Alzheimer’s Disease 3RD

YEAR,
PRPM161 LECTURE - CASE STUDY ANALYSIS 1ST SEM
GROUP # 6 Module 5

TYPES OF ALZHEIMER’S DISEASE

DEMENTIA
Early-onset Alzheimer
Dementia - umbrella term for a host of neurodegenerative
● Happens to people who are younger than age 65,
diseases which cause progressive cognitive decline that
often in their 40s or 50s when they’re diagnosed.
interferes with the body’s ability to function
● IT IS RARE – up to 5% of all people with AD this type.
independently.
● People with Down syndrome have a higher risk for it.
○ Symptoms are gradual, persistent, and progressive.
● The three single-gene mutations associated with
○ Memory, language, visuospatial and perceptual
early-onset Alzheimer’s are:
ability, thinking and problem solving, and personality
○ Amyloid precursor protein (APP) on chromosome 21
are affected.
○ Presenilin 1 (PSEN1) on chromosome 14
○ It is neurodegenerative, so there is gradual onset at
○ Presenilin 2 (PSEN2) on chromosome 1
times of stress or change.
Late-onset Alzheimer’s
○ THERE IS NO CURE FOR ANY OF THE DEMENTIAS,
● It is the most common form of the disease, which
except for pseudo-dementias.
happens to people age 65 and older
● APOE4 gene is the gene variant that increases risk of
TYPES OF DEMENTIA late-onset Alzheimer’s disease
● Alzheimer’s Disease (AD)
● Vascular dementia (VaD)
● Dementia with Lewy Bodies (DLB) PATHOPHYSIOLOGY
The rarer dementias ● Dominantly inherited forms of AD are fewer than 1% of
● Parkinson’s disease dementia cases
● Frontotemporal dementia ● Chromosomes 1, 14, or 21
● Corticobasal degeneration ○ attributed to more than half of young-onset,
● Progressive supranuclear palsy dominantly inherited cases
● Creutzfeldt-Jakob disease ● Apolipoprotein E (APOE) genotype
● Multiple sclerosis, Niemann-Pick disease type C, ○ is primary linked to the genetic susceptibility to
Normal pressure hydrocephalus, Posterior cortical late-onset AD
atrophy, Alcohol-related brain damage ○ but an interaction of multiple genes with the
Risk factors for dementia environment may be at play.

1. Age c

2. Lifestyle factors RISK FACTORS

3. Concomitant disease
4. Genetic (small-proportion of cases) ● Age ● Risk factors for
Protective factors for dementia ● Decreased reserve vascular disease,
1. Higher education capacity of the brain including
2. More mentally demanding occupations ● Head injury ○ Hypertension
3. Cognitive stimulation ● Down syndrome ○ Elevated low-density
4. Social engagement ● Depression lipoprotein
● Mild cognitive ○ Cholesterol
Differential diagnosis of dementia mnemonic impairment ○ Low high-density
D Drugs lipoprotein
E Emotional problems, eyes, ears cholesterol
M Metabolic ○ Diabetes
E Endocrine
N Nutritional deficiency
T Tumor
I Infection
A Anemia or alcohol
S Systemic disease

ALZHEIMER'S DISEASE
Alzheimer’s disease (AD) is a progressive and eventually
fatal dementia of unknown cause characterized by loss of
cognitive and physical functioning, commonly with
behavior symptoms.

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 DIAGNOSIS

Diagnostic features of AD
● An insidious onset of symptoms, predominantly
memory loss in the early stages.
● Progressive cognitive and physical decline is
observed, with emergence of aphasia and agnosia
(failure of recognition) in later stages.

Ascertaining Severity of AD
● Can be supplemented by clinically based
assessments such as biological review
SIGNATURE FINDINGS ○ Ex. Clinician Interview Based Impression of Severity
● Intracellular neurofibrillary tangles (NFTs) (CIBIS) and Clinician Interview Based Impression of
○ Density of NFTs correlates with severity of Change (CBIC)
dementia
● Extracellular amyloid plaques in the cortex and The Folstein Mini-Mental State Examination (MMSE)
medial temporal lobe ● Can help establish a history of deficits in two or more
● Degeneration of neurons and synapses and cortical areas of cognition at baseline against which to
atrophy. evaluate change in severity over time
● The average expected decline in an untreated patient
PROPOSED MECHANISMS is 2 to 4 points per year
1. β-amyloid protein aggregation leading to formation of
plaques Mild ● difficulty remembering recent
(MMSE score 26–18) events
2. Hyperphosphorylation of tau protein, leading to NFTs
● inability to manage finances,
3. Synaptic failure and depletion of neurotrophin and prepare food, and carry out other
neurotransmitters household activities declines
4. Mitochondrial dysfunction ● may get lost while driving
5. Oxidative stress ● begins to withdraw from difficult
tasks and to give up hobbies
● may deny memory problems
NEUROTRANSMITTER DEFICITS
● Loss of cholinergic activity is most prominent Moderate ● requires assistance with activities
(MMSE score 17–10) of daily living
○ Correlates with AD severity
● frequently disoriented with regard
● Cholinergic cell loss seems to be a consequence of to time (date, year, and season)
AD pathology, not the cause of it ● recall for recent events is severely
impaired
OTHER NEUROTRANSMITTER CONSIDERATIONS ● may forget some details of past life
1. Serotonergic neurons of the raphe nuclei and and names of family and friends
noradrenergic cells of the locus coeruleus are lost ● functioning may fluctuate from day
2. Mono-amine oxidase type B activity is increased to day
● patient generally denies problems
3. Glutamate pathways of the cortex and limbic
● may become suspicious or tearful
structures are abnormal ● loses ability to drive safely
4. Excitatory neurotransmitters, including glutamate, may ● agitation, paranoia, and delusions
be neurotoxic in AD are common

CLINICAL PRESENTATIONS Severe ● loses ability to speak, walk, and

(MMSE score 9–0) feed self
● incontinent of urine and feces
● Cognitive decline ● Depression ● requires care 24 hours a day, 7 days
○ Gradual ● Psychotic symptoms a week
○ Memory loss ● Aggression
○ Aphasia (unable to ● Motor hyperactivity
● The diagnostic criteria of the National Institute on
communicate) ● Uncooperativeness
Aging and the Alzheimer’s Association view AD as a
○ Apraxia (unable to ● Wandering
spectrum
perform tasks or ● Combativeness
○ Beginning with an asymptomatic preclinical phase
movements) ● Increasingly unable to
○ Progressing to the symptomatic preclinical phase
○ Agnosia (unable to care for themselves
○ Finally then to the dementia phase.
recognize and
● AD is a clinical diagnosis, based largely on identified
identify)
symptoms and difficulty
○ Disorientation
○ With Activities of daily living revealed by patient
○ Impaired executive
and caregiver interviews
function
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 ● In the future, improved brain imaging and validated ● Reasonable expectations of treatment may be a
biomarkers of disease will enable a more slowed decline in abilities and delayed long-term care
sophisticated diagnosis placement
○ With identified cognitive strengths and ● Those who respond to treatment may lose the
weaknesses and neuroanatomic localization of benefits when medication is stopped
deficits

METHOD OF DIAGNOSIS CHOLINESTERASE INHIBITORS

● Patients with suspected AD should have a history and
physical examinations with appropriate laboratory Drug (w/ Dose Other
tests brand name)
○ Serum B12, folate, thyroid panel, blood cell counts,
serum electrolytes, and liver function tests Donepezil Initial Dose: ● Available as: tablet,
(Aricept®, ● 5 mg daily in the orally disintegrating
● Computed tomography
Aricept ODT®) evening tablet (ODT)
● Magnetic resonance imaging may aid diagnosis Usual Range: ● Can be taken with or
● Cerebrospinal fluid analysis or an ● 5–10 mg daily in without food
electroencephalogram mild to moderate ● Weight loss
○ Done to exclude other diagnoses AD associated with 23
● 10–23 mg daily in mg daily dose
OTHER METHODS OF DIAGNOSIS moderate to
severe AD
- Obtain other medication use; alcohol or other
substance use
Rivastigmine Initial Dose: ● Available as:
○ Rule out the following medications as contributors
(Exelon®, ● 1.5 mg twice daily capsule, oral
to dementia symptoms Exelon (capsule, oral solution,
■ anticholinergics, sedatives, hypnotics, opioids, Patch®) solution) transdermal patch
antipsychotics, and anticonvulsants ● 4.6 mg/day ● Take with meals
○ Rule out medications that can cause delirium (transdermal ● Also indicated for
■ digoxin, nonsteroidal anti-inflammatory drugs patch) dementia associated
[NSAIDs], histamine 2 [H2] receptor Usual Range: with Parkinson’s
antagonists, amiodarone, antihypertensives, ● 3-6 mg twice disease
daily (capsule, ● Application of
and corticosteroids
oral solution) multiple transdermal
- Family medical history ● 9.5-13.3 mg/day patches at same
- History of trauma, depression, or head injury (transdermal time associated with
patch) hospitalization and
TREATMENT death
Goals of Treatment:
Galantamine Initial Dose: ● Available as:
● The goal of treatment in AD is to maintain functioning
(Razadyne®, ● 4 mg twice daily capsule, oral
as long as possible Razadyne (tablet, oral solution, extended
● Secondary goal is to treat the psychiatric and ER®) solution) release capsule
behavioral sequelae. ● 8 mg/day in the ● Take with meals
● For mild to moderate AD morning
○ consider use of a cholinesterase inhibitor, and (extended release
titrate to maintenance dose capsule)
● For moderate to severe AD Usual Range:
● 8-12 mg twice
○ consider adding memantine, and titrate to
daily (tablet, oral
maintenance dose. solution)
● Alternatively, consider memantine or cholinesterase ● 16-24 (extended
inhibitors alone release capsule)
● Treat behavior symptoms with support and behavior
interventions SPECIAL POPULATION DOSE
● Use pharmacological management only if necessary
Rivastigmine
NONPHARMACOLOGIC THERAPY ➔ Moderate to severe renal impairment, mild to
Behavioral and Environmental Interventions moderate hepatic impairment, or low body weight
● Sleep disturbances, wandering, urinary incontinence, (<50 kg [110 lb]): consider maximum daily dose of 4.6
agitation, and aggression should be managed mg every 24 hours (transdermal patch)
Galantamine
● Patients and caregivers should be educated on the:
➔ Moderate renal or hepatic impairment: maximum daily
○ course of illness dose of 16 mg
○ available treatments ➔ Severe renal or hepatic impairment: not
○ legal decisions recommended
○ changes in lifestyle that will become necessary
OVERALL CONSIDERATIONS
○ other quality-of-life issues.
● When switching from one cholinesterase inhibitor to
another, 1 week washout is generally sufficient
PHARMACOTHERAPY OF COGNITIVE SYMPTOMS ● No comparative trials have assessed the
● Managing blood pressure, cholesterol, and blood effectiveness of one agent over another.
sugar may reduce the risk of developing AD ○ Donepezil, rivastigmine, and galantamine are
indicated
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 ○ Donepezil is also indicated for severe AD
bleeding active or occult at increased risk of
GI bleeding developing ulcers,
such as those with a
● Change to a different cholinesterase inhibitor if: history of ulcer
○ Decline in MMSE score is more than 2 to 4 points disease or
after treatment for 1 year with the initial agent concurrently taking
○ Patient experiences severe adverse reactions NSAIDs
● Donepezil, Rivastigmine, and Galantamine have
similar efficacy in mild to moderate AD Insomnia, ● Complaints of ● Donepezil can be
○ Duration of benefit lasts 3 to 12 months vivid/abnormal sleep taken in the morning
dreams, disturbances, to decrease risk of
● Rivastigmine and Galantamine have short half lives
nightmares daytime sleep disturbances
○ Interrupted treatment for several days or longer drowsiness
must retitrate starting at the lowest dose once
medication is administered again
MECHANISM OF ACTION
ADVERSE EFFECTS ● Neurotransmitter Acetylcholine is vital for the brain’s
● Mild to moderate gastrointestinal (GI) symptoms state of attention and arousal, as well as for
(nausea, vomiting, and diarrhea), maintaining memory and cognitive function
● Urinary incontinence ● Alzheimer’s patients have reportedly low levels of
● Dizziness ACh due to the activity of Cholinesterase enzymes in
● Head-aches our neurons
● Syncope or loss of consciousness for a short period of ● Cholinesterase enzymes break down acetylcholine
time and prevent reuptake, causing low ACh levels
● Bradycardia ● Cholinesterase inhibitors block said enzymes to
● Muscle weakness prevent ACh breakdown
● Salivation NMDA RECEPTOR ANTAGONISTS
● Sweating
● Abrupt discontinuation can cause worsening of Drug (w/ Dose Other
cognition and behavior in some patients. brand name)

ADR Monitoring Comments Memantine Initial Dose: ● Available as: tablet,

Parameter (Namenda®, ● 5 mg daily oral solution,
Namenda ● 7 mg daily extended-release
Dizziness, Reports of: ● Dizziness is usually XR®) (extended- capsule
syncope, ● Dizziness or mild, transient, and ● release capsule) ● Can be taken with or
bradycardia, falls not related to Usual Range: without food
atrial ● Pulse. Blood cardiovascular ● 5–10 mg daily in
arrhythmias, pressure and problems mild to moderate
myocardial postural blood ● Routine pulse AD
infarction, pressure checks at baseline, ● 10 mg twice daily
angina, changes monthly during ● 28 mg daily
seizures, titration, and every 6 (extended-release
sinoatrial and months thereafter capsule)
atrioventricular
block
SPECIAL POPULATION DOSE
Nausea, ● Weight and GI ● Take with food to Memantine
vomiting, complaints decrease GI upset ➔ Severe renal impairment: target maintenance dose of
diarrhea, ● Usually transient, 5 mg twice daily (tablet, oral solution) or 14 mg daily
anorexia, dose-related GI (extended-release capsule)
and weight loss adverse effects seen
with drug initiation, OVERALL CONSIDERATIONS
dosage titration, or
drug switch ● Memantine blocks glutamatergic neurotransmission
● Debilitated patients by antagonizing N-methyl-d-aspartate receptors
or those weighing ● May prevent excitotoxic reactions
<55 kg (121 lb) may ● Used as monotherapy and in combination with a
be more likely to cholinesterase inhibitor
experience GI ● Indicated for treatment of moderate to severe AD,
adverse effects and
but not for mild AD
significant weight
loss, particularly ● Not metabolized by the liver but is primarily excreted
when rivastigmine is unchanged in the urine
prescribed or when ● Dosing must be adjusted in patients with renal
titrating to donepezil impairment
23 mg ● Usually well tolerated
● GI adverse effects
less prominent with
transdermal versus
oral rivastigmine

Peptic ulcer ● Signs or ● Of particular

disease, GI symptoms of concern for patients
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ADVERSE EFFECTS ● Avoid anticholinergic psychotropic medications as
they may worsen cognition.
● constipation, confusion, dizziness, and headache
CHOLINESTERASE INHIBS. AND MEMANTINE
ADR Monitoring Comments
Parameter
● Have shown modest improvement of behavioral
symptoms over time
Headache, Reports of: ● Confusion may be ● But may not significantly reduce acute agitation
confusion, ● Dizziness or observed during
dizziness, falls dose titration and is
ANTIPSYCHOTICS
hallucinations ● Hallucinations usually transient ● Have traditionally been used for disruptive behaviors
● Memantine may and neuropsychiatric symptoms
mitigate GI adverse ● Risks and benefits must be carefully weighed.
effects associated ● 17% to 18% of dementia patients showed a modest
with cholinesterase
treatment response with atypical antipsychotics
inhibitor therapy
● Adverse events offset advantages
Constipation ● GI complaints
○ eg, somnolence, extrapyramidal symptoms,
abnormal gait, worsening cognition,
cerebrovascular events, and increased risk of
MECHANISM OF ACTION death [see black-box warning]
● NMDA receptors are vital for neuronal mechanisms ● Aripiprazole, Olanzapine and Risperidone.
like memory formation ○ Patients treated display small but significant
● Presence of Tau Tangles (NFTs) or b-amyloid plaques improvement in behavioral symptom scores
may trigger an excess production of the ● Typical antipsychotics may also produce a small
neurotransmitter Glutamate increased risk of death, and more severe
● Interaction of excess Glutamate to NMDA receptors extrapyramidal effects and hypotension than the
can cause an influx of intracellular calcium atypicals.
● Hypercalcemia can promote apoptosis or cell death ● Antipsychotic treatment in AD patients should rarely
● NMDA receptor antagonists block NMDA receptors be continued beyond 12 weeks
from binding with glutamate in order to prevent
influx of intracellular calcium
Drug Starting Dose (mg) Maintenance Dose in
OTHER DRUGS Dementia (mg/day)
● Guidelines recommend low-dose aspirin in AD
patients with significant brain vascular disease. Aripiprazole 10–15 30 (maximum)
● Trials do not support the use of estrogen to prevent
Olanzapine 2.5 5-10
or treat dementia.
● Vitamin E is under investigation for prevention of AD
Quetiapine 25 100-400
and is not recommended for treatment of AD.
● Because of the incidence of side effects and a lack of
Risperidone 0.25 0.5-2
supporting evidence, neither NSAIDs nor prednisone
is recommended for treatment or prevention of AD.
● Trials of statin drugs have not shown significant TARGET SYMPTOMS
benefit in prevention or treatment of AD. ● Psychosis: hallucinations, delusions, suspiciousness
● Because of limited efficacy data, the potential for ● Disruptive behaviors: agitation, aggression
adverse effects (eg, nausea, vomiting, diarrhea, ANTIDEPRESSANTS
headache, dizziness, restlessness, weakness, and
hemorrhage), and poor standardization of herbal ● Depression and dementia share many symptoms
products, ginkgo biloba is not recommended for ● The diagnosis of depression can be difficult,
prevention or treatment of AD. especially later in the course of AD
● Do not use ginkgo biloba in individuals taking ● A selective serotonin reuptake inhibitor (SSRI) is
anticoagulants or antiplatelet drugs, and use usually given to depressed patients with AD the best
cautiously in those taking NSAIDs. evidence is for Sertraline and Citalopram
● Huperzine A has not been adequately evaluated and ● Tricyclic antidepressants are usually avoided.
is not currently recommended for treatment of AD.
Drug Starting Dose (mg) Maintenance Dose in
PHARMACOTHERAPY OF NONCOGNITIVE SYMPTOMS Dementia (mg/day)

● Symptoms target psychotic symptoms, inappropriate Citalopram 10 10-20

or disruptive behavior, and depression
● General guidelines include the following: Escitalopram 5 10 (maximum)
a. Use environmental interventions first and
pharmacotherapy only when necessary Fluoxetine 10 10-20
b. Identify and correct underlying causes of
disruptive behaviors when possible Paroxetine 10 10-40
c. Start with reduced doses and titrate slowly;
d. Monitor closely; Sertraline 12.5 150 (maximum)
e. Periodically attempt to taper and discontinue
medication; Mirtazapine 15 15-30
● Document carefully.
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 Trazodone 25 75-150

TARGET SYMPTOMS
● Depression: poor appetite, insomnia, hopelessness,
anhedonia, withdrawal, suicidal thoughts, agitation,
anxiety

MISCELLANEOUS THERAPIES
● Use of benzodiazepines is not advised except on an
“as needed” basis for infrequent episodes of
agitation.
● Carbamazepine, valproic acid, and gabapentin may
be alternatives
○ Evidence is conflicting.

Drug Starting Dose Maintenance Dose in

(mg) Dementia (mg/day)

Carbamazepine 100 300-600

Valproic acid 125 500-1,500

TARGET SYMPTOMS
● Agitation or aggression

PHARMACOTHERAPY OF NONCOGNITIVE SYMPTOMS

● At baseline interview both patient and caregiver,
identify target symptoms;
○ Define therapeutic goals
○ Document cognitive status, physical status,
functional performance, mood, thought processes,
and behavior.
● MMSE
○ for cognition, Physical Self-Maintenance Scale for
activities of daily living, and
● Neuropsychiatric Inventory Questionnaire
○ for assessment of behavioral disturbances
○ should be used to quantify changes in symptoms
and functioning
● Observe the patient carefully for potential side
effects
● The specific side effects to be monitored and the
method and frequency of monitoring should be
documented.
● Assess for drug effectiveness, side effects,
adherence to regimen, and need for dosage
adjustment or change in treatment at least monthly.
● Several months to 1 year of treatment may be
required to determine whether therapy is beneficial.

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