• AD is a spectrum of preclinical, preclinical symptomatic, and dementia stages
• Clinical diagnosis, mostly based on symptoms and difficulty with daily activities from patient and caregiver interviews.
• Laboratory tests (B12, folate, thyroid panel, blood cells, electrolytes, liver function) should be considered
• Structural imaging (non-contrast CT or MRI) might be done to assess brain structure and identify abnormalities, and possible cerebrospinal fluid and electroencephalogram tests might be used to rule out other diagnoses.
• Ruling out other causes (medication side effects, trauma, depression, head injury, substance use, medical history) is important.
• APOE genetic testing is not a recommended diagnostic tool currently.
• The Folstein Mini Mental State Examination (MMSE) helps assess cognitive decline over time.

Treatment

• Non-pharmacological therapy involves: identifying causative factors for symptoms and adapting the environment for better care, management of sleep disturbances, wandering, urinary incontinence and aggression, education for patient and caregivers about the disease course, lifestyle modifications (smoking cessation, increasing physical activity).
• Pharmacologic therapy includes:
  • Anti-amyloid monoclonal antibody therapies (like aducanumab) for mild-stage AD
  • Cholinesterase inhibitors (for moderate to moderate-severe stage)
  • Anti-glutamatergic agent memantine (for moderate to severe stages)
• Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) are often used with memantine.
• If symptoms warrant it, AD medication treatment often necessitates a gradual titration of medication doses.
• Treatment efficacy is measured by observing clinical and cognitive improvements.
• Success can involve a possible slowing-down of cognitive decline, and improvements in daily living activities.

Monitoring and Side Effects

• Monitoring parameters (skin rash appearance, reaction spread, dizziness, falls, hallucinations) are important due to possible adverse drug reactions associated with medications.
• Monitoring parameters often include frequent lab work, symptom checks, and physical examinations.
• Various adverse effects identified include skin rashes, allergic dermatitis, and dizziness / syncope.