ALZHEIMER’S DISEASE

 Alzheimer’s disease (AD) is the most common form of dementing illnessis

 It is a gradually progressive dementia affecting cognition, behavior, and functional status. The
exact pathophysiologic mechanisms underlying AD are not entirely known, and no cure
exists.Although drugs may reduce AD symptoms for a time, the disease is eventually fatal

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:

a) AMYLOID CASCADE HYPOTHESIS: Neuritic plaques (also termed amyloid or senile

plaques) are extracellular lesions found in the brain and cerebral vasculature. Plaques
from AD brains largely consist of a protein called βAP. βAP is produced via processing
of a larger protein, APP
 βAP gave rise to plaques, plaques induced neurodegeneration, and this neuronal loss resulted
in the clinical dementia syndrome typical of AD

b) NEUROFIBRILLARY TANGLES As βAP was being identified in plaques, other

researchers showed that NFTs are commonly found in the cells of the hippocampus and
cerebral cortex in persons with AD and are composed of abnormally hyperphosphorylated
tau protein.
 Tau protein provides structural support to microtubules, the cell’s transportation and skeletal
support system.
 When tau filaments undergo abnormal phosphorylation at a specific site, they cannot bind
effectively to microtubules, and the microtubules collapse.
 Without an intact system of microtubules, the cell cannot function properly and eventually
dies.
 The density of the NFTs correlates well with the severity of the dementia, because they are a
hallmark of neuronal death.
 NFTs are found in other dementing illnesses besides AD.

c) INFLAMMATORY MEDIATORS : brain amyloid deposition associates with local

inflammatory and immunologic alterations
 This inflammatory response may represent an attempt to clear amyloid deposition. However,
it is also associated with release of cytokines, nitric oxide, and other radical species, and
complement factors that can both injure neurons and promote ongoing inflammation
 Indeed, levels of multiple cytokines and chemokines are elevated in AD brains, and certain
proinflammatory gene polymorphisms are reported to be associated with AD

d) THE CHOLINERGIC HYPOTHESIS : Multiple neuronal pathways are destroyed in AD

 In late AD, the number of cholinergic neurons is reduced, and there is loss of nicotinic
receptors in the hippocampus and cortex.
 Presynaptic nicotinic receptors control the release of acetylcholine, as well as other
neurotransmitters important for memory and mood, including glutamate, serotonin, and
norepinephrine
 cholinergic cell loss appears to be a secondary consequence of Alzheimer’s pathology, not the
disease-producing event
 cholinergic neurons are only one of many neuronal pathways destroyed in AD.

e) OTHER NEUROTRANSMITTER ABNORMALITIES: , serotonergic neurons of the

raphe nuclei and noradrenergic cells of the locus ceruleus are lost
 monoamine oxidase type B activity is increased. Monoamine oxidase type B is found
predominantly in the brain and in platelets, and is responsible for metabolizing dopamine
 abnormalities appear in glutamate pathways of the cortex and limbic structures
 Glutamate is the major excitatory neurotransmitter in the cortex and hippocampus.
 If glutamate is allowed to remain in the synapse for extended periods of time, it can destroy
nerve cells.
 Toxic effects are thought to be mediated through increased intracellular calcium and
accumulation of intracellular free radicals.
 Dysregulated glutamate activity is thought to be one of the primary mediators of neuronal
injury after stroke or acute brain injury.
 f) BRAIN VASCULAR DISEASE AND HIGH CHOLESTEROL : Cardiovascular risk
factors that are also risk factors for dementia include hypertension, elevated low-density
lipoprotein cholesterol, low high-density lipoprotein cholesterol, and, particularly, diabetes.
 Brain vascular disease may augment the cognitive impairment
 Dysfunctional blood vessels may impair nutrient delivery to neurons and reduce clearance of
βAP from the brain.
 In addition, vascular disease may accelerate amyloid deposition and increase amyloid toxicity
to neurons
 Diabetes may increase the risk of dementia through factors related to “metabolic syndrome”
 Apo E is a lipoprotein that is synthesized in the liver, central nervous system, and
cerebrospinal fluid and is responsible for transporting cholesterol in the blood through the
brain. It is carried by low-density lipoprotein into neurons and binds to NFTs.
 Apo E4 is associated with increasing deposition of βAP and is thought to act as an
accelerating modulator in the course of vascular dementia.
 The elevated cholesterol levels in brain neurons may alter membrane functioning and result in
the cascade leading to plaque formation and AD

g) OTHER MECHANISMS: accumulation of free radicals in the brain of AD patients

 vitamin E and vitamin C, may prevent AD
 Estrogen is thought to be involved in promoting neuronal growth, and in preventing oxidative
damage, which would benefit cells exposed to βAP
 Estrogen may also increase NMDA receptor numbers in brain areas involved in recording
new memories and prevent cell damage by acting as an antioxidant
CLINICAL PRESENTATION

 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.

• Donepezil, or • Rivastigmine, or • Galantamine

• Titrate to recommended maintenance dose as tolerated.

In moderate to severe disease, consider adding antiglutamatergic therapy.

• Memantine • Titrate to recommended maintenance dose as tolerated.

• Alternatively, consider memantine or cholinesterase inhibitor therapy alone.
• Behavioral symptoms may require additional pharmacologic approaches.

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

Other Potential Treatment Approaches

3. Estrogen : Estrogen replacement has been studied extensively for the treatment and
prevention for AD
4. Antiinflammatory Agents: Epidemiologic studies suggest a protective effect against AD
in patients who have taken NSAID.
• Indomethacin, prednisone, and diclofenac/misoprostol administration have had
no cognitive benefit in AD patients
• gastritis and the possibility of gastrointestinal bleeds, NSAIDs and prednisone are
not recommended for general use in the treatment or prevention of AD at the
present time
• Rofecoxib has been compared to naproxen and placebo with no demonstrated
cognitive benefit after 1 year
5. Lipid-Lowering Agents: 3-hydroxy3-methylglutaryl-coenzyme A-reductase inhibitors
6. Vitamin E Based on pathophysiologic theories involving oxidative stress and the
accumulation of free radicals in AD, Vitamin E is often recommended as adjunctive
treatment for AD patient
• Side effects observed with vitamin E administration include impaired hemostasis,
fatigue, nausea, diarrhea, and abdominal pain. For example, vitamin E can cause
thinning of the blood if it is taken with other medications such as aspirin,
ibuprofen, and/or naproxen
7. Ginkgo Biloba : Ginkgo is one of the most popular dietary supplements used in AD.
 Hypothesized mechanisms of action in AD include increasing blood flow,
decreasing the viscosity of blood, antagonizing platelet activating factor
receptors, increasing tolerance to anoxia, inhibiting monoamine oxidase,
antiinfective properties, and preventing the damage of membranes caused by free
radicals.
 Ginkgo biloba may also inhibit catecholamine-O-methyl transferase
 Side effects reported in studies involving EGb 761 are rare and usually mild, and
may include nausea, vomiting, diarrhea, headaches, dizziness, palpitations,
restlessness, and weakness
8. Huperzine A: Huperzine A is an alkaloid isolated from the Chinese club moss, Huperzia
serrata. It reversibly inhibits acetylcholinesterase and is administered orally in doses of 50
to 200 mcg two to four times daily. Clinical studies suggest that huperzine A may be
promising for symptomatic treatment of Alzheimer’s disease
Antipsychotics Psychosis:
Haloperidol : starting dose(sd)-0.25mg , maintenance dose in dementia(md)-1–3 mg/day
Olanzapine : starting dose-2.5 mg, maintenance dose in dementia 5–10 mg/day
Quetiapine starting dose-25 mg, maintenance dose in dementia 100–300 mg/day
Risperidone starting dose-0.25 mg, maintenance dose in dementia 0.75–2 mg/day
Ziprasidone starting dose-20 mg, maintenance dose in dementia 40–160 mg/day
Target symptoms: hallucinations, delusions, suspiciousness Disruptive behaviors: agitation,
aggression
Antidepressants
Citalopram: sd-10mg, md- 10–20mg/kg
Escitalopram : sd-5mg, md- 20–40 mg/kg
Fluoxetine : sd-5mg, md- 10–40 mg/kg
Paroxetine: sd-10mg, md- 10–40 mg/kg
Sertraline : sd-25mg,md- 75–100 mg/kg
Venlafaxine : sd-25mg, md- 75–225 mg/kg
Trazodone : sd-25mg, md- 75–150 mg/kg
Target symptoms: Depression, poor appetite, insomnia, hopelessness, anhedonia, withdrawal, suicidal
thoughts, agitation, anxiety
Anticonvulsants
Carbamazepine: sd-100mg, md- 200–600 mg/kg
Valproic Acid: sd-125mg, md- 500–1,000mg/kg
Target syndrome: Agitation or aggression