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Alzheimer Disease
Alzheimer Disease
EPIDEMIOLOGY
AD is the most common cause of dementia. AD unassociated with any other pathology
accounts for 50% to 60% of cases of latelife cognitive dysfunction. The incidence increases to
80% if AD in conjunction with other pathologic lesions is considered.
Approximately 4.5 million Americans have AD.3 By the year 2050, 1 in 5 people will be
older than age 65 years, and the number of AD patients is projected to be 13.2 million
Most cases present in persons older than age 65 years, but approximately 5% of cases occur in
persons younger than age 65 years.
Onset can be as early as age 40 years, resulting in the arbitrary age classifications of early
onset (ages 40 to 64 years) and late-onset (ages 65 years and older)
ETIOLOGY
The exact etiology of AD is unknown; however, several genetic and environmental causes
have been explored as potential causes of AD.
The majority and most aggressive early onset cases are attributed to mutations of a gene
located on chromosome 14, which produces a protein called presenilin 1.7 A structurally
similar protein, presenilin 2, is produced by a gene on chromosome 1. Both presenilin 1 and
presenilin 2 encode for membrane proteins that may be involved in amyloid precursor protein
(APP) processing.
late-onset AD is thought to be primarily linked to the apolipoprotein E (apo E) genotype
AD occurs at an early age in some individuals, and AD is associated with vascular risk factors
such as obesity, diabetes, and hypertension.
Genetic variation at the angiotensin-converting enzyme locus may influence the risk for AD
Angiotensinconverting enzyme has also been demonstrated to inhibit βAP aggregation and
plaque formation in vitro
Alterations to chromosomes 1, 14, and 21 are associated with early onset AD, whereas the
presence of apo E4 alleles increases risk of developing late-onset AD
A number of environmental factors are associated with an increased risk of AD, including
age, decreased reserve capacity of the brain (reduced brain size, low educational level, and
reduced mental and physical activity in late life), head injury, and risk factors for vascular
disease (hypercholesterolemia, hypertension, atherosclerosis, coronary heart disease,
smoking, obesity, and diabetes)
PATHOPHYSIOLOGY
The signature lesions in AD are neuritic plaques and neurofibrillary tangles (NFTs) located in
the cortical areas and medial temporal lobe structures of the brain. Various theories are:
Cognitive
■ Memory loss (poor recall and losing items)
■ Aphasia (circumlocution and anomia)
■ Apraxia
■ Agnosia
■ Disorientation (impaired perception of time and unable to recognize familiar people)
■ Impaired executive function
Noncognitive
■ Depression, psychotic symptoms (hallucinations and delusions)
■ Behavioral disturbances (physical and verbal aggression, motor hyperactivity,
uncooperativeness, wandering, repetitive mannerisms and activities, and combativeness)
Functional
■ Inability to care for self (dressing, bathing, toileting, and eating)
DIAGNOSIS
Laboratory Tests
■ Rule out vitamin B12 and folate deficiency
■ Rule out hypothyroidism with thyroid function tests
■ Blood cell counts, serum electrolytes, liver function tests
Other Diagnostic Tests
■ CT or MRI scans may aid diagnosis
AD is through direct examination of brain tissue at autopsy or biopsy. Several criteria have
been developed for the detection and diagnosis of dementia, including the Diagnostic and
Statistical Manual of Mental Disorders, 4th ed. Text Revision (DSM-IV-TR) criteria
defective retention memory (amnesia) will implicate bimesiotemporal dysfunction.
Evidence of parietal cortical dysfunction (visuospatial dysfunction),
dorsolateral prefrontal dysfunction (executive dysfunction), or
lateral temporal dysfunction (language dysfunction)
TREATMENT
NONPHARMACOLOGIC THERAPY
Behavioral and psychiatric symptoms are among the most challenging and distressing
symptoms of the disease and may be the determining factor in a family’s decision to seek
institutional care.
Symptoms such as sleep disturbances, wandering, urinary incontinence, agitation, and
aggression in patients with dementia are best managed using behavioral interventions
Personal discomfort may also trigger behaviors, so it is important to monitor for pain, hunger,
thirst, constipation, full bladder, fatigue, infections and skin irritation, comfortable
temperature, fears, and frustrations
PHARMACOLOGICAL TREATMENT
In mild-moderate disease, consider therapy with a cholinesterase inhibitor.
1. Antiglutamatergic Therapy
• Memantine is the only NMDA antagonist currently available. Memantine blocks
glutamatergic neurotransmission by antagonizing NMDA receptors.
• Glutamate is an excitatory neurotransmitter in the brain implicated in long-term potentiation,
a neuronal mechanism important for learning and memory.
• By blocking NMDA receptors, excitotoxic reactions, which ultimately lead to cell death, may
be prevented
• It is currently indicated for use in AD patients with moderate to severe illness
• adverse events associated with memantine include constipation, confusion, dizziness,
headache, hallucinations, coughing, and hypertension
• Memantine is likely to be used as monotherapy and also in combination with cholinesterase
inhibitors
• Dose: initiated at 5 mg once a day and increased weekly by 5 mg a day to the effective dose
of 10 mg twice daily.
• It may be given with or without food. Dosing of 10 mg daily is recommended in patients with
severe renal impairment.
2. Cholinesterase Inhibitors
• Newer cholinesterase inhibitors donepezil, rivastigmine, and galantamine
• Donepezil specifically and reversibly inhibits acetylcholinesterase.
• Rivastigmine inhibits both butyrylcholinesterase and acetylcholinesterase.
• Galantamine is a selective, competitive, reversible acetylcholinesterase inhibitor and also
enhances the action of acetylcholine on nicotinic receptors
• The most frequent adverse events associated with these agents are mild to moderate
gastrointestinal symptoms (nausea, vomiting, and diarrhea
• Other cholinergic side effects are generally dose-related and include urinary incontinence,
dizziness, headache, syncope, bradycardia, muscle weakness, salivation, and sweating.
Gradual dose titration over several months can improve tolerability
• Abrupt discontinuation can lead to worsening cognition and behavior in some patients
• Donepezil 5 mg daily at bedtime
• Rivastigmine 1.5 mg twice a day , 4.6 mg/day (patch)
• Galantamine : 4 mg twice a day