Alzheimer’s Disease 

Alzheimer’s disease (AD) is the most common cause of dementia worldwide, accounting for ~60–70% of cases.

• Progressive neurodegenerative disorder
• Characterized by:
• Cognitive decline (memory first)
• Behavioral changes
• Functional impairment

1.  Epidemiology

• Prevalence ↑ with age:
• 65 years: ~5–10%
• 85 years: ~30–40%
• Slight female predominance
• Early-onset AD (<65 yrs):
• Often familial (autosomal dominant)

2. Pathophysiology 

A. Hallmark Pathology

1. Amyloid Plaques

• Extracellular deposition of β-amyloid (Aβ42)
• Derived from amyloid precursor protein (APP)

➡️ Pathway:

• APP → β-secretase + γ-secretase → Aβ (toxic)

2. Neurofibrillary Tangles

• Intracellular aggregates of hyperphosphorylated tau protein
• Leads to:
• Microtubule instability
• Neuronal death

3. Synaptic Dysfunction

• Early event → correlates best with cognitive decline

B. Neuroanatomy

• Earliest: Hippocampus + medial temporal lobe(Explains:Early episodic memory loss)
• Later:
• Parietal
• Frontal cortex

C. Neurotransmitter Changes

• ↓ Acetylcholine (basal forebrain degeneration)
• Also ↓ serotonin, norepinephrine

D. Genetic Factors 

3. Clinical Features

A. Cognitive Domains Affected

1. Memory (Earliest)

• Episodic memory loss
• Repeating questions

2. Language

• Word-finding difficulty (anomia)

3. Visuospatial

• Getting lost

4. Executive function

• Planning difficulty

B. Behavioral & Psychological Symptoms (BPSD)

• Agitation
• Depression
• Psychosis (late)
• Sleep disturbance

C. Disease Staging

1. Mild

• Memory loss
• Independent living

2. Moderate

• Functional impairment
• Behavioral issues

3. Severe

• Non-verbal
• Bed-bound
• Dysphagia

4. Diagnosis

A. Clinical Diagnosis

Based on:

• Progressive cognitive decline
• Interference with daily life
• No alternative cause

B. Cognitive Testing

• MMSE (Mini-Mental State Examination)
• MoCA (more sensitive early)

C. Investigations

1. Blood Tests (to exclude reversible causes)

• B12 deficiency
• Hypothyroidism
• HIV, syphilis

2. Neuroimaging

MRI Brain (Preferred)

• Medial temporal lobe atrophy
• Hippocampal volume loss

FDG-PET

• Temporoparietal hypometabolism

Amyloid PET

• Detects amyloid deposition

D. CSF Biomarkers

• ↓ Aβ42
• ↑ Total tau
• ↑ Phosphorylated tau

E. Diagnostic Criteria 

• Biological definition (ATN framework):
• A = Amyloid
• T = Tau
• N = Neurodegeneration

5. Differential Diagnosis 

6.  Management 

A. Non-Pharmacological (FIRST LINE)

• Cognitive stimulation therapy
• Structured routine
• Caregiver support

B. Pharmacological Treatment

1. Cholinesterase Inhibitors (1st Line)

• Donepezil
• Rivastigmine
• Galantamine

➡️ Indication:

• Mild–moderate AD

2. NMDA Receptor Antagonist

• Memantine

➡️ Indication:

• Moderate–severe AD

3. Behavioral Symptoms

• SSRIs for depression
• Antipsychotics (last resort, ↑ mortality risk)

C. Disease-Modifying Therapy 

• Anti-amyloid monoclonal antibodies:
• Lecanemab
• Aducanumab

 Notes:

• Early disease only
• Risk: ARIA (amyloid-related imaging abnormalities)

7.  Complications

• Aspiration pneumonia (most common cause of death)
• Malnutrition
• Falls
• Pressure sores

8.  Prognosis

• Gradual decline over 8–12 years
• Death due to complications, not dementia itself

9.  Exam PEARLS 

• Earliest pathology: hippocampus
• Best correlate with cognition: synaptic loss
• Most important genetic risk: APOE ε4
• Most common dementia worldwide: Alzheimer’s
• First-line drugs: cholinesterase inhibitors
• Definitive diagnosis: histopathology (post-mortem)
• CSF pattern: ↓ Aβ, ↑ tau