Alzheimer Clinical Overview
I. The "On-Call" Snapshot
Clinical Significance in Malaysia: Malaysia is an ageing population. You will frequently clerk confused elderly patients in A&E and on the wards. Your primary job is to differentiate dementia from delirium.
High-Yield Definition: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by an insidious onset of cognitive decline, most commonly affecting memory, which interferes with daily function and independence. (Source: UpToDate).
Clinical One-Liner: It's the most common cause of dementia, presenting as progressive short-term memory loss before hitting other cognitive domains.
II. Etiology & Risk Factors
Etiology: Progressive accumulation of extracellular amyloid-beta plaques and intracellular neurofibrillary tangles (hyperphosphorylated tau protein), leading to synaptic dysfunction, neuroinflammation, and widespread neuronal death.
Risk Factors:
Non-modifiable: Age (strongest factor), APOE ε4 genotype, positive family history.
Modifiable (Highly prevalent in Malaysia): Mid-life hypertension, T2DM, hyperlipidaemia, obesity, smoking, physical inactivity, low educational attainment, hearing loss, social isolation.
III. Quick Pathophysiology
The disease process starts in the medial temporal lobe, specifically the hippocampus.
Amyloid Plaques (Extracellular): Disrupt cell-to-cell communication at the synapse.
Tau Tangles (Intracellular): Hyperphosphorylated tau proteins destabilise microtubules, disrupting the cell's internal transport system and leading to cell death.
This hippocampal origin is why impaired encoding of new memories (short-term memory loss) is the first and most prominent symptom. The pathology then spreads to the association cortices, affecting language (temporal), visuospatial function (parietal), and executive function (frontal).
IV. Classification
By Onset:
Early-onset: <65 years old (rarer, higher genetic link, e.g., PSEN1, PSEN2, APP mutations).
Late-onset (Sporadic): >65 years old (most common, APOE4 is a major risk factor).
By Stage (Clinical):
Preclinical: Biomarker evidence without symptoms.
Mild Cognitive Impairment (MCI) due to AD: Cognitive complaint, objective impairment, but no functional decline.
Dementia due to AD (Mild, Moderate, Severe): Cognitive impairment is severe enough to interfere with daily function (IADLs/ADLs).
V. Clinical Assessment
🚩 Red Flags & Immediate Actions:
Sudden onset / acute confusion (hours to days): This is Delirium until proven otherwise.
Action: Full septic and metabolic screen (FBC, RP, LFT, UFEME, +/- BUSE, CXR). Find and treat the underlying cause (e.g., UTI, pneumonia).
Rapidly progressive cognitive decline (weeks to months): Suspect differentials like CJD, autoimmune encephalitis.
Action: Escalate to Neurology for urgent workup (MRI, LP, autoimmune panel).
Focal neurological deficits (e.g., sudden hemiparesis, visual field loss): Suggests stroke or space-occupying lesion (SOL).
Action: Urgent CT Brain.
New-onset seizures: Can occur in late AD, but must investigate for other causes (SOL, metabolic, stroke).
History:
Key Diagnostic Clues: Insidious onset and progressive decline. Short-term memory impairment is the primary symptom (e.g., "repeats questions," "forgets recent events"). Must be accompanied by functional decline (difficulty with IADLs like managing finances, medications, cooking, or later, ADLs like dressing, bathing).
Symptom Breakdown (Cognitive):
Common (>50%): Anterograde episodic memory loss (memory for recent events).
Less Common (as it progresses): Language (anomia - word-finding difficulty), Visuospatial dysfunction (getting lost in familiar places), Executive dysfunction (poor planning, judgment).
Rare (usually late): Apraxia (difficulty with motor tasks), Agnosia (inability to recognise objects/faces).
Behavioural and Psychological Symptoms (BPSD):
Common: Apathy (most common), depression, anxiety.
Less Common: Agitation, aggression, irritability.
Late-stage: Hallucinations (visual > auditory), delusions (e.g., "people are stealing from me"), wandering.
Pertinent Negatives:
No acute onset (rules out delirium/stroke).
No early prominent Parkinsonism or visual hallucinations (less likely Dementia with Lewy Bodies - LBD).
No early prominent behavioural change/disinhibition with spared memory (less likely Frontotemporal Dementia - FTD).
No clear stepwise decline (less likely Vascular Dementia, though mixed dementia is common).
Physical Examination (OSCE Approach):
General Inspection: Often normal in early stages. May look unkempt, disengaged, or confused in later stages.
Vitals: Usually normal.
Disease-Specific Examination (Neurology & Cognition):
Cognitive Screen: This is the core of your exam.
MoCA (Montreal Cognitive Assessment): Preferred tool, more sensitive for MCI. (Available in BM).
MMSE (Mini-Mental State Examination): Older, less sensitive, copyrights.
Look for specific deficits in delayed recall, orientation, and visuospatial tasks (clock drawing, cube copy).
Neurological Exam:
Positive Findings: The exam is typically normal in early-to-moderate AD. This is a key diagnostic feature.
Late-Stage findings: Primitive reflexes (grasp, palmomental), mild rigidity, gait disturbance (short-stepped).
Pertinent Negatives: Absence of focal deficits (motor/sensory), resting tremor/bradykinesia (Parkinsonism), cerebellar signs.
Examination for Differentials:
Vascular: Look for focal motor deficits, brisk reflexes, spasticity.
Parkinson's/LBD: Look for resting tremor, rigidity, bradykinesia.
NPH: Look for the triad of gait apraxia (magnetic gait), urinary incontinence, and cognitive decline.
Differentiating Disease Stage:
Early / Mild (MCI/Mild Dementia): Difficulty with IADLs (finances, complex tasks). MoCA score ~18-25. Aware of deficit.
Intermediate / Moderate: Needs help with basic ADLs (dressing, grooming). BPSD common. MoCA ~10-17.
Late / Severe: Fully dependent for all ADLs, often non-verbal, bed-bound. MoCA <10.
Clinical Pearl: Always get a collateral history from a family member or caregiver. The patient often lacks insight (anosognosia). The family sees the change. Ask: "How are they different from 1 year ago?"
VI. Diagnostic Workflow
Differential Diagnosis:
Delirium
Points For: Acute onset, fluctuating consciousness, inattention, underlying medical illness.
Points Against: Insidious onset, stable vitals (usually).
Differentiate: Collateral history, physical exam for infection/metabolic cause. Confusion Assessment Method (CAM).
Vascular Dementia
Points For: Stepwise decline, history of stroke/CV risk factors, focal neuro deficits.
Points Against: Insidious decline without clear "steps," normal neuro exam.
Differentiate: MRI Brain (will show infarcts, significant white matter lesions). (Note: Mixed AD + VaD is very common).
Dementia with Lewy Bodies (LBD)
Points For: Fluctuating cognition, early/prominent visual hallucinations, spontaneous Parkinsonism (within 1 year of cognitive decline).
Points Against: Memory loss as primary symptom, absence of these core features.
Differentiate: Clinical features are key.
Frontotemporal Dementia (FTD) - Behavioural Variant
Points For: Early and prominent personality change (disinhibition, apathy), relative sparing of memory. Younger onset.
Points Against: Memory loss as primary symptom.
Differentiate: Collateral history on behaviour. MRI (will show frontal/temporal atrophy).
Investigations Plan:
Purpose: Not to diagnose AD (which is clinical), but to rule out reversible causes and support the diagnosis.
Bedside / Initial (First 15 Mins):
Cognitive Screen (MoCA/MMSE).
Geriatric Depression Scale (GDS) - to rule out pseudodementia.
First-Line Labs (The "Dementia Screen"):
FBC (anaemia)
RP/LFT (uraemic/hepatic encephalopathy)
TFT (hypothyroidism is a key reversible cause)
Serum B12 / Folate (deficiency)
VDRL/TPHA (neurosyphilis - if risk factors)
FBS/HbA1c (T2DM control)
First-Line Imaging (Mandatory):
CT Brain (non-contrast): To rule out SOL, stroke, Normal Pressure Hydrocephalus (NPH), subdural haematoma. This is the minimum standard.
Confirmatory / Gold Standard (Specialist setting):
MRI Brain: More sensitive. Classically shows medial temporal lobe (hippocampal) atrophy, disproportionate to general atrophy.
Lumbar Puncture (for CSF): Measures CSF Aβ42 (low) and Tau/p-Tau (high). Not routine, used in atypical/rapid/early-onset cases.
VII. Staging & Severity Assessment
Clinical Dementia Rating (CDR): Global staging.
CDR 0.5: Mild Cognitive Impairment (MCI)
CDR 1: Mild Dementia
CDR 2: Moderate Dementia
CDR 3: Severe Dementia
Impact: Staging determines caregiver needs, safety planning (driving, finances), and eligibility for medications (cholinesterase inhibitors are for mild-moderate stages).
VIII. Management Plan
A. Principle of Management:
Symptomatic cognitive enhancement (no cure).
Manage Behavioural and Psychological Symptoms (BPSD).
Support the caregiver and plan for long-term safety.
Aggressively manage cardiovascular risk factors.
B. Immediate Stabilisation (The ABCDE Plan):
Not applicable for AD itself.
If the patient presents with delirium superimposed on dementia, the ABCDE approach is for the underlying cause (e.g., sepsis).
For severe agitation/aggression (BPSD) posing immediate risk:
First-line: Verbal and non-verbal de-escalation.
Pharmacological (last resort, low dose): PO/IM Haloperidol 0.5-1mg (watch for EPS, QTc) or PO Risperidone 0.25-0.5mg. (Avoid benzodiazepines - risk of paradoxical agitation and falls).
C. Definitive Treatment (The Ward Round Plan):
Non-Pharmacological (FIRST-LINE for all stages):
Cognitive stimulation, reality orientation, music therapy, reminiscence therapy.
Caregiver education and training (crucial).
Manage environment: reduce triggers, ensure safety (fall risk, wandering).
Pharmacological (Cognitive): (For Mild to Moderate AD)
Cholinesterase Inhibitors:
Donepezil (Aricept): Start 5mg ON, titrate to 10mg ON after 4-6 weeks. (Most common in KKM formulary).
Rivastigmine: PO or patch.
Side effects: Nausea, vomiting, diarrhoea, bradycardia (warn caregivers).
Pharmacological (Cognitive): (For Moderate to Severe AD)
NMDA-Receptor Antagonist:
Memantine (Ebixa): Start 5mg OD, titrate weekly to 10mg BD.
Can be used as monotherapy or added to a cholinesterase inhibitor.
Pharmacological (BPSD):
Principle: Start Low, Go Slow. Use only if non-pharma fails and patient/caregiver is in distress.
Depression: SSRIs (e.g., Escitalopram, Sertraline).
Psychosis/Agitation: Atypical antipsychotics (e.g., Risperidone 0.25-1mg daily). Black Box Warning: Increased risk of stroke and death in elderly with dementia. Must discuss risk/benefit with family.
Sleep: Trazodone 25-50mg ON (preferred over benzos).
D. Long-Term & Discharge Plan:
Follow-up: 3-6 monthly review with Geriatric/Psych/Neurology clinic to monitor cognition (MoCA) and BPSD.
Caregiver Support: Link to Alzheimer's Disease Foundation Malaysia (ADFM), local dementia daycares, and support groups.
Safety: Driving cessation, financial/legal planning (Lasting Power of Attorney), home safety assessment.
End-of-Life: Discuss advance care planning as disease progresses.
IX. Complications
Immediate: Falls (gait instability), wandering (getting lost), delirium (secondary to intercurrent illness).
Action: Environmental safety, "Pesakit Berisiko Jatuh" tag, caregiver supervision.
Short-Term: Malnutrition/dehydration (forgetting to eat/drink), medication errors.
Action: Supervised feeding, pillbox (dosette box).
Long-Term: Aspiration pneumonia (impaired swallow), pressure ulcers (immobility), joint contractures.
Action: Speech therapy review for swallow, regular turning, physiotherapy.
X. Prognosis
Average survival: Highly variable, ~3-10 years post-diagnosis.
Prognostic Factors:
Worse: Earlier onset, male, prominent BPSD, rapid decline, presence of extrapyramidal signs.
Better: Later onset, female, high education (cognitive reserve), good social support.
XI. How to Present to Your Senior
SBAR:
S: "Dr, I'm calling about Mr. Tan, a 75-year-old male in Ward 5A, who was admitted for ?dementia workup. The family reports 2 years of progressive memory loss, now impacting his ADLs."
B: "He has a background of HPT and T2DM. His MoCA score is 15/30, with significant deficits in delayed recall and orientation. His neurological exam is normal. We have a collateral history from his son, who confirms insidious onset."
A: "My primary diagnosis is dementia, likely Alzheimer's type. I have sent off the dementia screen (TFT, B12, RP, VDRL). His CT brain shows age-related atrophy with no acute infarct or SOL. I have ruled out delirium."
R: "I plan to review the blood results to exclude reversible causes. Pending that, I would like to start him on Donepezil 5mg ON and refer him to the Geriatrics clinic for follow-up. Is that acceptable?"
XII. Summary & Further Reading
Top 3 Takeaways:
AD is a clinical diagnosis of insidious, progressive memory loss + functional decline.
Your first job is to rule out reversible causes (TFT, B12, CT Brain) and delirium.
Management is supportive: Cholinesterase inhibitors (Donepezil) for cognition, non-pharma first for BPSD, and massive support for the caregiver.
Key Resources:
Local Guideline: Malaysian CPG on Management of Dementia (2nd Ed. 2009 - note this is old, supplement heavily with UpToDate). More importantly, manage risk factors using CPG Management of T2DM (6th Ed.) and CPG Management of Hypertension (2018).
UpToDate: "Clinical features and diagnosis of Alzheimer disease" and "Management of dementia".
Amboss: "Alzheimer Disease".
