The document provides an overview of dementia and Alzheimer's disease. It defines dementia and its main components. It describes the most common types of dementia, including Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, and others. It covers the pathology, risk factors, stages, diagnosis, differential diagnosis, and workup for Alzheimer's disease.

1. Approach to Dementia and
Alzheimer’s Disease
By
Dr. Madhumita Sen

2. Senior
moments!

3. What is Dementia?
 The word dementia comes from the Latin de meaning "apart"
and mens from mentis meaning "mind".
 Dementia consists of THREE components:
1. Impairment of cognitive skills
2. Resulting from disease of the brain
3. Which is severe enough to impair daily functioning
Hallucinations and delusions may be present at some point
during the disease.

4. Types of Dementia
 Most types of dementia are non-reversible
(degenerative).
 Alzheimer's disease is the most common type
of dementia. 62%
 Vascular Dementia are due to multiple small
strokes. 17%
 Mixed. 10%
 Lewy body disease/Parkinson’s disease
patients have abnormal protein structures in
certain areas of the brain. 6%
 Fronto-temporal dementias 2%

5. Reversible Causes
Some causes of dementia may be stopped or reversed if they
are found soon enough, including:
 Brain injury
 Brain tumours
 Chronic alcohol abuse
 Changes in blood sugar, sodium, and calcium levels
 Low vitamin B12 levels
 Normal pressure hydrocephalus
 Multiple sclerosis
 HIV/AIDS
 Wilson’s disease

6. Vascular (Multi-Infarct) Dementia
 Vascular dementia is the
second most common
cause of dementia, after
Alzheimer's disease.
 It also may result from
genetic diseases
(Cerebral autosomal
dominant arteriopathy
with subcortical infarcts
and and leuko-
encephalopathy -
CADASIL), endocarditis
or angiopathy.

7. Lewy Body Dementia (LBD)
 Lewy body dementia usually occurs sporadically, in people
with no known family history of the disease.
 Many of the remaining nerve cells in the substantia nigra
contain abnormal structures called Lewy bodies that are the
hallmark of the disease.
 Lewy body dementia typically also includes visual
hallucinations, parkinsonian symptoms such as a shuffling gait
and a flexed posture.
 Patients with Lewy body dementia live an average of 7 years
after symptoms begin.

8. Frontotemporal Dementia (FTD)
 Frontotemporal dementia describes a
group of diseases characterized by
degeneration of nerve cells in the frontal
and temporal lobes of the brain.
 Symptoms usually appear between the
ages of 40 and 65. In many cases, there is
a family history of dementia.
 People with frontotemporal dementia live
with the disease for an average of 5 to 10
years after diagnosis.

9. Dementia Pugilistica/Chronic Traumatic
Encephalopathy (CTE)
 Dementia pugilistica, also called chronic
traumatic encephalopathy or Punch Drunk
syndrome, is caused by reccurent head trauma.
 The most common symptoms of the condition
are dementia and parkinsonism, which can
appear many years after the trauma ends.
 Affected individuals may also develop poor
coordination and slurred speech.

10. Creutzfeldt-Jakob Disease (CJD)
 Creutzfeldt-Jakob disease (CJD) is a rare, degenerative, fatal
brain disorder that affects about one in every million people
per year worldwide.
 It belongs to a family of human and animal diseases known as
the transmissible spongiform encephalopathies (TSEs) or
PRION DISEASE.
 This includes bovine spongiform encephalopathy (BSE), which
is found in cows and often referred to as "mad cow" disease
(vCJD), Gerstmann-Sträussler-Scheinker disease (GSS) and
Fatal Familial insomnia.
 Kuru: was seen in New Guinea, caused by eating human brain
tissue contaminated with infectious prions.

11. Dementias in Children
 While it is usually
found in adults,
dementia can
also occur in
children.
 Causes include
Niemann-Pick
disease and
Batten disease.

12. What Conditions Are Not Dementia?
 Age-related cognitive decline. As people age, they
usually experience slower information processing and mild
memory impairment. In addition, their brains frequently
decrease in volume and some neurons are lost.
 Mild cognitive impairment. Some people develop
cognitive and memory problems that are not severe
enough to be diagnosed as dementia but are more
pronounced than with normal aging.
 Although many patients with this condition later develop
dementia, some do not.

14.  Depression. People with depression are
frequently passive or unresponsive, and
they may appear slow, confused, or
forgetful.
 Delirium. Delirium is characterized by
confusion and rapidly altering mental
states. The person be disoriented, drowsy,
or incoherent.
 Delirium is usually caused by a treatable
physical or psychiatric illness, such as
poisoning or infections.
 Patients with delirium usually, though not
always, make a full recovery after their
underlying illness is treated.

15. Alzheimer's Disease
 Alzheimer disease (AD) is a neurodegenerative
disorder marked by cognitive and behavioral
impairment that significantly interferes with
social and occupational functioning.
 It is an incurable disease with a long
preclinical period and progressive course.
 It is the most common cause of dementia in
people aged 65 and older.
 However, there are some early-onset forms of
the disease, usually linked to a specific gene
defect, which may appear as early as age 30.
Brain image reveals
hippocampal atrophy,
especially on the right side.

16. History
 In 1901, a German psychiatrist named Alois Alzheimer
observed a patient at the Frankfurt Asylum named Mrs.
Auguste D.
 This 51-year-old woman suffered from a loss of short-
term memory, among other behavioral symptoms. Five
years later, the patient died, and Dr. Alzheimer sent her
brain for autopsy to Dr. Emil Kraeplin.
 By staining sections of her brain in the laboratory, he
was able to identify amyloid plaques and neurofibrillary
tangles.
 Alzheimer published his findings in 1907.

17. Pathology
 The pathologic changes associated with AD
begin in the entorhinal cortex, and spread
to the hippocampus.
 1. Amyloid plaques (Senile plaques/SPs):
Plaques are made of beta-amyloid (Ab), a
protein fragment snipped from a larger
protein called amyloid precursor protein
(APP). These fragments clump together.
 2. Neurofibrillary tangles (NFTs) are
bundles of twisted filaments found within
neurons. These tangles are largely made
up of a protein called tau.

18.  In AD, plaques develop in the hippocampus, and in other areas of the cerebral cortex that
are used in thinking and making decisions.
 NFTs are initially and most densely distributed in the temporal lobe and the hippocampus.
As AD progresses, NFTs accumulate in many other cortical regions.
 Although NFTs and SPs are characteristic of AD, they are not pathognomonic. NFTs are
found in several other neurodegenerative disorders, including progressive supranuclear
palsy and dementia pugilistica (chronic traumatic encephalopathy).
 SPs may occur in normal aging.
 Dementia severity correlates better with the number of neocortical NFTs than with SPs.

19. Risk Factors
 Advancing age
 Family history
 APOE 4 genotype
 Presenilin 1 and 2 genomes
 Clusterin genotype
 Obesity & Insulin resistance
 Vascular factors
 Dyslipidemia
 Hypertension
 Chronic Inflammation
 Down’s syndrome
 Traumatic brain injury
 Estrogen loss

20.  Depression
 Depression has been identified as a risk factor for
AD and other dementias. Recent Framingham
data have helped bolster the epidemiological
association. The study showed a 50% increase in
AD and dementia in those who were depressed at
baseline.
 Epigenetics
 Caused by gene-environment interactions.
 Brain cells in AD exhibit overexpression of AD
genes, suggesting hypomethylation, which are
associated with oxidative stress.

21.  Circadian Rhythm Disturbances may be
an Alzheimer's Marker
 Sleep disturbances were associated with
an increased risk of developing dementia
in initially cognitively healthy men during
a 40-year observation period.
 Disrupted sleep has also been shown to
increase cerebrospinal fluid (CSF) levels
of amyloid beta and tau.
 https://doi.org/10.1016/j.jalz.2014.08.
104

22.  Sedatives:
 Investigators Yue Leng, PhD, and Kristine Yaffe,
MD, University of California, found that older
adults who reported taking sleep medications
often were more than 40% more likely to develop
dementia over 15 years than their peers who
rarely, or never, took sleeping pills.
 Frequent Sleeping Pill Use Linked to Increased
Dementia Risk - Medscape - Jul 19, 2019.

23. EpidemiologyIn the World Health
Organization’s
review in 2015 on the
Global Burden of
Dementia, rates for
dementia from any
cause are under 1% in
persons aged 60-69
years, rising to about
39% in persons 90-95
years old.
Almost two thirds of
Americans with AD
are women and this
may simply reflect
women’s higher life
expectancy.

24. Clinical Assessment
 History
 Insidiously progressive memory loss.
 Slowly progressive behavioral
changes.
 Patients may also experience
language disorders (eg, anomic
aphasia or anomia) and impairment
in their visuospatial skills and
executive functions.
 Many patients with AD lack insight
into impairments
Assessment consists of:
 Is dementia present?
 What brain disease is causing it?
 What are the risk factors?
 Is care needed/level of care?
 Assess functional abilities:
activities of daily living (ADLs) and
instrumental ADLs (IADLs).

26. Physical Examination
 General examination to establish state of health.
 A detailed neurologic examination and a mental status examination should be
performed to evaluate disease stage and rule out comorbid conditions.
 Initial mental status testing should include evaluation of the following:
1. Recent and remote memory
2. Language
3. Visuo-spatial function
4. Judgment and behaviour
5. Cognitive ability

27. Cognitive Screening

28. MMSE

29. The Alzheimer’s Disease Assessment Scale–
Cognitive Subscale (ADAS-Cog)
 The Alzheimer’s Disease (AD) Assessment Scale-Cognitive Subscale (ADAS-Cog) is
considered the gold standard for assessing the efficacy of antidementia treatments.
 Usually studies administer all 11 tasks and score them as a single scale from 0 to 70;
(“ADAS-Cog-11”).
 doi: 10.3233/JAD-170991

30. Clinical Stages of Alzheimer’s disease
 Preclinical Alzheimer disease
 The brain changes occur decades before any signs or symptoms appear.
 Memory loss, the first visible sign, is the main feature of amnestic mild cognitive
impairment (MCI).

31. 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

32. Moderate Alzheimer disease:
The symptoms of this stage can include the following:
 Increasing memory loss and confusion with 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
 Inability to learn new things or to cope with new or unexpected situations
 Restlessness, agitation, anxiety, tearfulness, wandering in the late afternoon or at night
 Repetitive statements or movement; occasional muscle twitches
 Hallucinations, delusions, suspiciousness or paranoia, irritability
 Loss of impulse control: behavior such as undressing at inappropriate times or places or vulgar
language
 Perceptual-motor problems, such as trouble getting out of a chair or sitting at the table

33. Severe Alzheimer disease:
 Patients with severe AD cannot recognize family or loved ones
and cannot communicate effectively. 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.

34. Differential Diagnoses
 Depression
 Chronic traumatic encephalopathy
 Age-associated memory impairment
 Alcohol or drug abuse
 Vitamin B12 deficiency
 Cerebrovascular disease (and
vascular dementia)
 Hearing or visual impairment
 Hypothyroidism or hyperthyroidism
 Hyper/hyponatremia
 Hypoglycemia
 Lewy body dementia
 Normal pressure hydrocephalus
 Parkinson's disease with dementia
 Polypharmacy
 Volume depletion
 Wernicke-Korsakoff Syndrome

35. Alzheimer Disease Workup
 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.
 The following tests and procedures may be done:
 Blood electrolytes
 Blood gas analysis
 Drug or alcohol levels (toxicology screen)
 Electroencephalograph (EEG)
 Head CT, MRI
 Lumbar puncture in select cases to rule out normal-pressure hydrocephalus or
infection (eg, neurosyphilis, neuroborreliosis, cryptococcosis).
 PET scan not routine

36.  Electroencephalography (EEG) is valuable when Creutzfeldt-Jakob disease or other prion-
related disease is a likely diagnosis.
 CSF levels of tau and phosphorylated tau are often elevated in AD, whereas amyloid
levels are usually 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.

37.  Plasma levels of APOE epsilon 4 (APOE ε4) are associated with the risk of dementia,
independent of the APOE genotype.
 Genotyping for apolipoprotein E (APOE), Amyloid precursor protein (APP) and
presenilin mutations: should be offered in the following situations:
1. In symptomatic patients with early-onset AD who have a family history of dementia or an
unknown family history (eg, because of adoption)
2. In persons with a family history of autosomal dominant dementia with one or more cases of
early-onset AD
3. In relatives with a mutation consistent with early-onset AD (ie, PS-1, PS-2,APP)
 Before undergoing testing, patients should receive appropriate counseling.

38.  Changes in blood levels of neurofilament light chain (NfL) protein over time can predict
neurodegeneration years before clinical symptoms appear in familial early-onset
Alzheimer's disease (AD), new research shows.
 NfL is a structural protein that forms the internal skeleton of neurons. When neurons are
damaged, NfL is released into cerebrospinal fluid (CSF) and blood.
 Ref:Nature Medicine volume 25, pages277–283 (2019)

39. Treatment
Manage Exacerbating conditions
 Anaemia
 Congestive heart failure
 Depression
 Infections
 Nutritional disorders
 Thyroid disorders
 Hypertension
 Hypercholesterolemia
Exercise programs, stress reduction techniques, and use of supplements, including
vitamin D3, fish oil, coenzyme Q10, melatonin, and methylcobalamin have been useful
in various studies.

40. Treatment of Mild to Moderate Disease
 Early diagnosis and treatment allows AD patients to maintain the highest levels of
cognitive and functional ability possible.
 Cholinesterase inhibitors (ChEIs) and mental exercises are used in an attempt to prevent
or delay the deterioration of cognition in patients with AD.
 Cholinesterase inhibition
 Numerous lines of evidence suggest 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. Three such agents have
been approved by the FDA for the treatment of AD, as follows:
 Donepezil (Aricept, Aricept ODT)
 Rivastigmine (Exelon, Exelon Patch)
 Galantamine (Razadyne, Razadyne ER)

41.  Mental activities: mentally challenging
activities, such as doing crossword
puzzles, learning a musical instrument
or dance, may reduce the risk in
patients with pre-Alzheimer’s.
 These activities should be administered
in a manner that does not cause
excessive frustration and motivates the
patient to engage in them frequently.
 Unfortunately, little standardization or
rigorous testing has been done to
validate this treatment modality.

42. 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
signal-to-noise ratio of glutamatergic
transmission at the NMDA receptor.
 The combination of memantine with a ChEI
has been shown to significantly delay
institutionalization in AD patients.
 Memory aids, such as mnemonics,
computerized recall devices, or note taking.

43. Managing Secondary Symptoms
 Secondary symptoms of AD (e.g., depression, agitation, aggression,
hallucinations, delusions, sleep disorders) can be problematic.
 The following classes of psychotropic medications have been used to treat
these secondary symptoms:
1. Antidepressants
2. Anxiolytics
3. Antiparkinsonian agents
4. Antiepileptic drugs (for their effects on behavior)
5. Neuroleptics

44.  A pilot study in AD patients with psychosis or agitation that responded to haloperidol
treatment found that discontinuation of the drug after 6 months was associated with a
higher risk of relapse.
 The Clinical Antipsychotic Trials found that the atypical antipsychotics olanzapine,
quetiapine, and risperidone were associated with worsening cognitive function at a
magnitude consistent with 1 year's deterioration.
 The general recommendation is to use such agents as infrequently as possible and at the
lowest doses possible.

45.  Citalopram may be beneficial in mood and other neuropsychiatric
symptoms in patients in the moderate stage of AD.
 Other mood modulators, such as valproic acid, can be helpful for the
treatment of disruptive behaviors.
 Research on the effects of prescribing hypnotics such as zolpidem, to
treat sleep problems in dementia patients found that they
significantly increase fracture risk.

46.  Suppression of Brain Inflammation
 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.

47. Experimental Therapies
 In the past 10 years, numerous anti-amyloid therapy studies have been conducted to
decrease toxic amyloid fragments in the brain:
 Vaccination with amyloid species
 Administration of monoclonal anti-amyloid antibodies
 Chelating agents to prevent amyloid polymerization
 Brain shunting to improve removal of amyloid
 To date, no phase III study of anti-amyloid therapies has shown a combination of
acceptable efficacy and side effects.

48.  In the Alzheimer’s Disease Cooperative Study, high-dose vitamin E (2000 units per day of
alpha-tocopherol) for 2 years slowed the progression of disease in patients with moderate
AD.
 Other studies, however, have suggested that vitamin E supplementation may increase risk of
adverse cardiovascular outcomes. Therefore, use of vitamin E is not currently recommended.
 Despite in vitro evidence of a protective effect of estrogen, no data show that women with
AD who are placed on estrogen therapy (ET) have fewer symptoms or progress more slowly
than women treated with placebo.

49.  Elevated cholesterol levels are a risk factor for AD, and epidemiologic data suggest
that the use of statins may reduce this risk.
 However, a trial of simvastatin in patients with mild to moderate AD and normal
lipid levels found that although statin treatment significantly lowered cholesterol
levels, it did not slow the progression of symptoms.
 Phase 2 results of edonerpic maleate (Fujifilm Toyama Chemical Co) reduced
cerebrospinal fluid (CSF) tau levels but had no clinical benefit at 1 year.

50. Dietary Measures
 Caprylidene (Axona), containing 20 g of
medium-chain triglycerides, is a prescription
medical food that is metabolized into ketone
bodies.
 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.
 Another source of MCTGs: coconut oil

51. Complications
 Abuse by an overstressed caregiver
 Increased infections anywhere in the body
 Loss of ability to function or care for self
 Loss of ability to interact
 Reduced lifespan
 Side effects of medications used to treat the disorder

52. Prognosis
 AD is initially associated with memory impairment that progressively worsens.
 As their disease progresses, patients with AD come to require assistance with basic
activities of daily living, including dressing, bathing, and toileting.
 Eventually, difficulties with walking and swallowing may develop. Feeding may be possible
only by gastrointestinal tube, and difficulty swallowing may lead to aspiration pneumonia.
 The time from diagnosis to death varies from as little as 3 years to as long as 10 or more
years.
 The primary cause of death is intercurrent illness, such as pneumonia.

53. Caring for People with Dementia
 People with moderate and advanced dementia typically need round-the-clock care
and supervision to prevent them from harming themselves or others.
 Meeting these needs takes patience, understanding, and careful thought by the
person's caregivers.
 While the patient is still able to make important decisions, contact an attorney about
drafting advance directives.
 Take Care of the Caregiver

54. VIPS
 Value – am I giving value to the patient?
 Individual – am I treating the person as a unique individual?
 Perspective – can I see the patient and family perspective?
 Social relationship – am I helping the patient to be socially confident that they
are not alone?
NICE Guidelines on Alzheimer’s management

55. Can Dementia be Prevented?
 The biological signs of Alzheimer disease are present 10-20 years
before symptom onset.
 Evidence, largely epidemiologic, suggests that healthy lifestyles
can reduce the risk of AD.
 People who maintain tight control over their glucose levels tend
to score better on tests of cognitive function than those with
poorly controlled diabetes.
 People who are socially active show decreased levels of
dementia.

56.  Nutritional patterns that appear beneficial for AD prevention
fit the Mediterranean diet.
 Physical activity has the added benefit of lowering the risk of
cardiovascular and metabolic disorders.
 Several studies also have suggested that people who engage in
intellectually stimulating activities, such as chess, crossword
puzzles, and playing a musical instrument, significantly lower
their risk of developing Alzheimer's disease and other forms of
dementia.

57. QUIZ!
1. Which of the following is the current standard pharmacologic treatment for Alzheimer disease
in the United States and Europe?
 Carbidopa/levodopa/entacapone
 Cholinesterase inhibitors (ChEIs) and partial N-methyl-D-aspartate (NMDA) receptor agonists
 Beta-blockers and 5-HT1 receptor agonists
 Calcium-channel blockers (CCBs) and angiotensin II receptor blockers (ARBs)
2. Which of the following has been shown to achieve the highest levels of cognitive and
functional abilities in patients with Alzheimer disease?
 Early diagnosis and treatment
 Antidepressants and benzodiazepines
 Loop diuretics and CCBs
 Daily jogging or running

58. 3.Which of the following has been shown to delay the institutionalization of patients with moderate to severe
Alzheimer disease?
 Creative art classes and antipsychotic medications
 Increased video game time
 Memantine and ChEIs
 Gabapentin 300 mg orally three times daily
4. In addition to the approved medications, which of the following strategies have been shown to prevent and
slow progression of Alzheimer disease?
 Solitary activities
 Muscle rest
 High-carbohydrate diet
 Regular physical and cognitive exercises
5. Which of the following represents the current focus of drug research and development Alzheimer disease?
 Development of medications for severe Alzheimer disease
 Prevention, early detection, and treatment of early-stage Alzheimer disease
 Investment in daycare programs for patients with advanced Alzheimer disease
 Early retirement programs to prevent Alzheimer disease

59. References
 https://emedicine.medscape.com/article/1134817-overview
 https://emedicine.medscape.com/article/2003174-overview#a5
 https://reference.medscape.com/viewarticle/912045
 https://www.medscape.com/viewarticle/915666
 https://www.medscape.com/viewarticle/904061
 https://doi.org/10.7554/eLife.36584.001
 ABC of Dementia by Coope and Richards
 https://www.medscape.com/viewarticle/915836

60. Any Questions?
Thank you!