Alzheimer's disease - Notes of etio-pathogenesis clinical features and treatment from Harrisons 20th Ed for Residents and medical students

1. ALZHEIMERS DISEASE
NOTES BY COL BHARAT MALHOTRA SENIOR ADVISOR MEDICINE (Aug 2021)
DEFINE
➢ It is a neurodegenerative disorder of uncertain cause and pathogenesis that primarily affects older
adults (>70yrs) and is the most common cause of dementia.
➢ Presentation:  Insidious onset episodic memory loss
 Followed by progressive dementia evolving over years
➢ Imaging:  Initially involvement of hippocampus and medial temporal lobe
 Spread to frontal area and other cortex association areas.
➢ Microscopically:  Neuritic plaques – amyloid beta (Aβ) (extracellularly)
 Neurofibrillary tangles (NFTs) – tau (intracellularly)
Aβ accumulation in blood vessel walls in cortex and leptomeninges
➢ Genetic risk (especially Apo E4)
A definitive diagnosis of AD requires histopathologic examination, but most epidemiologic studies of
AD rely on clinical criteria to define cases.
EPIDEMIOLOGY
Most important risk factor for AD is
age >70 years
prevalence of AD increases with each decade of adult life
Genetic contribution to AD especially Apo E4
History of head trauma with concussion
Vascular disease, and stroke, seems to lower the threshold for the clinical expression of AD
Amyloid angiopathy can lead to microhemorrhages, large lobar hemorrhages, ischemic infarctions
most often in the subcortical white matter
Diabetes increases the risk of AD threefold
Elevated homocysteine and cholesterol levels; hypertension; diminished serum levels of folic acid; low dietary intake of fruits,
vegetables and low levels of exercise are all being explored as potential risk factors for AD.
Environmental factors – failed to demonstrate risk
PATHOLOGY
At autopsy, the earliest and most severe degeneration is usually found in the medial temporal lobe
(entorhinal/perirhinal cortex and hippocampus), inferolateral temporal cortex, and nucleus basalis of
Meynert.

2. Part A Neuritic plaques – amyloid beta (Aβ) (extracellularly)
AMLOID PRECURSOR PROTEIN (APP) IS ESSENTIAL FOR NEURONAL GROWTH AND
REPAIR. APP HAS NEUROTROPHIC AND NEUROPROTECTIVE PROPERTIES
IN ALZEIMERS DISEASE – INCREASE BETA AMYLOID PRODUCTION
& DECREASE AMYLOID BREAKDOWN OCCURS
INCREASE BETA AMYLOID LEADS TO FORMATION OF SENILE PLAQUES  LEADING TO
NEURONAL COMMUNICATION BLOCK (EXTRACELLULARLY). THE ACCUMULATION OF Aβ
IN CEREBRAL ARTERIOLES IS TERMED AMYLOID ANGIOPATHY.
Aβ 42

3. PART B Neurofibrillary tangles (NFTs) – tau (intracellularly)
TAU PROTEIN IS IMPORTANT IN STABILIZING THE MICROTUBULES – IN
HYPERPOSPHORYLATED STATE TAO PROTEINS DETACH TO FORM
NEUROFIBRILLATORY TANGLES. THE MICROTUBULE BECOMES UNSTABLE
LEADING TO DISABLED INTRACELLULAR TRANSPORT
PART C Degeneration of cholinergic neurons- nucleus basalis of Meynert
IN ALZEIMERS DISEASE THERE IS DYSFUNCTIONAL CHOLINERGIC NEURONS -
REDUCTION IN ACETYLCHOLINE REFLECTS DEGENERATION OF CHOLINERGIC
NEURONS IN NUCLEUS BASALIS OF MEYNERT THAT PROJECTS THROUGHOUT THE
CORTEX.
There is also noradrenergic and serotonergic depletion due to degeneration of brainstem nuclei
such as the locus coeruleus and dorsal raphe, where tau-immunoreactive neuronal cytoplasmic
inclusions can be identified even in individuals lacking entorhinal cortex NFTs.

4. OVERVIEW OF CASCADE
PART 1 PART 2 PART 3
EXTRACELLULAR
SENILE PLAQUES
AMYLOID AB
INTRACELLULAR
NEUROFIBRILLARY
TANGLES TAO PROTEINS
DECREASE
ACETYLCHOLINE
BLOCK NEURONAL
JUNCTIONS
(Extracellular)
DISRUPT TRANSPORT
(Intracellular)
DECREASE
NEUROTRASMITTOR

5. Genetic Risk Factors for AD
Other Risk Factors
Lower Risk for AD Higher Risk for AD
High Intellectual Activities
Social Activities
Physical activities
Healthy Diet
Flavonoids
Long term NSAID use
Old age
Positive family history
Female
Genetic – Apo E4 allele
Head trauma
Low educational attainment
Diabetes, Hypertension
Hypercholesterolemia
Smoking
Environmental
Disease Progression
The average life expectancy after a diagnosis of AD has been reported to be between 8 and 10 years
but may range from 3 to 20 years, and it depends heavily on how impaired the person is at the time of
diagnosis. Survival also relates to age at onset of symptoms.

6. CLINICAL MANIFESTATIONS
AGE
AD is characteristically a disease of older age (>70 years). It is exceptional for AD to occur before
age 60 years. Early-onset AD (onset of symptoms before 65 years of age) is unusual but can occur.
CARDINAL SYMPTOMS
Typical Amnestic AD
Memory Impairment Deficits in Other Cognitive Domains
EARLY: Visuospatial impairment & Executive dysfunction
LATE: Language and Behavioural symptoms
Atypical AD  Word finding, organizational difficulty, navigational difficulty.
 Posterior cortical atrophy syndrome (Visual processing dysfunction)
 Corticobasal syndrome (Asymmetric akinetic-rigid-dystonic features)
 Frontal variant of AD (Dysexecutive/behaviour problem)
Memory Impairment
The pattern of memory impairment in AD is distinctive.
Memory deficits develop insidiously and progress slowly over time
Declarative episodic memory (memory of events occurring at a particular time and place) is usually
profoundly affected in AD. This type of memory depends heavily on the hippocampus and other
medial temporal lobe structures.
By contrast, subcortical systems supporting procedural memory and motor learning are relatively
spared until quite late in the disease. Memory for facts such as vocabulary and concepts (semantic
memory) often become impaired somewhat later. Semantic memory is supported by neocortical
temporal regions, particularly in the anterior temporal lobe
Type of memory Mental status examinations can be used to
evaluate the following domains
Sensory
Short term
Long term
Episodic – stories of life
Declarative – facts and knowledge
Semantic – meaning of things
Procedural – how to do stuff
Flashbulb – emotional
●Level of consciousness (arousal)
●Attention and concentration
●Memory
●Language
●Visuospatial perception
●Praxis
●Calculations
●Executive functioning
●Mood and thought content
Within episodic memory, there is a distinction between
➢ Immediate recall (e.g. mental rehearsal of a phone number),
➢ Memory for recent events (which comes into play once material that has departed from
consciousness must be recalled), and
➢ Remote memory (memory of more distant events).

7. Memory for recent events, served by the hippocampus, entorhinal cortex, and related structures in the medial temporal lobe, is
prominently impaired in early AD. By contrast, immediate memory (encoded in the sensory association and prefrontal cortices) is spared
early on, as are memories that are consolidated for long periods of time (years), which can be recalled without hippocampal function.
Executive function and judgment/problem solving
In early stages of AD, impairment in executive function may range from subtle to prominent. Family members and co-workers may find
the patient less organized or less motivated; multitasking is often particularly compromised. In addition to poor insight, reduced ability
for abstract reasoning may be elicited. As the disease progresses, an inability to complete tasks typically emerges.
Behavioural and psychologic symptoms
Neuropsychiatric symptoms are common in AD, particularly in the middle and late course of disease. These can begin with relatively
subtle symptoms including apathy, social disengagement, and irritability.
Other signs and symptoms
Apraxia — Dyspraxia, or difficulty performing learned motor tasks, usually occurs later in the disease after deficits in memory and
language are apparent.
Sleep disturbances — Sleep disturbances are common in patients with AD.
Seizures — Seizures occur in 10 to 20 percent of patients with AD, usually in the later stages of disease.
Motor signs — In the early stages, patients with AD generally have a normal neurologic examination except for the cognitive examination.
While pyramidal and extrapyramidal motor signs, myoclonus, and seizures do occur in patients with AD, these are typically late-stage
findings.
Myoclonus may emerge in some patients with AD, typically those with more rapid than usual decline. Similarly, primitive reflexes (grasp,
snout reflexes) and incontinence are late, rather than early, features of AD
.
EARLY STAGE MIDDLE STAGES LATE STAGES
MCI
memory loss < 1.5 SD memory test
“Prodromal AD”
“Early symptomatic AD”
partial / generalized seizures herald AD
and can occur even prior to dementia
onset.
Eventually, with AD, the cognitive
problems begin to interfere with
daily activities, such as keeping track of
finances, following instructions on the job,
driving, shopping, and housekeeping.
Some patients are unaware of these
difficulties (anosognosia)
Changes in environment (travel,
relocation, hospitalization) tend to
destabilize the patient.
Over time patients become lost on walks
or while driving.
Social graces, routine behaviour, and
superficial conversation may be
surprisingly intact, even into the later
stages of the illness
Patient is unable to work, is easily
lost and confused, and requires daily
supervision.
Language becomes impaired—first
naming, then comprehension, and finally
fluency.
Word-finding difficulties and
circumlocution can be evident in the early
stages, even when formal testing
demonstrates intact naming
and fluency.
Apraxia emerges, and patients have trouble
performing learned sequential motor tasks.
Visuospatial deficits begin to interfere with
dressing, eating, or even walking, and
patients fail to solve simple puzzles or
copy geometric figures.
Simple calculations and clock reading
become difficult in parallel
some persons remain ambulatory,
wandering aimlessly. Loss of judgment
and reasoning is inevitable.
Delusions are common, usually simple,
with common themes of theft, infidelity, or
misidentification. Approximately 10% of
AD patients develop Capgras’ syndrome,
believing that a caregiver has been
replaced by an impostor.
Disinhibition and uncharacteristic
belligerence may occur and
alternate with passivity and withdrawal.
Sleep-wake patterns are disrupted, and
night-time wandering becomes disturbing
to the household.
Some patients develop a shuffling gait with
generalized muscle
rigidity associated with slowness and
awkwardness of movement.
Patients often look parkinsonian but rarely
have a high amplitude, low-frequency
tremor at rest. There is a strong overlap
between Parkinson’s disease (PD) and AD,
and some AD patients develop more
classical PD features.
LATE STAGES  END STAGES
In the end stages, AD patients become rigid, mute, incontinent, and bedridden, and help is needed with eating, dressing,
and toileting.
Hyperactive tendon reflexes and myoclonic jerks (sudden brief contractions of various muscles or the whole body) may
occur spontaneously or in response to physical or auditory stimulation.
Often death results from malnutrition, secondary infections, pulmonary emboli, heart disease, or, most commonly,
aspiration.

8. THE TYPICAL DURATION
The typical duration of AD is 8–10 years, but the course ranges from 1 to 25 years. For unknown
reasons, some patients with AD show a steady decline in function while others have prolonged plateaus
without major deterioration.
DIAGNOSIS
The clinical criteria for AD include a history of insidious onset and progressive course of cognitive
decline, exclusion of other etiologies, and documentation of cognitive impairments in one or more
domains.
CLINICAL ASSESSMENT- SCORING TOOLS
MMSE – It is a 30-point questionnaire that is used extensively in clinical settings to measure
cognitive impairment. While different cut off points have been used across studies, scores ≤23 are most
commonly regarded as abnormal and indicative of cognitive impairment. However, age, education, race
each appear to have significant effects on overall MMSE scores.

9. Montreal Cognitive Assessment (MoCA) - The MoCA is a good screening test for
individuals who score above the cut-off on the MMSE and for a well-educated person who complains
only of memory impairment. It was designed to detect mild cognitive impairment in elders scoring in
the normal range on the MMSE.
The typical cut off score for normal performance on the MoCA is < 26.

10. Clinical Dementia Rating scale (CDR) is a structured, clinician-rated interview that
collects information on cognitive capacity from both the collateral source and patient for the evaluation
of staging severity of dementia. Six domains are assessed and then synthesized to assign a Global
CDR score. The domains are memory, orientation, judgment and problem solving, community affairs,
home and hobbies, and personal care.
Clock drawing has also become popular as a screening tool for cognitive problems as a single
task that covers multiple cognitive domains
Role of neuropsychologic testing
Formal neuropsychologic assessment can be helpful in the evaluation of individuals with cognitive
impairment and dementia. Cognitive testing under standardized conditions using demographically
appropriate norms is more sensitive to the presence of impairments, especially impairments of executive
function. Neuropsychologic assessment can be useful in a variety of settings
Neuroimaging:
Although CT is able to demonstrate the characteristic patterns of cortical atrophy, MRI is more sensitive
to these changes and better able to exclude other causes of dementia (e.g. multi-infarct dementia) and
as such is the favored modality. In addition to structural imaging, molecular imaging with PET is
increasingly of value in the diagnosis of Alzheimer disease.

11. Structural MRI findings in AD include both generalized and focal atrophy, as well as white matter
lesions. In general, these findings are nonspecific. The most characteristic focal finding in AD is
reduced hippocampal volume (age corrected norms) or medial temporal lobe atrophy.
The diagnosis should be made on the basis of two features:
• Mesial temporal lobe atrophy (particularly the hippocampus, entorhinal cortex and perirhinal cortex) Direct
assessment is of hippocampal or Para hippocampal volume loss while indirect assessment relies on an enlargement
of the Para hippocampal fissures
• Temporoparietal cortical atrophy
Nuclear medicine- FDG PET, SPECT, Amyloid PET, Tau PET
Functional brain imaging with 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) or
single-photon emission computed tomography (SPECT) reveals distinct regions of hypometabolism
(PET) and hypoperfusion (SPECT) in AD. These areas include the hippocampus, the precuneus (mesial
parietal lobes), and the lateral parietal and posterior temporal cortex. In practice, FDG-PET may be
most useful in distinguishing AD from FTD in patients with atypical presentations.
The volume of hippocampus or medial temporal lobe, the most studied brain regions, showed low
sensitivity and specificity and did not qualify structural MRI as a stand-alone add-on test for an early
diagnosis of dementia due to Alzheimer's disease in people with MCI. This is consistent with
international guidelines, which recommend imaging to exclude non-degenerative or surgical causes
of cognitive impairment and not to diagnose dementia due to Alzheimer's disease
Other laboratory testing — Routine laboratory tests are not useful in the positive diagnosis of AD;
however, some laboratory tests are indicated to exclude contributing secondary causes.
Genetic testing is not recommended in the routine evaluation of patients with AD. APOE genotyping
adds marginally to the predictive value of clinical criteria for AD and may stratify risk of conversion of
amnesic MCI to AD.
SEVERITY
MMSE MoCA CDR
Normal >25 >26 0 to 0.5
Mild/Mod MCI 18-24 Average 22 1, 2
AD <17 Average 16 3

12. TREATMENT
The primary focus
• Long-term amelioration of associated behavioural and neurologic problems
• Building rapport with the patient, family members, and other caregivers
• Providing caregiver support.
In the early stages of AD
• Memory aids such as notebooks and posted daily reminders can be helpful.
• Family members should emphasize activities that are pleasant while curtailing those that
increase stress on the patient.
• Kitchens, bathrooms, stairways, and bedrooms need to be made safe.
• Eventually patients will need to stop driving.
• Loss of independence and change of environment may worsen confusion, agitation, and
anger. Communication and repeated calm reassurance are necessary.
• Caregiver “burnout” is common, often resulting in nursing home placement of the patient or
new health problems for the caregiver. Respite breaks for the caregiver help to maintain a
successful long-term therapeutic milieu. Use of adult day care centres can be helpful.
Medications
Initial
Dose
Increase by Target Dose
Donepezil 5mg 4wk 10 mg daily Mild to severe AD
Rivastigmine 1.5 mg BD 4wk 6 mg BD or
9.5mg patch OD
Mild to mod AD
Galantamine 4mg BD 4wk 12 mg BD or
24 mg daily ER
Mild to mod AD
Memantine 5mg OD 4wk 10 mg twice daily moderate to severe AD
as a add on therapy
Dose escalations - must be carried out over 4–6 weeks to minimize side effects.
Pharmacologic action - of donepezil, rivastigmine, and galantamine is inhibition of the cholinesterase,
primarily acetylcholinesterase, with a resulting increase in cerebral acetylcholine levels. Memantine
appears to act by blocking overexcited (NMDA) glutamate receptors.
Side Effects- Cholinesterase inhibitors are relatively easy to administer, and their major side effects are
gastrointestinal symptoms (nausea, diarrhoea, cramps), altered sleep with unpleasant or vivid dreams,
bradycardia (usually benign), and muscle cramps.

13. Tight control of Diabetes and use of Statins – Prior to onset
Several retrospective studies suggest that nonsteroidal anti- inflammatory agents and 3-hydroxy-3-
methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) may have a protective effect on
dementia if used prior to the onset of disease but do not influence clinically symptomatic AD. Finally,
there is now a strong interest in the relationship between diabetes and AD, and insulin- regulating
studies are being conducted.
Treat Depression- SSRI
Mild to moderate depression is common in the early stages of AD and may respond to antidepressants
or cholinesterase inhibitors. Selective serotonin reuptake inhibitors (SSRIs) are commonly used due to
their low anticholinergic side effects (for example, escitalopram, target dose 5–10 mg daily).
Neuropsychiatric symptoms – low dose atypical antipsychotics
Agitation, insomnia, hallucinations, and belligerence are especially troublesome characteristics of some
AD patients, and these behaviours can lead to nursing home placement. The newer generation of
atypical antipsychotics, such as risperidone, quetiapine, and olanzapine, are being used in low doses to
treat these neuropsychiatric symptoms. The few controlled studies comparing drugs against behavioural
intervention in the treatment of agitation suggest mild efficacy with significant side effects related to
sleep, gait, and cardiovascular complications, including an increased risk of death. All antipsychotics
carry a black box FDA warning for use in elderly patients with dementia and thus should be prescribed
only with caution; however, careful, daily, nonpharmacologic behaviour management is often not
available, rendering medications necessary for some patients.
Seizures can be treated with levetiracetam unless the patient had a different regimen that was effective
prior to the onset of AD.
Finally, medications with strong anticholinergic effects should be vigilantly avoided, including
prescription and over-the-counter sleep aids (e.g., diphenhydramine) or incontinence therapies
(e.g., oxybutynin).
RECENT ADVANCES
Aducanumab is an amyloid beta-directed antibody indicated to treat Alzheimer’s disease. It is
approved under the accelerated approval pathway, which provides patients with a serious AD earlier
access to drugs (NEJM Aug 2021)
Notes from Harrison’s Text Book of Medicine 20th Ed