Neuroscience/Objectives/Lecture 48

From PhysioWiki

Alzheimer's disease

Understand the basic pathophysiology of Alzheimer's disease.

In addition to sporadic AD (the most common type), there are also genetic forms of AD, and Down syndrome-associated AD. All share the basic pathophysiology of amyloid plaques, neurofibrillary tangles, and neurodegeneration (especially in the medial temporal lobe) that underlie the characteristics of AD. Amyloid plaques are the primary cause of AD's neuropathology.

Plaques result from extracellular deposits of amyloid-β peptide, a 42-amino acid derivative of amyloid precursor peptide (APP) that is overexpressed in AD. Three genes—APP (chromosome 21), PS1 (chromosome 14), and PS2 (chromosome 1)—are associated with familial (genetic) AD. The presenilins PS1 and PS2 are associated with the γ-secretase commplex, an enzyme responsible for the normal cleavage of APP. Specific mutations in APP, PS1, and PS2 lead to hyperactivity of the γ-secretase pathway, leading to inappropriate cleavage of APP to Aβ₄₂. Aβ₄₂ plaques are highly neurotoxic (via inflammation and oxidative stress) and may mediate the neurodegenerative processes of AD. Mutations in the APP gene may also accelerate the rate at which the APP protein is cleaved by β-secretase.

That amyloid plaques are responsible for most of the pathophysiology of AD is supported by several observations. Mutations in PS1 and PS2 are associated with increased γ-secretase activity and increased plaque formation. Similarly, APP mutations lead to increased cleavage by γ- and β-secretase. Also, Down syndrome patients have an extra chromosome 21, the chromosome on which APP is encoded. These patients have 50% more APP than normal, which would explain why nearly all DS patients eventually develop AD.

Describe the clinical manifestations of Alzheimer's disease.

Alzheimer's disease is the most common type of dementia. The diagnostic criteria for AD include:

• memory disturbance
• other dementia (deficit in one or more additional cognitive domain)
• language impairment
• impaired visuospatial function
• impaired executive function (foresight, planning, anticipation, insight)
• impaired praxis (learned motor skills)
• impaired function
• gradual onset and progressive cognitive decline
• not delirious
• must rule out other conditions that cause dementia

AD is characterized by a progressive decline in functional ability that correlates with MMSE scores. During the controversial prodromal period, patients may present with mild cognitive impairments or may have only slight functional impairments. At the onset of mild AD, patients exhibit gradual alterations in cognition, function, behavior, and mood, with hallmarks of forgetfulness and repetitive questions.

Patients with moderate AD exhibit short-term memory loss, impaired verbal fluency, the latter characterized by bouts of anomia. Severe AD begins when patients become agitated, delusional, aggressive, and wandering, and begin suffering from hallucinations. Afflicted patients become gradually dependent on others for daily tasks.

List tests and additional diagnostic tools for Alzheimer's disease.

Initial evaluation

• Vitamin B₁₂ and TSH tests: can be corrected easily
• Mini-mental state examination (which examines orientation, attention, immediate and delayed recall, visuospatial ability, aphasia, agnosia, and apraxia)
• Clock drawing test (evaluates presence of dementia)

Additional diagnostic tools

• Apolipoprotein E genotype: presence of the ε4 allele increases the likelihood of AD
• CSF Aβ and tau: patients with AD have ↓Aβ and ↑tau
• Functional imaging: PET and SPECT scans may show temporal-parietal hypofunction
• Structural imaging: rate of hippocampal and entorhinal cortex atrophy may be useful

Describe the current treatment options for Alzheimer's disease.

Cholinesterase inhibitors (eg, galantamine) and NMDA receptor antagonists (eg, memantine) are among the treatments for AD. AChE inhibitors enhance cholinergic signaling in the basal forebrain, while NMDAR antagonists relieve AD symptoms by unknown mechanisms involving the impairment of glutamate signaling. Antioxidants such as vitamin E are also used to slow cognitive decline.

Standard treatment includes:

• AChE inhibitor
• Memantine (for moderate AD)
• Vitamine E (in some cases)

Understand the strategies for developing new treatments for this illness.

• Amyloid peptide vaccines: immunization leads to antibodies that bind amyloid and promote its phagocytosis and clearance
• Secretase inhibitors: β- and γ-secretase are enzymes in the APP cleavage pathway. γ-secretase is essential for normal life, while β-secretase appears unnecessary and is therefore a great target for AD therapy.
• Amyloid binding compounds: promote clearance or disrupt aggregation of amyloid
• Anti-inflammatory agents: blocks one of the neurodegenerative mechanisms of AD
• Estrogen may be beneficial, based on epidemiological studies
• Statins may also be beneficial