One of the most commonly seen Neuro-degenerative disease. Let's go through the Pathophysiology and management of AD.

1. ASSIGNMENT
ALZHEIMER’S DISEASE
Submitted to,
Dr. Sreeja P A
Dept. of Pharmacy Practice
Submitted By,
Ameena Kadar K A
Second Sem M Pharm
Dept. of Pharmacy Practice
Sanjo College of Pharmaceutical Studies

2. ALZHEIMER’S DISEASE
 INTRODUCTION
 Alzheimer’s is a disease of the brain that causes problems with memory, thinking and
behavior. It is not a normal part of aging.
 Alzheimer's disease (AD), also known as Senile Dementia of the Alzheimer Type (SDAT)
or simply Alzheimer’s is the most common form of dementia.
 This incurable, degenerative, terminal disease was first described by a German
psychiatrist and neuropathologist Alois Alzheimer in 1906 and was named after him.
 Alzheimer disease (AD) is the most common form of dementing illness, and the prevalence
of AD increases with each decade of life.
 The etiology of AD is unknown, and current pharmacotherapy neither cures nor arrests the
pathophysiology.
 Neuritic plaques and neurofibrillary tangles (NFTs) are the pathologic hallmarks of AD;
however, the definitive cause of this disease is yet to be determined.
 Alzheimer disease affects multiple areas of cognition and is characterized by a gradual onset
with a slow, progressive decline.
 EPIDEMIOLOGY
 Alzheimer disease is the most common cause of dementia, accounting for approximately
60% of cases in persons over age 65 years.
 Its prevalence among dementia patients increases to 80% if AD lesions in conjunction with
other pathologic brain lesions are considered.
 Alzheimer’s is predicted to affect 1 in 85 people globally by 2050.
 In 2006, there were 26.6 million sufferers worldwide.

3.  ETIOLOGY
 The exact etiology of AD is unknown; however, several genetic and environmental factors
have been explored as potential causes.
1. Genetic factors have been linked to both early- and late-onset AD.
 More than half of early-onset, dominantly inherited cases of AD can be attributed to
alterations on chromosomes 1, 14, or 21.
 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.
 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.
 Scientists have identified more than 160 mutations in presenilin genes, and these mutations
appear to result in reduced activity of γ-secretase, an enzyme important in β-amyloid
peptide (Aβ) formation.
 APP is encoded on chromosome 21.
 Only a small number of early-onset familial AD cases have been associated with mutations
in the APP gene, resulting in overproduction of Aβ or an increase in the proportion of Aβ
ending at residue 42.
 Genetic susceptibility to late-onset AD is primarily linked to the apolipoprotein E (APOE)
genotype.
 There are three major subtypes or alleles of APOE (eg, *2, *3, and *4).
 Inheritance of the APOE*4 allele is believed to account for much of the genetic risk in late-
onset AD.
 The mechanism through which APOE*4 confers an increased risk is unknown, although
APOE*4 is associated with factors that may contribute to AD pathology, such as
abnormalities in mitochondria, cytoskeletal dysfunction, and low glucose usage.
 The risk for AD is twofold to threefold higher in individuals with one APOE*4 allele and 12-
fold higher in individuals with two APOE*4 alleles compared to those with no APOE*4
alleles.
 Moreover, onset of symptoms occurs at a relatively younger age as compared with patients
having zero or only one copy of APOE*4 in their genotype10 Of note, the APOE*4 allele is
not diagnostic of AD or even essential for disease presence.
2. Environmental and Other Factors
 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, Down syndrome, depression,

4. mild cognitive impairment (MCI), and risk factors for vascular disease
(hypercholesterolemia, hypertension, atherosclerosis, coronary heart disease, smoking,
elevated homocysteine, obesity, metabolic syndrome, and diabetes).
 The incidence of AD rises with increasing age, and AD may develop in individuals over the
course of decades, suggesting that AD is a disease most people are in the process of
developing throughout adulthood.
 PATHOPHYSIOLOGY
 The signature lesions in AD are amyloid plaques and neurofibrillary tangles (NFTs) located
in the cortical areas and medial temporal lobe structures of the brain.
 Several mechanisms have been proposed to explain changes in the brain that result in
symptoms of AD, including:
 Misfolding of proteins (Aβ aggregation and deposition leading to the formation of
plaques and hyperphosphorylation of tau protein leading to NFT development)
 Synaptic failure and depletion of neurotrophin and neurotransmitters
 Mitochondrial dysfunction (oxidative stress, impaired insulin signaling in the brain,
vascular injury, inflammatory processes, loss of calcium regulation, and defects in
cholesterol metabolism).

5. 1. Amyloid Cascade Hypothesis
Amyloid plaques are extracellular lesions found in the brain and cerebral vasculature. Plaques
largely consist of Aβ. Aβ peptides consisting of 36 to 43 amino acids are produced via
processing of a larger protein, APP. Aβ42 is less common than other Aβ peptides, but is prone to
aggregation and plaque formation. The amyloid cascade hypothesis states that there is an
imbalance between the production and clearance of Aβ peptides resulting in aggregation that
causes accumulation of Aβ ultimately leading to AD.
Studies on early-onset AD and patients with Down syndrome led to the formulation of the
amyloid cascade hypothesis. Recent versions of the amyloid cascade hypothesis assume Aβ that
is not sequestered in plaques actually drives the disease. Even so, the amyloid cascade
hypothesis seems most applicable in cases of early-onset, autosomal dominant AD.
2. Neurofibrillary Tangles
At the same time as Aβ 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 with the severity of the dementia. NFTs are found in other dementing illnesses besides
AD, and may represent a common method by which various inciting factors culminate in cell
death.
3. Inflammatory Mediators
Inflammatory or immunologic paradigms are often viewed as a corollary of the amyloid cascade
hypothesis. Certainly, brain amyloid deposition associates with local inflammatory and
immunologic alterations. This led some to propose that inflammation is relevant to AD neuro-
degeneration.
Inflammatory/immunologic hypotheses argue that although Aβ may have direct neurotoxicity, at
least some of its toxicity might actually be an indirect consequence of an Aβ protofibril-induced
microglia activation and astrocyte recruitment. 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 pro-inflammatory gene polymorphisms are reported to be
associated with AD. Consistent with these molecular observations are epidemiologic data

6. suggesting that exposure to Non-steroidal anti-inflammatory drugs (NSAIDs) may reduce
AD risk. However, multiple prospective short duration trials of NSAIDs in AD prevention and
of NSAIDs as AD treatment have been disappointing.
4. The Cholinergic Hypothesis
Multiple neuronal pathways are destroyed in AD. Neuronal damage can be seen in conjunction
with plaque structures. Wide spread cell dysfunction or degeneration results in a variety of
neurotransmitter deficits, with cholinergic abnormalities being the most prominent. Loss of
cholinergic activity correlates with AD severity. In the late stage of 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. The discovery of vast cholinergic cell loss led to the development of a
cholinergic hypothesis of the pathophysiology of AD.
The cholinergic hypothesis targeted cholinergic cell loss as the source of memory and
cognitive impairment in AD. Consequently, it was presumed that increasing cholinergic function
would improve symptoms of memory loss. This approach is flawed because cholinergic cell loss
appears to be a secondary consequence of AD pathology, not the disease-producing event, and
cholinergic neurons are only one of many neuronal pathways destroyed in AD. Simple addition
of acetylcholine cannot compensate for the loss of neurons, receptors, and other
neurotransmitters lost during the course of the illness. Thus the goal is to minimize or improve
symptoms through augmentation of neurotransmission at remaining synapses.
5. Other Neurotransmitter Abnormalities
Serotonergic neurons of the raphe nuclei and noradrenergic cells of the locus ceruleus are
lost, while 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. In
addition, abnormalities appear in glutamate pathways of the cortex and limbic structures,
where a loss of neurons leads to a focus on excitotoxicity models as possible contributing factors
to AD pathology.
Glutamate is the major excitatory neurotransmitter in the cortex and hippocampus. Many
neuronal pathways essential to learning and memory use glutamate as a neurotransmitter,
including the pyramidal neurons (a layer of neurons with long axons carrying information out of
the cortex), hippocampus, and entorhinal cortex. Glutamate and other excitatory amino acid
neurotransmitters have been implicated as potential neurotoxins in AD. Dysregulated glutamate
activity is thought to be one of the primary mediators of neuronal injury after stroke or acute
brain injury. Although intimately involved in cell injury, the role of excitatory amino acids in
AD is as yet unclear; however, blockade of N-methyl-D-aspartate (NMDA) receptors decreases

7. activity of glutamate in the synapse and may hypothetically lessen the degree of cellular injury in
AD.
6. Brain Vascular Disease and High Cholesterol
There is growing evidence of a causal association between cardiovascular disease and its risk
factors and the incidence of AD. Cardiovascular risk factors that are also risk factors for
dementia include hypertension, hypercholesterolemia, and diabetes. Brain vascular disease may
augment the cognitive impairment observed for a given amount of AD pathology in the brain.
Dysfunctional blood vessels may impair nutrient delivery to neurons and reduce clearance of Aβ
from the brain.
AD PROGRESSION

8. CLINICAL MANIFESTATION
1) Early Stage
The duration period is 2-4 years.
 Frequent recent memory loss
 Repeated questions,
 Problems expressing and understanding language.
 Writing and using objects become difficult and depression and apathy can occur.
 Drastic personality changes may accompany functional decline.
 Need reminders for daily activities and difficulties with sequencing impact driving early in
this stage.
2) Second stage
 This is considered as a middle/moderate stage and the duration is 2-10 years.
 Persistent memory loss
 Rambling speech, unusual reasoning, confusion about current events, time, and place
 Potential to become lost in familiar settings, sleep disturbances, and mood or behavioral
symptoms accelerate
 Nearly 80% of patients exhibit emotional and behavioral problems which are aggravated by
stress and change
 Slowness, rigidity, tremors, and gait problems impact mobility and coordination
 Need structure, reminders, and assistance with activities of daily living.
3) Last stage
 This is considered as the severe stage and the duration is 1-3 years.
 Confused about past and present
 Loss of recognition of familiar people and places
 Generally incapacitated with severe to total loss of verbal skills
 Unable to care for self, Falls possible and immobility likely

9.  Problems with swallowing, incontinence, and illness
 Extreme problems with mood, behavioral problems, hallucinations, and delirium
 Patients need total support and care.
DIAGNOSIS
• Current health and medical history.
• Changes in Daily routine and behavior.
• Memory, problem-solving, attention, and language abilities.
• Lab tests, such as blood or urine tests.
• Brain scan

11. TREATMENT
 Treatment Goals:
 To symptomatically treat cognitive difficulties and preserve patient function as long as
possible.
 Managing psychiatric and behavioral sequel.
NON-PHARMACOLOGIC THERAPY
1) Consider vision, hearing, or other sensory impairments.
2) Find optimal level of autonomy and adjust expectations for patient performance over time
3) Avoid confrontation. Remain calm, firm, and supportive if the patient becomes upset
4) Maintain a consistent, structured environment with stimulation level appropriate to the
individual patient
5) Provide frequent reminders, explanations, and orientation cues.
6) Employ guiding, demonstration, and reinforcement
7) Reduce choices, keep requests and demands of the patient simple, and avoid complex tasks
that lead to frustration
8) Bring sudden declines in function and the emergence of new symptoms to professional
attention.
Education, communication, and planning are key nonpharmacologic components of caring for a
patient with AD. Preparation in the early stages of illness may lessen some of the caregiver stress
as the illness progresses.
PHARMACOLOGIC THERAPY
 PHARMACOTHERAPY OF COGNITIVE SYMPTOMS:
 In mild to moderate disease, consider therapy with a cholinesterase inhibitor:
 Donepezil
 Rivastigmine
 Galantamine
 Titrate to recommended maintenance dose as tolerated
 In moderate to severe disease, consider adding anti-glutamatergic therapy:
 Memantine
 Titrate to recommended maintenance dose as tolerated
 Alternatively, consider Memantine or cholinesterase inhibitor therapy alone
 Behavioral symptoms may require additional pharmacologic approaches.

12. Cholinesterase Inhibitors
 In the early 1980s, researchers began to examine means to enhance cholinergic activity in
patients with AD by inhibiting the hydrolysis of acetylcholine through reversible inhibition
of cholinesterase.
 Tacrine was the first such drug to be examined in a systematic fashion.
 However, tacrine was fraught with significant side effects, including hepatotoxicity, which
severely limited its usefulness.
 The newer cholinesterase inhibitors donepezil, rivastigmine, and galantamine show similar
modest symptomatic improvements in cognitive, global, and functional outcomes in patients
with mild to moderate AD, and duration of benefit varies from 3 to 24 months.
 The mechanism of action differs slightly between drugs in this class.
 Donepezil specifically and reversibly inhibits acetyl cholinesterase.
 Rivastigmine inhibits both butyryl cholinesterase and acetyl cholinesterase.
 Galantamine is a selective, competitive, reversible acetyl cholinesterase inhibitor and also
enhances the action of acetylcholine on nicotinic receptors.
Dosing of Drugs Used for Cognitive Symptoms

13. Monitoring Drug Therapy for Cognitive Symptoms
Other Drugs
 Memantine (Namenda) blocks glutamatergic neurotransmission by antagonizing N-methyl-
d-aspartate receptors, which may prevent excitotoxic reactions. It is used as monotherapy and
in combination with a cholinesterase inhibitor. It is indicated for treatment of moderate to
severe AD, but not for mild AD. It is not metabolized by the liver but is primarily excreted
unchanged in the urine. Dosing must be adjusted in patients with renal impairment. It is
usually well tolerated; side effects include constipation, confusion, dizziness, and headache.
 Guidelines recommend low-dose aspirin in AD patients with significant brain vascular
disease.
 Trials do not support the use of estrogen to prevent or treat dementia.
 Vitamin E is under investigation for prevention of AD and is not recommended for treatment
of AD. Because of the incidence of side effects and a lack of supporting evidence, neither
NSAIDs nor prednisone is recommended for treatment or prevention of AD.
 Trials of statin drugs have not shown significant benefit in prevention or treatment of AD.
Because of limited efficacy data, the potential for adverse effects (Eg, nausea, vomiting,
diarrhea, headache, dizziness, restlessness, weakness, and hemorrhage), and poor
standardization of herbal products, ginkgo biloba is not recommended for prevention or
treatment of AD.

14.  Do not use ginkgo biloba in individuals taking anticoagulants or antiplatelet drugs, and use
cautiously in those taking NSAIDs.
 Huperzine A has not been adequately evaluated and is not currently recommended for
treatment of AD.
PHARMACOTHERAPY OF NONCOGNITIVE SYMPTOMS
 Pharmacotherapy for non-cognitive symptoms targets psychotic symptoms, inappropriate or
disruptive behavior, and depression.
 General guidelines include the following:
(1) Use environmental interventions first and pharmacotherapy only when necessary
(2) Identify and correct underlying causes of disruptive behaviors when possible
(3) Start with reduced doses and titrate slowly
(4) Monitor closely
(5) Periodically attempt to taper and discontinue medication
(6) Document carefully.
Avoid anticholinergic psychotropic medications as they may worsen cognition.
 Cholinesterase Inhibitors and Memantine
Cholinesterase inhibitors and memantine have shown modest improvement of behavioral
symptoms over time but may not significantly reduce acute agitation.
 Antipsychotics
 Antipsychotic medications have traditionally been used for disruptive behaviors and
neuropsychiatric symptoms, but the risks and benefits must be carefully weighed.
 A meta-analysis found that only 17% to 18% of dementia patients showed a modest
treatment response with atypical antipsychotics. Adverse events (Eg, somnolence,
extrapyramidal symptoms, abnormal gait, worsening cognition, cerebrovascular events, and
increased risk of death [see black-box warning]) offset advantages.

15.  Another systematic review and meta-analysis found small but significant improvement in
behavioral symptom scores in patients treated with aripiprazole, olanzapine, and
risperidone.
 Typical antipsychotics may also produce a small increased risk of death, and more severe
extrapyramidal effects and hypotension than the atypicals.
 Antipsychotic treatment in AD patients should rarely be continued beyond 12 weeks.
 Antidepressants
 Depression and dementia share many symptoms, and the diagnosis of depression can be
difficult, especially later in the course of AD.
 A selective serotonin reuptake inhibitor (SSRI) is usually given to depressed patients with
AD, and the best evidence is for sertraline and citalopram. Tricyclic antidepressants are
usually avoided.
 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, but evidence is
conflicting.

16. Medications Used for Non-cognitive Symptoms of Dementia

17. TREATMENT ALGORITHM
REFERENCES
1. Pharmacotherapy Handbook Ninth Edition Barbara G. Wells, PharmD, FASHP, FCC, Joseph
T. DiPiro, PharmD, FCCP: Page No. 511-517.
2. Pharmacotherapy: A Pathophysiologic approach: 10th
Edition, Joseph T. Dipiro et.al., Page
No. 2406-2440.