CLINICAL FEATURES

OF ALZHIEMERS
DISEASE

Chairperson: Dr. Anupama

Presenter: Dr. Wilona

Introduction: Dementia
A disease process marked by
progressive cognitive impairment in
clear consciousness
Development of multiple cognitive
deficits manifested by both memory
impairment and impairment in at least
one other cognitive domain including
language, praxis, gnosis, and
executive functioning

Introduction: Dementia
Decline from a previous level of
functioning
Involves multiple cognitive domains
Significant impairment in social or
occupational functioning

Introduction: Dementia
Divided into various types based on
aetiology:
Alzhiemers
Lewy body
Vascular
Frontotemporal
Other medical and neurological
conditions

Introduction: Alzhiemers
Until recently, the most common form of
dementia
Onset and progression follows a
characteristic pattern
Probable diagnosis can be made on the
basis of clinical history
Associated with specific neuropathological
changes seen in the brain on histology
Definitive diagnosis can be made only at
autopsy

Introduction: Alzhiemers
Alzheimer's disease is a growing problem
affecting the lives of not only the sufferers, but
also their families
Huge costs to society, to the families of those
affected, and to the individuals themselves
Direct & indirect financial costs
Emotional impact resulting in distress and
psychiatric morbidity
Better health care services; substantial rise in
elderly population of developing countries

History

November 25th, 1901

51-year-old woman
Auguste Deter
Presented with
progressive impairment
of
memory,
aphasia,
disorientation,
psychosocial
incompetence
hallucinations
Presenile dementia

History

Dr. Alois Alzhiemer

Worked in Frankfurt
with Franz Nissl
Examined Auguste
Deter
Working under Kraeplin
in Munich a time of her
death
Requested for her
medical records
Presented his findings
in November 1906

Definition
DSM-IV-TR
Dementia of the Alzheimer's type
The gradual onset and continuing
cognitive decline involving:
- Memory impairment and one or more
of
- Aphasia,
- Apraxia,
- Agnosia, and

Definition
- Significant impairment in social or
occupational functioning
- Represent a significant decline from a
previous level of functioning
- Must not be due to:
other central nervous system conditions
or
systemic conditions or
the result of substances

Definition
- Must not occur exclusively during the
course of a delirium
- Must not be accounted for by another
Axis I disorder
- Further divided into two types:
Early onset (before the age of 65 yrs)
Late onset (65 and above)

Definition
ICD- 10
A) Presence of dementia.
B) Insidious in onset with slow
deterioration.
C) Absence of clinical evidence or
findings from special investigations,to
suggest that the mental state maybe
due to other systemic or brain
disease,which can induce dementia.

Definition
ICD- 10
D) Absence of a sudden,apoplectic
onset ,or of neurological signs of focal
damage,such as hemiparesis,sensory
loss,visual field defects & incoordination occurring early in the
illness

Epidemiology
Incidence increases with age
0.5 percent per year at age 65 to
69,
1 percent per year from age 70 to
74,
2 percent per year from age 75 to
79,
3 percent per year from age 80 to
84,
and 8 percent per year after age

Epidemiology
Affects women three times as often as
men
More common in black than in white
American women
Other risk factors:
- Presence of a positive family history
- Downs syndrome
- History of head trauma
- Low level of education

Neuropathology

Postmortem: brain in AD
Lighter
More prominent sulci
Larger ventricular volume

Microscopic examination:
- Extracellular amyloid plaque
- Intracellular neurofibrillary
tangle

Neuropathology: Amyloid
Plaque

Defining lesion of Alzheimer's disease

Consists of an amyloid core
Insoluble deposits of fibrillar A
Surrounded by dystrophic neurites,
microglial cells, and reactive
astrocytes
Filled with highly phosphorylated tau
protein
Found throughout the neocortex,
entorhinal cortex, hippocampus,

Neuropathology: Amyloid
Plaque
Plaque formation
- Peptides derived from APP deposited
in a diffuse plaque
- Over time this becomes organized
- Amyloid peptides become fibrillar
- Form the amyloid deposit
- Neuritic change then occurs
- Plaque becomes fully mature

Neuropathology
Plaque formation
- Peptides derived from APP deposited
in a diffuse plaque
- Over time this becomes organized
- Amyloid peptides become fibrillar
- Form the amyloid deposit
- Neuritic change then occurs
- Plaque becomes fully mature

Neuropathology: Neurofibrillary
tangle
Intracellular inclusion bodies
Contain paired helical filaments
Composed of aggregates of
hyperphosphorylated MAPT
Found in the entorhinal cortex,
hippocampus, lateral temporal lobe,
neocortex
Not pathognomonic for Alzheimer's
disease

Neuropathology: Other findings

Hiranos bodies
Intracellular aggregates ofactin and
actin-associated proteins
Rod-shaped, crystal-like, and
eosinophilic
Seen inhippocampalpyramidal cells
Found in patients of AD
Not pathognomonic

Neuropathology: Other findings

Degeneration of nerve cells
Amyloid deposition in leptomeningeal
blood vessels: amyloidangiopathy
Neuropil threads are short neuronal
processes found in the cortical regions
associated with tangle pathology
Shrinkage of neurons & loss of dendritic
spines
Atrophy is most apparent in the
associational cortex areas

Neuropathology: Other findings

Granulovacuolar degeneration
Significant degenerative changes in
neurons are seen in the hippocampus,
locus ceruleus, and nucleus basalis of
Mynert
Loss of cholinergic neurons in the
nucleus basalis
Loss of brainstem noradrenergic and
serotonergic neurons
Abnormal aggregation of -synuclein

Neuropathology: Other findings

Loss of large neurons:
- Layer II of entorhinal cortex
- Pyramidal neurons in layers III and V of
neocortex
- Cholinergic neurons in the basal forebrain
- Select subcortical nuclei
- Relative sparing of occipital and
cerebellar area
Shrinkage of golgi apparatus

Aetiology

Multi-factorial
Genetic & environmental factors
Multiple pathways & agents involved
Various hypotheses put forward
Dynamic interaction between the
different protective as well as risk
factors

Aetiology: Genetic factors

Mutations or copy number variations
within several genes that result in the
cleavage of APP into A: early-onset
Alzheimer's disease
Late-onset Alzheimer's disease is a
complex disorder, in which risk is
influenced by multiple genes, by
environmental factors, and by their
interactions

Genetics: Early onset AD

Mutations at three genetic loci: autosomal
dominant inheritance
Amyloid precursor protein (APP) gene
located on chromosome 21
- Over 20 different mutations in fewer than
100 families worldwide
- Recently, families with duplications of APP
found
- Similar to the increased risk of AD
associated with trisomy 21

Genetics: Early onset AD

Presenilin-1 (PS 1) on chromosome 14
More than 160 mutations reported
Onset of symptoms before age 50
Autosomal dominant traits with nearly
complete penetrance
Presenilin- 2 (PS 2) on chromosome 1
Rare
AD but not fully penetrant
Onset before 65yrs

Genetics: Early onset AD

PS 1: 20%
PS 2: 1%
APP: 5%
Remainder: Single/ multigenic causation

Genetics: Late onset AD

One gene with a clearly established
relationship to late-onset AD is apolipoprotein
E gene
APOE gene on chromosome 19
Three common alleles, coding for three
protein isoforms that differ by the substitution
of an amino acid at just two positions
It has been demonstrated that the 4 allele
confers risk, whilst the 2 may be protective

Genetics: Late onset AD

Increased risk of AD in individuals carrying the
4 allele (APOE4) in both familial and sporadic
cases
Increased risk and the mean age of onset of
AD is earlier: number of APOE4 alleles from 0
to 2
Single copy of allele: 2-4 fold increased risk
Two APOE4 alleles: increase the risk by 4-8
fold

Genetics: Late onset AD

Accounts for 50 per cent of the genetic
variance
Carrying one or even two APOE4 alleles is
neither necessary nor sufficient for the
development of AD.
For those who are disease-free at age 65, at
most 50 percent of APOE4 homozygotes will
develop Alzheimer's disease within their
lifetimes
Thus limiting the use of the APOE4 genotype
as a predictive test
When APOE4 testing is added to the
evaluation of individuals clinically diagnosed

Genetics: Late onset AD

Genes contributing to the remaining ~50% of
risk for late-onset AD are unknown
Many regions throughout the genome
implicated as possibly harboring risk genes,
though no genes have been definitively
identified
A combination of linkage and association
studies using large populations will identify
the other genes that influence AD, either
alone or in interactions with other genes or

Genetics: Late onset AD

Genes contributing to the remaining ~50% of
risk for late-onset AD are unknown
Many regions throughout the genome
implicated as possibly harboring risk genes,
though no genes have been definitively
identified
A combination of linkage and association
studies using large populations will identify
the other genes that influence AD, either
alone or in interactions with other genes or

Genetics: Other genes involved

Susceptible loci on chromosome 10
VR22 gene, IDE gene.
Susceptible loci on chromosome 12
Alpha-2 macroglobulin gene, LDL receptor
related protein gene,Glyceraldehyde-3phosphate dehydrogenase gene.
Microtubule- associated protein tau
Chromosome 17q21.

Genetics: Other genes involved

Neprilysin
Chromosome 3q25.
Zn metalloproteinase- Abeta degrading
enzyme.
Ubiquilin 1
Chromosome 9q22
Promotes the accumulation of uncleaved PS-1
& PS-2
BACE 1- on 11q23.
TNF-alpha- on 6p21.

Aetiology: Amyloid protein

In 1984, the protein deposited in blood
vessels (congophilic angiopathy) in AD was
shown to be a 4-kDa peptide -amyloid
This peptide, which is identical to the amyloid
in plaques, is derived from a larger peptide,
APP
Mutations in the APP gene were found in a
family with autosomal dominant early-onset
AD
These two discoveries led the way to the
amyloid cascade hypothesis
Dominant molecular model of the disorder
Mutations in APP, PS1, and PS2 all result in

Aetiology: Amyloid protein

Formation of b-amyloid is reported as the
initiating, or at least early event
LeadS to all the other changes observed
including
- tau aggregation and phosphorylation
- neuronal loss
- cholinergic deficits
- clinical symptoms

Aetiology: Amyloid protein

APP is a ubiquitous single-pass cellmembrane protein expressed in many cell
lines
APP protein is cleaved by three enzymes, -,
-, and -secretase .
-Secretase: cleaves at the outer cellmembrane surface at a site within the bamyloid moiety itself.
-secretase cleaves beyond the amino
terminus of b-amyloid
-secretase (PS1, PS2) cleaves at the carboxy
terminus in the cell

Aetiology: Amyloid protein

Cleavage by -secretase then -secretase
generates A, while cleavage by -secretase
yields a nontoxic peptide.

Aetiology: Amyloid protein

The -amyloid products vary in length
Predominant species having a length of 40 or
42 amino acids
Longer peptides are somewhat more prone to
forming fibrils in vitro
Extracellular aggregation of A-42 forms the
nidus for additional amyloid deposition &
plaque formation
Pathogenic mutations of PSEN 1 and PSEN 2
alter the -secretase cleavage of APP
resulting in the enhanced production of the
longer A

Aetiology: Amyloid protein

Evidence indicates that self-aggregation of A into
soluble low-n oligomers is a primary source of
synaptotoxicity.
Post mortem studies in animals transgenic for
mutant human APP shows that deficits in synaptic
structure and function precede deposition of
insoluble A into plaques and correlate with
cortical soluble A levels, but do not correlate with
plaque numbers or APP levels.
Human studies indicate that cortical synapse loss is
an early pathological event and that cognitive
impairments and synapse loss correlate most
strongly with soluble A, even in subjects with
early disease.

Aetiology: Amyloid protein

A may lead to synapse loss and neuronal death via
other downstream effectors.
A contributes to the hyperphosphorylation of
microtubule-associate protein Tau (MAPT), which
enhances its aggregation.
Overproduction and aggregation of MAPT cause
synapse loss independent of the effects of A.
Soluble A oligomers exist in equilibrium with
fibrillar deposits of A in plaques which form
substantial space-occupying lesions in the cortex of
individuals with AD and serve as a site for
inflammatory responses.
Both these mechanical and inflammatory
processes may further contribute to synapse loss
and neuronal death.

Aetiology: Amyloid protein

Aggregation of -synuclein also occurs in some
individuals with AD, and can contribute independently
to cognitive impairments
Also, the presenilins participate in NOTCH signalling
a complex signal-transduction cascade
Critical in determining neuronal cell fate
Mutations in the presenilin genes may result in an
interference with the normal functioning of the
protein or may induce a gain in a novel pathogenic
function

Aetiology: Amyloid protein

Mechanisms of A clearance:
- Metallopeptidases such as Insulin degrading
enzyme (IDE) have A degrading activity
- Zinc metalloproteinases may have A
degrading activity
- Abnormal endosomal function may impair
clearance of A
- Any abnormality in degradation or clearance
may contribute to the pathogenesis

Aetiology: Amyloid protein

Amyloid cascade hypothesis:
Amyloid production and accumulation play a
central role in initiatng a cascade of events
that leads to cellular dysfunction, neuron loss
and eventually disease manifestations

Aetiology: Amyloid protein

Amyloid cascade hypothesis:
Amyloid production and accumulation play a
central role in initiatng a cascade of events
that leads to cellular dysfunction, neuron loss
and eventually disease manifestations

Aetiology: Neurochemistry
Most consistent changes involve loss of
cholinergic, serotonergic and glutamatergic
markers
Evidences for failed cholinergic transmission
causing clinical symptoms:
- Decreased presynaptic cholinergic markers in
neocortex and hippocampus in AD; corelates
with disease severity
- Degeneration of basal forebrain neurons
- Basal forebrain lesions/ pharmacological
blockade of mAch receptors impairs learning,
memory, attention

Aetiology: Neurochemistry
The activity of choline acetyltransferase,
the enzyme responsible for the final step of
ACh synthesis, is substantially reduced in
patients with AD
Confirmed on autopsy of patients with at
least a moderate stage but not in patients
with mild illness
Particularly evident in the nucleus basalis of
Meynert and several neocortical regions
Forms the rationale for treatment with
choline-esterase inhibitors
Simplification of aetiology

Aetiology: Neurochemistry
Serotonin plays a key role in mood and
anxiety disorders which are commonly found
to coexist with AD
There is a loss of the noradrenergic neurons in
the locus coerulus in AD
This has been found to be associated with
exacerbated amyloid pathology, behavioural
deficits and neuron loss
May contribute to the development/
progression of AD

Aetiology: Neurochemistry
Glutamate excitotoxicity may play a role in
neurodegeneration
Reductions in glutamate receptors,
predominantly located at postsynaptic sites
on dendritic spines
A appears to destabilize dendritic spines,
resulting in retraction and synapse loss, via
modulation of the function of both -amino-3hydroxy-5-methyl-4-isoazole-proprionic acid
(AMPA) and N-methyl-D-aspartate (NMDA)
classes of postsynaptic glutamate receptors

Aetiology: Age
Greatest risk factor
3 percent of people older than 65 years of age
20 to 30 percent of people older than 85
years.
Is it a correlated observation or whether there
are specific age-related processes that
enhance pathological processes in AD is not
known.

Aetiology: Education
Epidemiological studies people with less
education are at increased risk of developing
AD
Functional neuroimaging people with higher
educational attainment or higher premorbid
intellectual functioning but similar levels of
dementia severity have more severe findings.
Suggests a protective effect of education
Relationship between cognitive decline and
neocortical synaptic density in AD.
There is also some evidence that education
can increase synaptic density

Aetiology: Estrogen

Estrogen replacement after menopause may reduce

the risk of AD
Estrogen increases density of synaptic population &
excitatory synapses onto dendritic spines, in both
hippocampus and cortex.
It also may interact with APP processing, to increase
brain A concentrations.
Estrogen inhibits oxidation of lipids, lipoproteins, and
nucleic acids in vitro and is protective of cells in
culture against a number of insults, including A.
Prospective studies of estrogen treatment: little
evidence of cognitive enhancement or reduced
cognitive decline
Womens health initiative study: no prevention of

Aetiology: Traumatic brain injury

Can increase the rate of cognitive decline in
the elderly
Increase the risk for subsequent Alzheimer's
disease
Head trauma can lead to overexpression of
APP,
increase inflammatory mediators,
cause A deposition in the brain.
The effects may be mediated by APOE
genotype

Aetiology: Inflammation
Population studies show that NSAID or corticosteroid
use decreases the risk of developing AD.
Studies support the hypothesis that some NSAIDs
lower A42 by directly modulating the activity of secretase
Neuropathological studies demonstrate that the
brains of AD patients have increased concentrations
of acute-phase reactants, cytokines, and complement
protein, when compared to age-matched controls.
Clinical trials of NSAIDs in Alzheimer's disease
generally do not support an effect on slowing disease
progression
Strongest association of NSAIDs has been with drug
exposure 2-3 yrs before onset of disease; protective role
only in preclinical stages

Aetiology: Nicotine
Case-control studies reduced likelihood of
AD in smokers.
Cohort studies have found the opposite
relationship.
Indirect stimulation of nicotinic receptors via
use of acetylcholinesterase inhibitors has
benefit in the treatment of AD.
There is also in vitro evidence that nicotine
may protect against A toxicity.
Increased incidence in smokers may be due to
deletrious effect of smoking on cardiovascular
health

Aetiology: Oxidative injury &

mitochondrial dysfunction
Oxidative injury is caused by reaction of free
radicals with cellular components
Brain highly susceptible to oxidative injury
Evidences for oxidative damage in AD:
- Higher levels of oxidized lipids, proteins, DNA
in brains of AD patients
- Highest oxidative damage in most affected
areas and lowest in most spared areas
- Pathological lesions show signs of oxidative
injury
- Oxidative damage promotes protein

Aetiology: Oxidative injury &

mitochondrial dysfunction
Epidemiological studies and randomized
controlled trials using antioxidants as a mode
of treatment have had mixed results

Aetiology: Risk Factors

Category

Factor

Influence on AD risk

Life events

Aging

Increases risk

Early life linguistic ability

Decreases risk

Traumatic brain injury

Increases risk

APOE4

Increases risk

Downs syndrome

Greatly increases risk

Female vs male

Increases risk

Estrogen replacement

May lower risk

Vitamin/ nutrient
supplementation

Vitamins C & E may be

protective

NSAID use

Decreases risk

Statin use

Decreases risk

Genetics
Sex
Diet/
medication

Cardiovascul Hypercholesterolemia
ar risk factors Hypertension

Increases risk
Increases risk

Elevated plasma homocysteine

Increases risk

Diabetes mellitus

Increases risk

Clinical features
The hallmark feature of dementia is
cognitive impairment
Patients must demonstrate
impairment in memory and at least
one other cognitive domain
The early course is usually difficult to
ascertain as the patient is a poor
informant
Also early signs may be subtle and
may be missed by the caregivers

Clinical features: Cognitive

Cognitive decline is manifested as

Amnesia,
Aphasia,
Agnosia, and
Apraxia

Clinical features: Amnesia

Memory loss in AD is early and
inevitable.
Recent memories are lost before
remote memories
There is individual variation, with
some patients able to recall specific
and detailed events of childhood and
others apparently having few distant
memories accessible.
With disease progression, even

Clinical features: Amnesia

Primary problem is of acquisition or
retrieval of memory rather than a
destruction of memory,but as the
disease progresses it is likely that all
memory processes are impaired
Retrieval of remote memory is
assumed to be preserved for longer
because of rehearsal over life.

Clinical features: Amnesia

Short-term memory is impaired
before long-term memory
Patients are unable to learn new
information or new skills
May become disoriented and
confused in new environments
Later in the illness progression, longterm memory will become impaired

Clinical features: Amnesia

Patients will no longer recall their
personal past history
Will forget previously highly learned
material
Procedural memory for previously
learned skills may be retained longer

Clinical features: Aphasia

Language deficits in AD are not very
prominent
May only be apparent on detailed
examination
Word-finding difficulties (nominal
dysphasia): earliest phenomena
observed
Accompanied by circumlocutions,
word substitutions, or
mispronouncing words

Clinical features: Aphasia

As the disorder progresses, syntax is
affected and speech becomes
increasingly paraphasic
Patients have difficulty maintaining
conversations
Then they stop initiating
conversation.
They may appear more withdrawn
and disengaged as their ability to
engage with others through

Clinical features: Aphasia

Receptive aphasia, or comprehension
of speech, is almost certainly
affected.
In the final stages, speech is grossly
deteriorated with decreased fluency,
preservation, echolalia, and abnormal
non-speech utterances
Eventually, speech may become
incomprehensible and unintelligible

Clinical features: Agnosia

Failure to recognize or identify
objects despite intact sensory
function
reflected in the inability to recognize
familiar objects, familiar faces, or, in
later stages, one's own reflection in
the mirror
It also manifests as lack of insight
into one's own impairment and
unrealistic assessment of one's

Clinical features: Agnosia

Mirror sign Patients will interpret the
face in the mirror as some other
individual and respond by talking to it or
by apparent fearfulness.
Can present as an apparent hallucinatory
experience, until it is realized that the
hallucination' is fixed in both content and
space, occurring only when self-reflection
can be seen
Implications for care needs and safety if
the unrecognized objects are important

Clinical features: Apraxia

Difficulties with complex tasks (not due to
motor impairment) become apparent in
the moderate stages.
Difficulties with dressing or tasks in the
kitchen are noticed first, but these are
inevitably preceded by loss of ability for
more difficult tasks.

Clinical features: Apraxia

Strategies to avoid such tasks are often
acquired as the disease progresses, and it
is only when these fail that the dyspraxia
becomes apparent.

Clinical features: Other

cognitive functions

Impairment in executive functioning

planning,
organizing,
sequencing, and
Abstracting
Reflected in difficulty performing complex
tasks or problem solving
Judgment is often impaired and bad
decisions are made
Visuospatial functioning can also be

Clinical features:
Functional impairment
Has the most impact on the person themselves
and necessitates most of the care needs of
patients
Abilities to function in ordinary life (ADLs) are
lost, starting with the most subtle and easily
avoided and progressing to the most basic and
essential
Functional abilities decline alongside cognitive
abilities but the precise correlation between
these functions is not perfect, suggesting that

Clinical features:
Functional impairment
Instrumental ADLs, those related to the use of
objects or the outside world, are lost first and
can be subtle.
Self-care ADLs include dressing and personal
hygiene and are also lost gradually;
Personal hygiene becomes poor as dentures are
not cleaned and baths taken less often, before
finally assistance is required with all self-care
tasks.

Clinical features:
Functional impairment
Represents a decline from a previous
level of functioning
If patients are still working, there must be
difficulties with job performance
There must also be difficulties in social
functioning

Clinical features:
Neuropsychiatric
features
Behavioral disturbances:

- Common in many types of dementia

- Prevalence increases with advancing
dementia.
- Include disinhibition, agitation, aggressive
behavior, uncooperative behavior, and
wandering
- Agitation, particularly worsening in the
evening hours, is common
- Eating disturbances may be seen

Clinical features:
Neuropsychiatric
features
Behavioral disturbances:

- Wandering away from home can pose a

great threat to safety
- Excessive or inappropriate vocalizations
(grunting and screaming) occur in the
late stages
- Incontinence may pose hygiene issues
- Account for substantial caregiving burden
- Often the trigger for moves to higher
levels of care.

Clinical features:
Neuropsychiatric
features
Mood
changes:
The relationship between AD and depression is
complex.
Depression is a risk factor for AD,
depression can be confused with dementia
(pseudodementia),
depression occurs as part of dementia,
cognitive impairments are found in depression.
Assessing the mood of a person with dementia is
difficult.
Psychomotor retardation, apathy, crying, poor
appetite, disturbed sleep, and expressions of

Clinical features:
Neuropsychiatric
features
Mood changes:

Major depressive episode is found in-10%,

Minor depressive episode in 25%,
Some features of depression in 50%
Assessment of depression in a carer in up to 85
%

Depression is more common in the early than in

the later stages of AD but this may reflect the
difficulties of assessing depression in the more
severely affected and least communicative

Clinical features:
Neuropsychiatric
features
Mood changes:
Severely affected patients in nursing homes
may be particularly prone to depression.
Elation, disinhibition, and hypomaniainfrequent, elevated mood being found in only
3.5 %
Cause- not known.
loss of serotonergic and noradrenergic
markers accompanies cholinergic loss;
studies have found a greater loss at
postmortem in AD patients with depression
than in non-depressed patients.

Clinical features:
Neuropsychiatric
features
Anxiety:
Fairly common throughout the course of
dementia
Estimated to occur in about 60 percent of
patients.
Often manifest as fear of being alone,
and patients will search for their
caregivers so as not to be alone

Clinical features:
Neuropsychiatric
features
Personality Changes
Changes in personality are an almost
inevitable
profound cognitive impairment
resulting in the loss of recognition of
loved ones,
Loss of understanding of and ability to
react with the outside world,
Personality change is most frequently one
of loss of awareness and normal

Clinical features:
Neuropsychiatric
features
Personality Changes
Individuals may become more anxious or
fearful, there is a flattening of affect, and
a withdrawal from challenging situations
Pre-existing personality traits may
become stronger or exaggerated during
the course of a dementing illness
Less commonly, disinhibition with
inappropriate sexual behaviours or
inappropriate affect & aggressiveness

Clinical features:
Neuropsychiatric
features
Psychosis
Generally occur in the middle stages of
illness
Co-occur with behavioral disturbance
10 - 50 % suffer from delusions and 10 25 % experience hallucinations
Paranoia: belief that belongings have
been stolen

Clinical features:
Neuropsychiatric
features
Psychosis
Inability to find a lost or misplaced object
is interpreted in a paranoid way with the
conviction that the object must have
been stolen
Can become more pervasive as the
illness progresses
In later stages, patients may have
hallucinations in any modality, but most
commonly visual hallucinations

Clinical features:
Neuropsychiatric
features
Psychosis
May see deceased relatives
Misidentification syndromes- Capgras'
syndrome may occur
Hallucinations are often congruent with
delusions of the same theme
Psychotic symptoms can sometimes lead
to behavioral disturbance as patients act
out on them

Clinical features:
Neuropsychiatric
features
Sleep Disturbance
Altered sleep-wake cycles can result in
disrupted and fragmented sleep
Seen in about half of patients
Patients may have phase-shifted sleep,
going to bed late and sleeping late in the
morning.
May also take frequent naps: more
prevalent in less stimulating
environments

Clinical features:
Neuropsychiatric
features
Catastrophic reaction:

- The emotional and behavioral reaction

- To a situation that either overwhelms or
creates stress on the individual
experiencing dementia
- Because the situation (or stimulus) is
beyond the person's ability to
comprehend
- Short-lived
- Patient is confronted, and cannot avoid,

Clinical features:
Neuropsychiatric
features
Sundowning phenomenon:

- Unique toAlzheimer's disease

- The person becomes more
confusedandagitatedin the late
afternoon and early evening
- Several theories have been proposed
about why sundowning occurs, such as
increased confusiondue to darkness and
shadows, fatigue, and a reduced ability to
tolerate stressful situations

Characteristic

Early onset

Late onset

Age of onset

< 65yrs

>65 yrs

Family history

Present . Common in
siblings

Absent. Common in
offspring

Genetic causes

APP, PS-1 &2

APOE epsilon4

Unique problems
associated

Patients are still working

& raising the family.
Problems related to the
disorder appear in job or
at home & are
mistakenly blamed on
laziness/or mental
health problems.
Patients with early onset
Alzheimers disease will
eventually need to quit
working, but many
medical benefits and
social support programs
for Alzheimers patients
arent offered for people
under age 65. A younger
person may need to get
special permission to

Many medical benefits

and social support
programs for
Alzheimers patients are
offered.

Characteristic

Early onset

Late onset

Deficits

Severe marked
parietal & motor signs.
More dyspraxic & visuospatial deficits.
Language deficitsprominent(word
comprehension &
naming)

Less severe, gait

disturbances common

EEG changes

More severe
abnormalities

Lesser abnormalities

Progression

Rapid

Insiduous

Neurochemical

Massive neuronal loss in Basal ganglia neuronal

locus ceruleus & nucleus loss & cholinergic
basalis of Meynert.
changes.
Diminuition in choline
acetyltransferase
activity in frontal cortex.
Involves GABA,&
Somatostatin also.

Characteristic

Early onset

Late onset

Imaging

Severe Cortical &

subcortical
involvement.marked
decrease in
hippocampal
volume.greater
ventricular enlargement

Less marked cortical

involvement

Myoclonus

Common

CSF

Nothing significant

Lower ABeta1-42
Higher p Tau

Incidence of Downs
syndrome and
myeloproliferative
disorders

Common

Uncommon

Age adjusted mortality

Higher

Lower

Rare

Newer advances
A study measuring the rate of falls
among seemingly cognitively healthy
older adults with and without
preclinical Alzheimer's and a brain
PET scan looking for deposits of
amyloid: Those people with amyloid
deposits had twice the risk of falls.
These study results suggest that, in
some people, changes in gait and
balance may appear as early
indicators of Alzheimer's, even before
memory changes.

Newer advances
It has been found that the most
significant factors related to
maintaining healthy cognition
included low scores on measures of
stress, anxiety, depression and
trauma despite participants'
experiencing life-threatening
illnesses, violence, or living with
addicted parents and spouses.
Hence it was hypothesized that
resilience in the face of distressing
life events is likely related to positive

Newer advances
The earliest Alzheimer's related brain
changes are usually seen in the
hippocampus, the "control center" of
memory-related activity in the brain
which often is one of the first brain
areas affected by Alzheimer's.
Research is now being conducted on a
protocol for MRI-based evaluation of
Alzheimer's disease-related
hippocampal shrinkage.

Newer advances
Some individuals with MCI have an
increased risk of developing
Alzheimer's.
A global perspective on MCI including
data from six countries found that a
number of common factors emerge as
indicators of the progression from
MCI to Alzheimer's, including:
depression, apathy, anxiety, age, loss
of ability in activities of daily living,
cardiovascular factors (including
stroke and diabetes), and low levels