Dementia

1. ALZHEIMER'S DEMENTIA
Presenter -Dr.ANUSREE.N

2. DEFINITION
The word Dementia derives from the Latin worddementatus, meaning out of one’s mind,
and, as such, was potentially applicable to any state of psychopathology.
Dementia refers to a disease process marked by progressive cognitive impairment in clear
consciousness.
The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)
describes dementia, now subsumed under the term major neurocognitive disorder, as
significant cognitive impairment in one or more of the domains of
1) complex attention,
2) executive function,
3) learning and memory,
4) language,
5)perceptual motor ability, and
6)social cognition.

3. • These deficits represent a decline from a previous level
of functioning, so dementia does not refer to low
intellectual functioning or mental retardation that are
developmental and static conditions.
• This decline is often noted by the individual affected, a
family member or other caretaker, or the clinician, and
should be demonstrated on standardized
neuropsychological testing, and if that is not possible,
another measurable clinical assessment.
• These cognitive deficits interfere with independent
functioning in daily activities, and cannot occur
exclusively in the context of a delirium, or be better
explained by another mental disorder.

4. Dementia of the
Alzheimer's
Type
• In 1907, Alois Alzheimer first described
the condition that later assumed his
name.
• In 1906 , he reported the case of a 51-
year-old woman with a progressive
cognitive disorder marked by memory
loss, confusion, topographical
disorientation, aphasia, and prominent
neuropsychiatric manifestations of
persecutory delusions, misidentifications,
and behavioral disturbances. At her death
4 years later, autopsy revealed profound
atrophy, amyloid plaques, and
neurofibrillary tangles.

5. EPIDEMIOLOGY
• The incidence of Alzheimer disease increases
with age from about 0.5 percent per year at ages
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 85.
• With the aging of the population, projections
estimate that, by the year 2050, 13.8 million
people over the age of 65 are estimated to have
Alzheimer disease.

6. • While MCI is more common in men, the prevalence of AD dementia is
higher in women.
• The lifetime risk of developing Alzheimer dementia from the age of 45
is approximately 10% for men and 20% for women
• Age is the most important risk factor for AD dementia

7. Etiology
• The etiology of Alzheimer disease is multifactorial &
is influenced by multiple genes, by environmental
factors, and by their interactions.
• 1) GENETICS: play a major role as evident by twin
studies the concordance rate for monozygotic twins,
which is higher than the rate for dizygotic twins ( 43
percent vs. 8 percent, respectively).
A) Early-Onset Alzheimer Disease.: (<65 years)
Mutations at three genetic loci :
-APP gene located on chromosome 21 (Autosomal
Dominant)
- Presenilin-1 (PS1) on Chromosome 14
(Autosomal Dominant)
- Presenelin-2 (PS2) on Chromosome 2.(These
mutations appear to be rare)

8. Etiology
1) GENETICS:
B) Late-Onset
Alzheimer
Disease.: (>65
years)
Signifigant
association with

9. Etiology
2) Neuropathology.
The classic gross neuroanatomical observation
of a brain from a patient with Alzheimer's
disease
is diffuse atrophy with :flattened cortical sulci
and enlarged cerebral ventricles.
• Macroscopically:
• the brains of early Alzheimer disease patients
may appear grossly normal, or with atrophy
confined to the hippocampus, and often most
easily recognized by increased volume of the
inferior horn of the lateral ventricles.
• As the disease progresses, widened sulci
throughout the cortex and increased
ventricular size are seen.
• Atrophy in the posterior temporal, parietal,
and frontal lobes is often most prominent.

10. Etiology
2) Neuropathology.
The classic and pathognomonic microscopic findings are
- Senile Amyloid plaques,
-neurofibrillary tangles,
-neuronal loss (particularly in the cortex and the hippocampus ),
-synaptic loss (perhaps as much as 50 percent in the cortex),
and granulovascular degeneration of the neurons.

11. Etiology
• Senile plaques, also referred to as amyloid plaques,
more strongly indicate Alzheimer's disease, although
they are also seen in Down syndrome and, to some
extent, in normal aging.
• are the defining lesion of Alzheimer disease, composed
of insoluble deposits of fibrillar Aβ protein, /31A4.
• Surrounding this central core are dystrophic neurites,
microglial cells, and reactive astrocytes.
• Amyloid plaques are first found throughout the
neocortex, followed by entorhinal cortex and
hippocampus, then subcortical regions.
• The number and the density of senile plaques present in
postmortem brains have been correlated with the
severity of the disease that affected the persons.

12. Etiology
• Neurofibrillary tangles :
• are intracellular inclusion bodies, composed of cytoskeletal
elements which contain paired helical filaments composed of
aggregates of hyperphosphorylated MAPT .
• Neurofibrillary tangles are first found in the entorhinal cortex
and spread from there to the hippocampus and lateral
temporal lobe, then more widely through the neocortex.
• The presence of neurofibrillary tangles is not pathognomonic
for Alzheimer disease, as they are the principal lesion in
MAPT-related FTDs
• they also occur in Down syndrome, dementia pugilistica
(punch-drunk syndrome), Parkinson-dementia complex of
Guam, Hallervorden Spatz disease, and the brains of normal
people as they age.

14. Etiology
• Additional pathological features of Alzheimer disease include :
• α-synuclein, which may be detectable in as many as one half of individuals
with Alzheimer disease.
• These Abnormal aggregates most commonly are found as thread-like
deposits or as intraneuronal inclusions (Lewy bodies) in the amygdala and
transentorhinal cortex, though Lewy bodies may also be present in the
neocortex.
• Transactive response DNA-binding protein of 43 kDa (TDP-43) is the most
frequently aggregated disease protein in frontotemporal lobar degeneration.
• Recently it has been found that TDP-43 proteinopathy is also present in many
cases of Alzheimer disease.
• found predominantly in the mesial temporal lobe, and to a lesser degree in
neocortical areas.
• Neuronal loss, most markedly in the entorhinal cortex and hippocampus.
Later in disease, loss of cholinergic neurons in the nucleus basalis, as well as
loss of brain stem noradrenergic and serotonergic neurons, occurs.
• Granulovacuolar degeneration and the presence of Hirano bodies, most
commonly affecting pyramidal neurons in the hippocampus, may be found.

16. Etiology
2)Neuropathology. Overproduction
& self-aggregation of Aβ into soluble
low-n oligomers is a primary source
of synaptotoxicity in Alzheimer
disease

17. Etiology
• In addition to the direct effects of Aβ on
synapse loss, Aβ may lead to synapse loss
and neuronal death via other downstream
effectors.
• For example, Aβ contributes to the
hyperphosphorylation of microtubule-
associate protein τ (MAPT), which enhances
its aggregation. Overproduction and
aggregation of MAPT have been shown to
cause synapse loss and neuronal death
independent of the effects of Aβ.

19. Etiology
• 3) Neurotransmitters:
• The neurotransmitters that are most often implicated in
the pathophysiological condition of Alzheimer's disease are
• 1)Acetylcholine : Level decreased due to specific
degeneration of cholinergic neurons is present in the
nucleus basalis of Meynert .
• Decreased Choline Acetyltransferase concentration in Brain (
Key Enzyme for synthesis of Ach)
• Cholinergic antagonists, such as scopolamine and atropine,
impair cognitive abilities, whereas cholinergic agonists, such
as physostigmine and arecoline, enhance cognitive abilities.
• 2) Norepinephrine, Level decreased due to degeneration of
norepinephrine-containing neurons in the locus ceruleus.
• 3) Two other neurotransmitters implicated in the
pathophysiological condition of Alzheimer's disease are the
neuroactive peptides:
• somatostatin and corticotropin

20. Etiology
• 3) Other Causes:
• Abnormality in the regulation of membrane phospholipid
metabolism results in membranes that are less fluid-that is,
more rigid-than normal.
• Several investigators are using molecular resonance
spectroscopic imaging to assess this hypothesis directly in
patients with dementia of the Alzheimer's type.
• Aluminum toxicity has also been hypothesized to be a
causative factor because high levels of aluminum have been
found in the brains of some patients with Alzheimer’s disease,
but this is no longer considered a significant etiological factor.
• Excessive stimulation by the transmitter glutamate that may
damage neurons is another theory of causation.
• Aβ appears to destabilize dendritic spines, resulting in
retraction and synapse loss, via modulation of the function of
both α-amino-3-hydroxy-5-methyl-4-isoazole-proprionic acid
(AMPA) and N-methyl-D-aspartate (NMDA) classes of
postsynaptic glutamate receptors. It is therefore not surprising
that memantine (Namenda), a low-affinity NMDA antagonist
that functions to modulate activation of NMDA receptors, has
been shown to be of benefit in Alzheimer disease.

21. RISK AND
PROTECTIVE
FACTORS.
• 1) Age. Age is the greatest risk factor for developing Alzheimer
disease. Whereas approximately 3 percent of people older than 65
years of age have Alzheimer disease, about one third of people older
than 85 years of age have Alzheimer disease.
• 2)Education. people with less education are at increased risk of
developing Alzheimer disease.
• Functional neuroimaging findings of patients with Alzheimer disease
indicate that people with higher educational attainment or higher
premorbid intellectual functioning but similar levels of dementia
severity have more severe findings on neuroimaging.
• This suggests a protective effect of education, in that greater
neuropathology is needed to produce the same clinical changes.
• Those with higher levels of cognitive reserve may be able to utilize
other alternative neural networks as levels of neuropathology
increase, thus compensating for the disease burden, up to a point.
• Studies have reported that there is a relationship between cognitive
decline and neocortical synaptic density in Alzheimer disease.
• There is also some evidence that education can increase synaptic
density.

22. • In addition to education, participation in certain leisure activities,
including reading, dancing, playing board games, and playing musical
instruments, is associated with a decreased dementia risk
• Early-life cognitive abilities also may play an important role in
dementia risk. (good linguistic ability and grammatical complexity in
early life>less chance of AD in adult life)

23. RISK AND
PROTECTIVE
FACTORS.
• 3) Estrogen. A number of observational studies have
suggested that estrogen replacement after menopause
reduced the risk of Alzheimer disease.
1.On a neuronal level, estrogen increases
-density of a synaptic population lost in Alzheimer disease,
-excitatory synapses onto dendritic spines, in both
hippocampus and cortex.
2. It also may interact with APP processing, to increase
brain Aβ concentrations.
3. Estrogen inhibits oxidation of lipids, lipoproteins, and
nucleic acids in vitro and is protective of cells in culture
against a number of insults, including Aβ.
However current recommendation does not approve HRT
in Alzheimers disease.

24. RISK AND
PROTECTIVE
FACTORS.
4) Head Trauma. can lead to overexpression of APP,
increase inflammatory mediators, and cause
deposition in the brain.
The effects of traumatic injury on Aβ may be
mediated by APOE genotype .
5) Inflammation. increased concentrations of acute
phase reactants, cytokines, and complement protein.
Population studies have demonstrated that
nonsteroidal anti-inflammatory drug (NSAID) or
corticosteroid use is associated with a decreased risk
of developing Alzheimer disease;
But timing of NSAID use & associated risk of bleeding
and peptic ulcer is debatable topic.

25. RISK AND
PROTECTIVE
FACTORS.
6) Nicotine. The literature is unclear.
Indirect stimulation of nicotinic receptors via use of
acetylcholinesterase inhibitors has benefit in the treatment
of Alzheimer disease..
However Smoking causes signifigant cerebro-
cardiovascular risk and associated oxidative stress ,
neuroinflammation leads to the development of Dementia.
7) Oxidative Stress. Aβ can damage and kill neurons by
inducing oxidative stress, as can the microglial
inflammatory reaction surrounding plaques.
Increased markers of oxidative stress seen in Alzheimers
Disease.
However Antioxidants VIT E & Ginkgo Biloba being tried
but no conclusive evidence

26. • Impaired sleep
• Hypertension (SBP>160)
• High cholesterol levels
• Elevated blood glucose are all risk factors for AD

27. Dietary factors
• Dietary fat intake has been associated with AD dementia risk
• heavy drinking associated with a higher AD dementia risk
• adherence to the Mediterranean diet, which recommends fish intake,
is associated with decreased risk of AD and decreased risk of
converting from MCI to AD dementia

28. Diagnosis
and Clinical
Features
• Alzheimer disease dementia has a gradual and
insidious onset, and there must be two
cognitive domains affected, as well as
functional impairment.
• The most common presentation is an amnestic
one, in which the primary deficits are in the
learning and memory domain.
• There are also non-amnestic presentations,
where the prominent impairment could be in
the language, visuospatial or executive
functioning domains.
• Individuals will have increasing difficulty
functioning in their daily activities as the
disease progresses.

29. Alzheimer Clinical Features
• Early Presentation::
• Typical AD dementia initially presents with an episodic memory
impairment reflecting the selective vulnerability of the medial
temporal lobe to AD pathology
• Recent episodic memory is particularly impaired in early AD.

30. Pattern of Progression
• While episodic memory is the hallmark of early AD, subsequent
cognitive decline is heterogeneous as the pathology spreads to the
association cortices. While individual presentations vary significantly,
• Feldman and Woodward have described the typical symptom
progression in AD dementia

31. *Mild AD (recent memory impairment, repetitive questions, loss
of interest in hobbies, anomia, impaired instrumental ADLs),
*moderate AD (aphasia, executive dysfunction, impaired basic
ADLs),
* severe AD (agitation, complete loss of independence, sleep
disturbance)

32. Common Clinical Features
• Semantic memory dysfunction can be an early feature of AD but
occurs after episodic memory involvement.
• The preservation of semantic memory in a subset of early AD cases
indicates that transentorhinal dysfunction is inadequate to disrupt
semantic memory, which likely requires extension of pathology into
the temporal neocortex

33. • Executive function (planning, organization, problem solving, set
switching) decline occurs in mild AD
• The executive dysfunction in AD dementia is mild until later in the
disease course compared to bvFTD.

34. • Language disturbance often occurs in the mild-moderate stage of AD
dementia.
• Initial complaints often include word-finding difficulty.
• In time, other features of aphasia may develop, and in the late stages,
language output can be limited.
• Decline in visuospatial skills is common, often manifesting early
with the complaint of becoming lost or being disorientated in
unfamiliar places.

35. • Apraxia often occurs later in the course of typical AD, although it may
be an early feature in atypical AD.
• Strikingly, several abilities are preserved until very late in the
development of AD dementia. For example, AD dementia patients
have preserved motor learning (procedural) motor, and sensory skills.

36. • Patients with AD dementia have episodic memory loss and develop
anomia, executive dysfunction, and visuospatial difficulty in the
setting of preserved ability to walk, see, hear, and feel.
• AD dementia is also characterized by the juxtaposition of “knowing
how” (procedural memory) and “not knowing what” (declarative
memory). The clinical picture of deficits and preserved abilities is
explained by the anatomical distribution of the NFT pathology.

37. • Tangle burden is greatest in the medial temporal lobe but spares the
primary sensory and motor cortices until very late in the course
• Early AD is characterized by an isolated memory impairment resulting
from significant pathology in the entorhinal cortex and hippocampus,
which serves to disconnect the medial temporal
lobe from other cortices.

38. The spread of pathology to other association cortices results in
accumulation of other symptoms:
semantic memory involvement from spread to the anterior
temporal lobes,
executive dysfunction from spread to the frontal lobes, and
visual-spatial dysfunction from spread to the occipitotemporal
lobes

39. • In contrast, the primary motor and sensory cortices are only affected
late in the course.
• The preserved basal ganglia and cerebellum are involved in the
procedural/motor learning (or knowing how).

40. Neuropsychiatric Features of Alzheimer
Disease Dementia
• apathy (72%) was the most common neuropsychiatric symptom,
followed by agitation (60%) and anxiety (48%)
• Identification of delusions is important because it often precedes
physically aggressive behavior .
• Common delusions in AD include paranoia and infidelity.
• Identification of neuropsychiatric features is important because these
symptoms result in significant caregiver burden and can be targeted
for treatment

41. DSM 5 &
ICD10 Criteria

42. DIFFERENTIAL
DIAGNOSIS

44. Pathology
and
Laboratory
Examination.
• There is no standard specific & sensitive
diagnostic lab test available. However some
battery of test available to differentiate
Alzhiemer’s from others:

45. NEUROIMAGING
• (CT or MRI), is used largely to identify or exclude
other causes of cognitive impairment.
• Quantification of change in global (whole brain
and ventricles) and regional (entorhinal cortex,
hippocampus, corpus callosum) volumes in
patients with Alzheimer disease frequently
demonstrate group differences in comparison to
cognitively intact elderly patients, with MCI
patients intermediate.
• SPECT or FDG-PET can increase the diagnostic
accuracy.
• PET-amyloid imaging : absence of tracer
retention indicates that dementia is unlikely to be
due to Alzheimer disease

47. • CSF
• Decreased level of Aβ (Aβ1–42)
• Increased Level of total and phosphorylated tau protein.
• Genetic marker APOE4, is diagnostic predictor of late
onset Alzhiemers
• Current Neuropathological diagnostic criteria for
definite, or a high likelihood of, Alzheimer disease
require
• The presence of a Clinical history of progressive
dementia during life and
• The presence of both Amyloid plaques and
neurofibrillary tangles on postmortem examination.

48. Biomarkers in Alzheimer Disease
-Cerebrospinal Fluid Biomarkers
• reduction in the CSF Aβ42 and elevation in the CSF tau protein has a
sensitivity of 85% and specificity of 86% for diagnosis of AD dementia
• elevated phosphorylated tau - evidence of pathological tau
accumulation
• the less specific total tau is used as a neurodegenerative biomarker
• novel CSF markers like neurofilament light protein, may be good
index of neurodegeneration

49. Neuroimaging Biomarkers
• Structural imaging(MRI>CT):
• Medial temporal lobe atrophy of the hippocampus and entorhinal
cortex with concomitant dilatation of the temporal horns is an early
characteristic of AD dementia and can predict conversion from normal
cognition to MCI and MCI to AD dementia
*Reduction in hippocampal volumes correlates with NFT
pathology at autopsy and cognitive decline
* In MCI, atrophy is limited to the medial temporal lobe structures while
with AD onset, atrophy spreads to the lateral temporal and parietal
cortices.

51. • The presence of white matter hyperintensities observed by FLAIR or
T2 MRI also appears to contribute to cognitive impairment in AD
• *Tau imaging
• *Amyloid imaging

52. Functional imaging
• Decreased blood flow in a temporal-parietal distribution seen on
SPECT correlates with hypometabolism seen on FDG-PET and is
suggestive of AD.
• In MCI, hypometabolism is primarily in the hippocampus and
posterior cingulate. In AD dementia, the hypometabolism includes
these regions as well as the temporal-parietal regions

53. Alzheimer Pathophysiology
• The basic hypothesis is that abnormal Aβ metabolism altering the
Aβ42/Aβ40 ratio in the brain causes Aβ oligomer formation and
aggregation to form fibrils, which form the amyloid plaque.
• This oligomer formation and aggregation results in a cascade of
events, including tau protein tangle formation, increased
inflammatory response, and oxidative injury, to cause neurotoxicity
and neurodegeneration

54. • Aβ is derived from APP through proteolytic processing.
• Aβ is produced normally in the body but under normal circumstances
it is removed efficiently by a number of mechanisms.
• These include breakdown by extracellular proteases, such as insulin-
degrading enzyme, and receptor-mediated endocytosis followed by
lysosomal degradation and drainage through the cerebral vasculature
and into the CSF via the glymphatic system

56. • In the amyloidogenic pathway, APP is first cleaved by β secretase.
• This cleavage produces a β C-terminal fragment, which stays on the
membrane and soluble APP Aβ.
• This β C-terminal fragment is then cleaved by γ secretase in the
transmembrane region producing APP intracellular domain (AICD)
and Aβ peptide, which is then released into extracellular space.

57. Alzheimer Pathology
• Alzheimer disease is defined by two pathological findings:
extracellular plaques composed primarily of amyloid and
intraneuronal neurofibrillary tangles composed primarily of
hyperphosphorylated tau.
• Both involve abnormal conformational changes in proteins.
• Proteolytic events are critical in APP processing that leads to Aβ.
• In neurofibrillary pathology, phosphorylation of tau is a critical event.

58. • Macroscopically, AD is characterized by diffuse brain atrophy
including significantly decreased weight at autopsy.
*Some areas are preferentially affected, including multimodal
association areas, while others, like primary motor, somatosensory,
auditory, and visual cortices, are relatively spared.
• The limbic areas including hippocampi and cingulate gyrus are
severely affected.
• Substantia nigra (unlike in parkinsonian disorders) is relatively spared
while locus coeruleus is severely affected

60. Amyloid Plaques
• Aβ deposition in the brain occurs in a sequential manner starting in the
cortex, followed sequentially by the hippocampus, basal ganglia, thalamus,
and basal forebrain before in the final stages reaching the brainstem and
cerebellum
• Plaques are complicated heterogeneous lesions composed of extracellular
protein deposits and certain cellular components.
• Aβ derived from APP is the sine qua non of plaques, which are in turn the
defining pathological finding in AD.
• Despite the strong association of Aβ with plaques, in reality plaques
contain many other components.
• Other associated components of the plaque include APOE,
alpha-1 antitrypsin, complement factors, and immunoglobulins

61. • Plaques can be divided into diffuse (Aβ mainly) and neuritic plaques
(includes damaged tau containing axons and dendrites, i.e., neurites).
• Cell components seen in plaques include neurites, microglia, and
astrocytes.
• The typical neuritic plaque has a dense core of Aβ and less compact rim
consisting of neurites, microglia, and astrogliosis at the periphery.
• Diffuse plaques have less diagnostic specificity and can be seen in a variety
of different disorders.
• They contain Aβ but do not stain with tau-containing neurites
and are not associated with synaptic loss, reactive astrocytes, or microglia.

62. Neurofibrillary Tangles
• The major component of the NFT is tau within neurons and their
cell processes.
* First, pretangles form in the neuron cytoplasm, often concentrated
around the membrane. Then, tau is organized into
fibrils as NFTs. When the cell dies, the tangle may be situated
extracellularly.
Normal tau is a microtubule-associated protein and is not visible within
the brain
In NFTs, tau has become hyperphosphorylated and abnormally
conformed. This tau can be detected with immunostains that bind
abnormally conformed tau.

63. Other pathological findings in AD
• CAA, often present in leptomeningeal vessels, capillaries, small arterioles, and
middle-sized arteries, is seen in over 80% of AD cases. In contrast to cerebral
plaques consisting primarily of Aβ42, CAA’s major component is Aβ40.
• Granulovacuolar bodies, typically found in the
hippocampus, are small dense granules within the vacuole and can be
labeled with acid phosphatase, tubulin, ubiquitin, and neurofilament.
• Hirano bodies (eosinophilic rod bodies), also typically found in the
hippocampus, are often in neuronal processes and contain actin and
actin-binding proteins

64. Treatment
• 1)Acetylcholinesterase Inhibitors:
Donepezil,Rivastigmine,Galantamine
(advanced AD demonstrated depleted cholinergic neurons in the basal
forebrain)
2)NMDA antagonists: Memantine
3) Vitamin E
4) Estrogen replacement therapy
5)Antiinflammatory medications

65. Course
and
Prognosis.

66. Course
and
Prognosis.

67. Course
and
Prognosis.

68. Course
and
Prognosis.