Alzheimer’s Disease

Shaik Nishan Ashraf

AD is the most common cause of dementia
occurring in patients over 45 years
15% of the cases are familial
AD has 2 types:
i) Early onset autosomal dominant type
ii) Late onset type
Presents with subtle onset of memory loss
followed by relentless slowly progressing
dementia that has a course of several years
Etiology and Pathogenesis
The number of neurofibrillary tangles (NFT) better
correspond to the degree of dementia than does the
number of neuritic plaques
Biochemical markers are
a. Loss of choline acetyl transferase
b. Synaptophysin immunoreactivity
c. Amyloid reaction
Aβ is the critical molecule in the pathogenesis of AD
How is Aβ formed?
By the activity of α secretase or β secretase followed by
γ secretase on Amyloid Precursor Protein (APP)

The proteolytic activity of β-secretase inevitably leads

to formation of amyloid fibrils
Genetic Basis
 Gene for APP on Chr. 21
Mutations result in increased formation of Aβ
AD seen in Trisomy 21 explained on the basis of extra
gene dose in such patients
Genetic Basis Contd.
Chr. 14 and Chr. 1 - associated with early onset familial
AD
Codes for highly related intracellular proteins
Presenilin 1 (PS1) and Presenilin 2 (PS2)

Phenotype of such mutations is an increased level of

Aβ generation, esp Aβ42
Genetic basis contd..
ε4 allele of the Apolipoprotein E (ApoE) gene on
Chr. 19
Increase the risk and lowers age of onset of AD
Apo E binds to Aβ and is present in plaques
Individuals with ε4 allele are over represented in
populations with AD, compared to control
populations
Mechanism of action of this allele is still unclear.
Other gene loci includes:
Chr. 12 and
Chr. 10

Evidence suggests that Aβ aggregates, small and

large fibrils alike, are directly neurotoxic and elicit
various cellular responses including oxidative
damage and alteration of calcium homeostasis
Imaging and Diagnosis
In the initial stages, CT and MRI images appear
normal compared to those of normal patients for
the given age.

As the disease progresses, Diffuse Cortical

Atrophy becomes apparent.

MRI now shows atrophy of hippocampus.

Imaging and Diagnosis contd.

Functional imaging studies with

fluorodeoxyglucose PET reveal hypoperfusion or
hypermetabolism in posterior temporal cortex.
Imaging and Diagnosis contd.
EEG
Usually normal or shows non-specific slowing.

CSF
Aβ amyloid level is lowered.
τ protein level is seen increased.
 Slowly progressive decline in memory and
orientation, normal results on laboratory tests and
MRI or CT showing only diffuse or posteriorly
predominant cortical and hippocampal atrophy is
highly suggestive of Alzheimer’s Disease.
Clinical Manifestations
Initially, word finding, organizational and navigational
difficulties.

Progresses to MCI ( Mild Cognitive Impairment).

50% patients with MCI progress on to AD.

Affects daily activities like keeping track of finances,

following instructions on the job, driving, shopping,
housekeeping.
Some patients are unaware of this:
Anosognosia
The patients gets lost on taking walks and driving

In the Middle Stages of AD:

Unable to work
Easily lost and confused
Requires daily supervision
Surprisingly however, Social graces, Routine
behavior, and superficial conversation remain intact
Later on as the disease progresses,
Language becomes impaired, firstly naming followed by
comprehension, finally affecting fluency
Aphasia is an early and prominent symptom in some
patients
Word finding difficulty and circumlocution maybe a
problem in some
Apraxia emerges gradually and patients have trouble
performing sequential motor tasks
Visuospatial deficits interfere with daily activities such as
dressing.
In the Late stages,
If ambulatory, wanders aimlessly
Loss of judgment, reason and cognitive abilities
Delusions are common, usually of simple type like
infidelity, theft or misidentification
10% develop Capgras’ syndrome, believing that the
caregiver has been replaced by an imposter
Sleep pattern is hampered and nighttime wandering are
common
A shuffling gait with generalized muscle rigidity
associated with slowness and awkwardness of movement
is seen in some patients
AD patients become Rigid, Mute, Incontinent and
Bedridden.
May show hyperactive tendon reflexes.
Myoclonic jerks (sudden brief contractions of various
muscles or the whole body) in response to physical or
auditory stimulus or spontaneously.
Generalized seizures may also occur.
The disease progresses till the death of the patient due to
malnutrition, infection, pulmonary emboli, heart disease,
etc.
Typical duration of Alzheimer’s Disease is 8 to 10 years,
though it could be as short as 1 year or as long as 25 years.

Progression of the disease could be either a steady

downhill curve, or a downhill path with several plateaus
in between.
Thank You