This document discusses Alzheimer's disease (AD), including its definition, etiology, risk factors, pathophysiology, clinical symptoms, diagnosis, and treatment. Some key points include: - AD is the most common cause of dementia and is characterized by cognitive and behavioral impairment. While the exact cause is unknown, risk factors include age, family history, and genetics such as the APOE E4 allele. - Pathologically, AD is defined by amyloid plaques and neurofibrillary tangles in the brain. It results from the death of brain cells, affecting processes like memory, thinking, and behavior. - Diagnosis involves assessing symptoms, ruling out other conditions through tests, and structural imaging of the brain

1. Presented by
Akpan Edidiong Anieti
5th Course
Lugansk State Medical University

2. Defination
 Alzheimer disease (AD) is an acquired disorder of
cognitive and behavioral impairment that markedly
interferes with social and occupational functioning. It
is an incurable disease with a long and progressive
course.

3. ETIOLOGY
 The cause of AD is unknown. Several investigators
now believe that converging environmental and
genetic risk factors trigger a pathophysiologic cascade
that, over decades, leads to Alzheimer pathology and
dementia.

4.  The following risk factors for Alzheimer-type
dementia have been identified:
 Advancing age
 Family history

5. APOE 4 genotype: APOE
 The gene encoding the cholesterol-carrying apolipoprotein
E (APOE) on chromosome 19 has been linked to increased
risk for AD, principally late-onset but also some early-onset
cases. The gene is inherited as an autosomal codominant
trait with 3 alleles. The APOE E2 allele, the least prevalent
of the 3 common APOE alleles, is associated with the
lowest risk of developing AD,with a lower rate of annual
hippocampal atrophy and higher cerebrospinal fluid Aβ
and lower phosphotau, suggesting less AD pathology.

6.  The E3 allele confers intermediate risk of developing AD,
with less risk than the E4 allele. The E3 allele, which is
more common than the E2 allele, may protect tau from
hyperphosphorylation, and the E2 allele’s effect on tau
phosphorylation is complex.
 APOE E4 gene “dose” is correlated with increased risk and
earlier onset of AD.Individuals who are genetically
predisposed to AD are advised to closely control their
blood pressure closely. Hypertension has been shown to
interact with APOE E4 genotype to increase amyloid
deposition in cognitively healthy middle-aged and older
adults; controlling hypertension may significantly decrease
the risk of developing amyloid deposits, even in those with
genetic risk.

7.  Persons with 2 copies of the APOE E4 allele (4/4 genotype)
have a significantly greater risk of developing AD than
persons with other APOE subtypes. Mean age at onset is
significantly lower in the presence of 2 APOE E4 copies. A
collaborative study has suggested that APOE E4 exerts its
maximal effect before the age of 70 years.
 Many APOE E4 carriers do not develop AD, and many
patients with AD do not have this allele. Therefore, the
presence of an APOE E4 allele does not secure the
diagnosis of AD, but instead, the APOE E4 allele acts as a
biologic risk factor for the disease, especially in those
younger than 70 years.

8.  Obesity
 Infection: Treponemas and Borrelia burgdorferi, as well
as pathogens such as herpes simplex virus type 1

9.  Insulin resistance
 Vascular factors
 Dyslipidemia
 Hypertension
 Inflammatory markers
 Down syndrome
 Traumatic brain injury

10.  Midlife hypertension is an established risk factor for
late-life dementia, of which AD is the most common
type. A brain autopsy study evaluating the link
between hypertension and AD found that patients
using beta-blockers to control blood pressure had
fewer Alzheimer's-type brain lesions on autopsy
compared to patients taking no drug therapy or those
taking other medications.

11.  In addition, epidemiologic studies have suggested
some possible risk factors (eg, aluminum, previous
depression) and some protective factors (eg,
education,long-term use of nonsteroidal antiinflammatory drugs ).

12. Genetic causes
 Although most cases of AD are sporadic (ie, not inherited), familial
forms of AD do exist. Autosomal dominant AD, which accounts for less
than 5% of cases, is almost exclusively early onset AD; cases occur in at
least 3 individuals in 2 or more generations, with 2 of the individuals
being first-degree relatives.
 Mutations in the following genes unequivocally cause early-onset
autosomal dominant AD:
 The amyloid precursor protein (APP) gene on chromosome 21
 The presenilin-1 (PS1) gene on chromosome 14
 The presenilin-2 (PS2) gene on chromosome 1

13. PATHOPHYSIOLOGY
 A continuum exists between the pathophysiology of normal aging and that of
AD. Pathologic hallmarks of AD have been identified; however, these features
also occur in the brains of cognitively intact persons. For example, in a study in
which neuropathologists were blinded to clinical data, they identified 76% of
brains of cognitively intact elderly patients as demonstrating AD.
 AD affects the 3 processes that keep neurons healthy:
communication, metabolism, and repair. Certain
nerve cells in the brain stop working, lose connections with other nerve cells,
and finally die. The destruction and death of these nerve cells causes the
memory failure, personality changes, problems in carrying out daily activities,
and other features of the disease.
 The accumulation of SPs primarily precedes the clinical onset of AD. NFTs, loss
of neurons, and loss of synapses accompany the progression of cognitive
decline.

14.  Amyloid, or senile, plaques are dense, insoluble
deposits of amyloid-beta proteins, which are
fragments of amyloid precursor proteins (APP), a
transmembrane neuronal protein. As these proteins
are enzymatically broken down, they clump together,
forming the dense structures identifiable as amyloid
plaques. These plaques primarily accumulate in the
association cortices and hippocampus.

15.  a structure deep in the brain that helps to encode
memories, and in other areas of the cerebral cortex
that are used in thinking and making decisions.
Plaques may begin to develop as early as the fifth
decade of life. Whether Ab plaques themselves cause
AD or whether they are a by-product of the AD process
is still unknown. It is known that changes in APP
structure can cause a rare, inherited form of AD.

17.  Neurofibrillary tangles develop when microtubule tau (a protein that
binds to and regulates the assembly and stability of neuronal
microtubules and that is found in an abnormal form as the major
component of neurofibrillary tangles—called also tau protein) proteins
become hyperphosphorylated and aggregate within the neuronal cells.
These tangles break down the neurons' ability to transport molecules
along the axon. Neurofibrillary tangles initially form in the medial
aspect and pole of the temporal lobe, especially the hippocampus.
With increasing disease progression, they spread throughout the
cortex, beginning in the high-order association regions and less
commonly in the primary motor and sensory regions.

18.  Tangles are insoluble twisted fibers that build up
inside the nerve cell. Although many older people
develop some plaques and tangles, the brains of people
with AD have them to a greater extent, especially in
certain regions of the brain that are important in
memory. There are likely to be significant age-related
differences in the extent to which the presence of
plaques and tangles are indicative of the presence of
dementia.

20.  In addition to NFTs and SPs, many other lesions of AD
have been recognized since Alzheimer’s original
papers were published. These include the
granulovacuolar degeneration of Shimkowicz; the
neuropil threads of Braak et al ; and neuronal loss and
synaptic degeneration, which are thought to ultimately
mediate the cognitive and behavioral manifestations
of the disorder

22. Inflammatory reactions
 Inflammatory and immune mechanisms may play a role in the
degenerative process in AD. Reactive microglia are embedded in
neuritic plaques. Increased cytokine levels are seen in the serum,
cortical plaques, and neurons of patients with AD, as compared with
aged-matched control patients. Interestingly, transforming growth
factor beta 1 (TGF-β1), which is an anti-inflammatory cytokine, has
been found to promote or accelerate the deposition of amyloid.
 Classical complement pathway fragments are also found in the brains
of patients with AD, and amyloid may directly activate the classical
complement pathway in an antibody-independent fashion.

23.  Whether markers of immune and inflammatory processes
actively participate in the neurodegenerative process or instead
represent an epiphenomenon remains unclear. Brain specimens
from elderly patients with arthritis treated with nonsteroidal
anti-inflammatory drugs (NSAIDs) have similar numbers of
senile plaques as do control brains.
 However, less microglial activation is seen in the brains of the
patients with arthritis. This suggests that although NSAIDs may
not impede senile plaque formation, they may delay or prevent
clinical symptoms by limiting the associated inflammation.

24.  As mentioned above, RAGE has been shown to mediate the
interaction of amyloid and glial cells, producing cellular
activation and an inflammatory response with cytokine
production, chemotaxis, and haptotaxis. The expression of this
receptor appears to be upregulated in neurons, vasculature, and
microglia in affected regions of AD brains.
 The unrelated class A scavenger receptor (class A SR) also
mediates the adhesion of microglial cells to amyloid fibrils. SPs
contain high concentrations of microglia that express class A
SRs. RAGE and class A SRs may represent novel pharmacologic
targets for diminishing the inflammatory a

25. CLINICAL SYMPTOMS AND
DEGREES
Preclinical Alzheimer disease
 A patient with preclinical AD may appear completely
normal on physical examination and mental status
testing. Specific regions of the brain (eg, entorhinal
cortex, hippocampus) probably begin to be affected 1020 years before any visible symptoms appear.

26. Mild Alzheimer disease
 Signs of mild AD can include the following:
 Memory loss
 Confusion about the location of familiar places
 Taking longer to accomplish normal, daily tasks
 Trouble handling money and paying bills
 Compromised judgment, often leading to bad decisions
 Loss of spontaneity and sense of initiative
 Mood and personality changes; increased anxiety

27. Moderate Alzheimer disease
 The symptoms of this stage can include the following:
 Increasing memory loss and confusion
 Shortened attention span
 Problems recognizing friends and family members
 Difficulty with language; problems with reading, writing,
working with numbers
 Difficulty organizing thoughts and thinking logically

28.  Inability to learn new things or to cope with new or unexpected





situations
Restlessness, agitation, anxiety, tearfulness, wandering, especially in
the late afternoon or at night
Repetitive statements or movement; occasional muscle twitches
Hallucinations, delusions, suspiciousness or paranoia, irritability
Loss of impulse control: Shown through behavior such as undressing at
inappropriate times or places or vulgar language
Perceptual-motor problems: Such as trouble getting out of a chair or
setting the table

29. Severe Alzheimer disease
 Patients with severe AD cannot recognize family or loved ones and cannot
communicate in any way. They are completely dependent on others for care,
and all sense of self seems to vanish.
 Other symptoms of severe AD can include the following:
 Weight loss
 Seizures, skin infections, difficulty swallowing
 Groaning, moaning, or grunting
 Increased sleeping
 Lack of bladder and bowel control
 In end-stage AD, patients may be in bed much or all of the time. Death is often
the result of other illnesses, frequently aspiration pneumonia.

30. APROACH CONSIDERATIONS &
DIAGNOSIS
Blood Studies
 Laboratory tests can be performed to rule out other conditions that may cause
cognitive impairment. Current recommendations from the American Academy
of Neurology (AAN) include measurement of the cobalamin (vitamin B12) level
and a thyroid function screening test. Additional investigations are left up to
the physician, to be tailored to the particular needs of each patient. Initial test
results that require further investigation include the following:
 Abnormalities in complete blood cell count and cobalamin (vitamin B-12)
levels require further workup to rule out hematologic disease
 Abnormalities found in screening of liver enzyme levels require further workup
to rule out hepatic disease

31.  Abnormalities in thyroid-stimulating hormone (TSH)
levels require further workup to rule out thyroid disease
 Abnormalities in rapid plasma reagent (RPR) require
further workup to rule out syphilis
 There is a possible link between vitamin D deficiency and
cognitive impairment. However, vitamin D deficiency has
not been identified as a reversible cause of dementia.

32. Brain MRI or CT Scanning
 American Academy of Neurology (AAN) recommendations
indicate that structural neuroimaging with either a
noncontrast computed tomography (CT) scan or magnetic
resonance image (MRI) is appropriate in the initial
evaluation of patients with dementia, in order to detect
lesions that may result in cognitive impairment (eg, stroke,
small vessel disease, tumor).

33.  In clinical research studies, atrophy of the hippocampi (structures
important in mediating memory processes) on coronal MRI is
considered a valid biomarker of AD neuropathology. Nonetheless,
measurement of hippocampal volume is not used in routine clinical
care in the diagnosis of AD.
 A study by Chen et al suggests that resting state functional MRI can
help classify patients with AD, patients with amnestic mild cognitive
impairment (MCI), and cognitively healthy patients. Default mode
network (DMN) imaging appears to distinguish AD, MCI, and controls
well, and it may complement positron emission tomography (PET)
scanning or prove to be more sensitive.

36. Electroencephalography
 Electroencephalography (EEG) is valuable when CreutzfeldtJakob disease or other prion-related disease is a likely diagnosis
(see EEG in Dementia and Encephalopathy). Periodic high-amplitude
sharp waves can eventually be detected in most cases of CreutzfeldtJakob disease.
 EEG is also useful if pseudodementia is a realistic consideration when a
normal EEG in a patient who appears profoundly demented would
support that diagnosis. Multiple unwitnessed seizures rarely can
present as dementia, and an EEG would be valuable for evaluating such
a possibility.

37. Genotyping
 Genotyping for apolipoprotein E (APOE) alleles is a
research tool that has been helpful in determining the risk
of AD in populations, but until recently it was of little, if
any, value in making a clinical diagnosis and developing a
management plan in individual patients. Numerous
consensus statements have recommended against using
APOE genotyping for predicting AD risk.

38.  Investigators from the Copenhagen General Population Study and the
Copenhagen City Heart Study have reported that plasma levels of
APOE epsilon 4 (APOE ε4) are associated with the risk of dementia,
independent of the APOE genotype. The risk of Alzheimer disease
increased with decreasing levels of APOE levels, with a highly
significant 3-fold increased risk for the lowest tertile of APOE levels
relative to the highest tertile—an association that remained even after
adjusting for the APOE genotype. The APOE genotypes with highest
risks of Alzheimer disease were ε43 and ε44, whereas those with the
lowest risks were ε22, ε32, ε42, and ε33.

39. Lumbar Puncture
 Perform lumbar puncture in select cases to rule out conditions such as normal-pressure
hydrocephalus or central nervous system infection (eg, neurosyphilis, neuroborreliosis,
cryptococcosis).
 CSF levels of tau and phosphorylated tau are often elevated in AD, whereas amyloid
levels are usually low. The reason for this is not known, but perhaps amyloid levels are
low because the amyloid is deposited in the brain rather than the CSF. By measuring both
proteins, sensitivity and specificity of at least 80%—and more often 90%—can be
achieved.
 At present, however, routine measurement of CSF tau and amyloid is not recommended
except in research settings. Lumbar puncture for measurement of tau and amyloid may
become part of the diagnostic workup when effective therapies that slow the rate of
progression of AD are developed, particularly if the therapies are specific for AD and
carry significant morbidity.

40. TREATMENT
 To date, only symptomatic therapies for Alzheimer disease (AD) are
available. All drugs approved by the US Food and Drug Administration
(FDA) for the treatment of AD modulate neurotransmitters, either
acetylcholine or glutamate. The standard medical treatment for AD
includes cholinesterase inhibitors (ChEIs) and a partial N-methyl-Daspartate (NMDA) antagonist.
 Secondary symptoms of AD (eg, depression, agitation, aggression,
hallucinations, delusions, sleep disorders) can be problematic.
Behavioral symptoms in particular are common and can exacerbate
cognitive and functional impairment. The following classes of
psychotropic medications have been used to treat these secondary
symptoms:

41.  Antidepressants
 Anxiolytics
 Antiparkinsonian agents
 Beta-blockers
 Antiepileptic drugs (for their effects on behavior)
 Neuroleptics

42. Treatment of Mild to Moderate Disease
 Cholinesterase inhibition
 Numerous lines of evidence suggest that cholinergic systems that
modulate information processing in the hippocampus and neocortex
are impaired early in the course of AD. These observations have
suggested that some of the clinical manifestations of AD are due to loss
of cholinergic innervation to the cerebral cortex.
 Centrally acting ChEIs prevent the breakdown of acetylcholine. Four
such agents have been approved by the FDA for the treatment of AD, as
follows:
 Tacrine
 Donepezil (Aricept, Aricept ODT)
 Rivastigmine (Exelon, Exelon Patch)
 Galantamine (Razadyne, Razadyne ER)
 Mental activity to support cognition

43. Treatment of Moderate to Severe Disease
 The partial N -methyl-D-aspartate (NMDA) antagonist memantine
(Namenda, Namenda XR) is believed to work by improving the signalto-noise ratio of glutamatergic transmission at the NMDA receptor.
Blockade of NMDA receptors by memantine is thought to slow the
intracellular calcium accumulation and thereby help prevent further
nerve damage. This agent is approved by the FDA for treating moderate
and severe AD.
 Several studies have demonstrated that memantine can be safely used
in combination with ChEIs. The combination of memantine with a
ChEI has been shown to significantly delay institutionalization in AD
patients. Studies suggest that the use of memantine with donepezil
affects cognition in moderate to severe AD but not in mild to moderate
AD.Dizziness, headache, and confusion are some of the most common
side effects of memantine.

44.  In June 2013, the FDA approved rivastigmine
transdermal for severe AD.Approval was based on the
ACTION (ACTivities of Daily Living and CognitION in
Patients with Severe Dementia of the Alzheimer's
Type) study, in which a higher dose of the drug (13.3
mg/24 hr) demonstrated statistically significant
improvement in overall cognition and function
compared with a lower dose (4.6 mg/24 hr).

45.  OTHER TREATMENT:
Suppression of Brain Inflammation
 Many studies have suggested that intense
inflammation occurs in the brains of patients with AD.
Epidemiologic studies suggest that some patients on
long-term anti-inflammatory therapy have a decreased
risk of developing AD. Nonetheless, no randomized
clinical trial longer than 6 months has demonstrated
efficacy of anti-inflammatory drugs in slowing the rate
of progression of AD.

46. Experimental Therapies
 A variety of experimental therapies have been proposed for AD. These include antiamyloid therapy,
reversal of excess tau phosphorylation, estrogen therapy, vitamin E therapy, and free-radical
scavenger therapy. Studies of these therapies have yielded mostly disappointing results.
 In the past 10 years, numerous antiamyloid therapy studies have been conducted to decrease toxic
amyloid fragments in the brain, including studies of the following:
 Vaccination with amyloid species
 Administration of monoclonal antiamyloid antibodies
 Administration of intravenous immune globulin that may contain amyloid-binding antibodies
 Selective amyloid-lowering agents
 Chelating agents to prevent amyloid polymerization
 Brain shunting to improve removal of amyloid
 Beta-secretase inhibitors to prevent generation of the A-beta amyloid fragment

47. Dietary Measures
 There are no special dietary considerations for Alzheimer
disease. However, caprylidene (Axona) is a prescription
medical food that is metabolized into ketone bodies, and
the brain can use these ketone bodies for energy when its
ability to process glucose is impaired. Brain-imaging scans
of older adults and persons with AD reveal dramatically
decreased uptake of glucose. A study of 152 patients with
mild to moderate AD found that at day 45, Alzheimer’s
Disease Assessment Scale–cognitive subscale (ADAS-Cog)
scores stabilized in the caprylidene group but declined in
the placebo group.

48. Physical Activity
 Routine physical activity and exercise may have an impact on AD progression
and may perhaps have a protective effect on brain health.[6] Increased
cardiorespiratory fitness levels are associated with higher hippocampal
volumes in patients with mild AD, suggesting that cardiorespiratory fitness
may modify AD-related brain atrophy.
 The activity of each patient should be individualized. The patient’s
surroundings should be safe and familiar. Too much activity can cause
agitation, but too little can cause the patient to withdraw and perhaps become
depressed. Maintaining structured routines may be helpful to decrease patient
stress in regard to meals, medication, and other therapeutic activities aimed at
maintaining cognitive functioning.
 The patient needs contact with the outside environment. The physician should
encourage participation in activities that interest the patient and result in
cognitive stimulation but do not stress the patient. The range of possibilities is
wide and may include visits to museums, parks, or restaurants.

49. Essential update: FDA approves flutemetamol F18 to evaluate for
Alzheimer disease and dementia
 In October 2013, the FDA approved the radioactive diagnostic drug
flutemetamol F18 injection (Vizamyl) for use with positron emission
tomography (PET) brain imaging in adults undergoing evaluation for
Alzheimer disease (AD) and dementia. This agent attaches to beta
amyloid in the brain and produces a PET image that can be used to
assess its presence. A positive scan indicates there is likely a moderate
or greater amount of amyloid in the brain, but it does not establish a
diagnosis of AD or other dementia.
 The effectiveness of flutemetamol F18 was established in 2 clinical
studies with 384 participants who had a range of cognitive function.
This agent is not indicated to predict development of AD or to
determine response to treatment for AD.

50. THANK YOU FOR YOUR ATTENTION