INTRODUCTION

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia, responsible for about 60–70% of all cases. The earliest and most frequent initial symptom is difficulty remembering recent events. As the condition worsens, people may experience language problems, disorientation, mood changes, lack of motivation, neglect of personal care, and behavioral disturbances. With advancing decline, individuals gradually withdraw from social interaction. Over time, bodily functions deteriorate, ultimately leading to death. The rate of progression differs among individuals, but life expectancy after diagnosis typically ranges from three to twelve years.

The exact cause of Alzheimer’s is still unclear. Both genetic and environmental factors contribute to its development. The strongest known genetic risk factor is a specific allele of the apolipoprotein E gene. Other risks include past head trauma, depression, and hypertension. Alzheimer’s is marked by the buildup of abnormal proteins in the brain—amyloid plaques and tau tangles—which interfere with normal cell activity and progressively destroy neurons and synapses. Diagnosis is generally based on medical history, cognitive tests, and imaging or blood work to rule out other disorders. Early symptoms are often mistaken for normal aging. A definite diagnosis can only be made by examining brain tissue after death.

There is currently no cure or treatment that can halt or reverse the disease, although some medications may temporarily relieve symptoms. A healthy diet, exercise, and social engagement can promote overall brain health and may reduce the risk of cognitive decline. As the disease progresses, individuals require increasing levels of support, placing emotional, physical, and financial strain on caregivers. Exercise-based interventions may help maintain daily functioning. Behavioral symptoms or psychosis are sometimes managed with antipsychotic medications, though these drugs increase the risk of early death.

As of 2020, around 50 million people worldwide were living with Alzheimer’s disease. It most commonly affects individuals over the age of 65, but up to 10% of cases are early-onset and appear in people aged 30–60. About 6% of those older than 65 are affected, and women are diagnosed more often than men. The disease is named after Alois Alzheimer, who first identified it in 1906. Globally, Alzheimer’s imposes a huge economic burden, costing about US $1 trillion each year, and is ranked as the seventh leading cause of death.

Because of its immense impact, Alzheimer’s research receives significant international funding. For example, the U.S. National Institutes of Health allocates nearly US $4 billion annually toward Alzheimer’s research, while the EU’s Horizon Europe program contributed over €570 million to dementia-related studies.

Signs and Symptoms

Alzheimer’s disease typically progresses through three stages: early (mild), middle (moderate), and late (severe). The illness usually begins in the hippocampus—an area crucial for memory—which explains why memory loss appears first.

Initial Symptoms

Early signs are often mistaken for aging or stress. Detailed cognitive testing can detect subtle problems years before a clinical diagnosis is made. The most obvious early issue is short-term memory loss, such as struggling to retain new information. Difficulties in attention, planning, reasoning, or abstract thinking may also appear. Apathy and depression are common early features, with apathy often persisting throughout the illness. Individuals with noticeable cognitive decline but not full dementia may be diagnosed with mild cognitive impairment, especially if memory loss is the main feature.

Early Stage

Gradually, memory and learning difficulties worsen enough for a clear diagnosis. Some people show early language deficits, problems with perception, or difficulty performing coordinated movements. Not all types of memory are affected equally—older personal memories and learned skills may remain intact longer than newly acquired information. Vocabulary shrinks, and language becomes less fluent, although basic communication is usually still possible. Subtle coordination problems may appear. People can still perform many tasks independently but need help with more complex activities.

Middle Stage

Increasing cognitive decline disrupts daily living. Speech becomes noticeably impaired due to frequent word-finding difficulties. Reading and writing skills deteriorate. Motor coordination worsens, raising the risk of falls. Memory problems intensify, and familiar people may no longer be recognized. Behavioral and psychological symptoms—such as wandering, irritability, emotional instability, aggression, or delusions—become more common. Many individuals lose awareness of their condition. Incontinence may develop. These challenges often lead families to seek long-term care support.

Late Stage

In the final phase, people become completely dependent on caregivers. Speech is reduced to very few words and eventually disappears, though emotional understanding may remain. Severe apathy and exhaustion are typical. Mobility and muscle strength decline until the person becomes bedridden. Death usually results from complications such as infections or pneumonia. Some individuals may briefly experience unexpected mental clarity shortly before death.

Causes and Contributing Factors

Alzheimer’s develops when abnormal levels of amyloid-β and tau proteins accumulate in the brain, impairing neurons and their connections. Most cases have no single identifiable cause, though 1–2% arise from specific genetic mutations. The amyloid hypothesis—the idea that amyloid buildup is the earliest and central event—remains the dominant explanation. Genetic evidence strongly supports this view. The tau hypothesis suggests that tau abnormalities may drive disease onset in some cases. Both processes likely interact.

Genetic Factors

• Late-onset Alzheimer’s is mostly sporadic but influenced by genetics, especially the APOE ε4 allele.
  
  

• Early-onset familial cases (1–2%) are caused by mutations in APP, PSEN1, or PSEN2.
  
  

• Other genes such as ABCA7, SORL1, and TREM2 also contribute to risk.
  
  

Other Proposed Factors

Multiple theories attempt to explain additional contributors:

• Hormonal changes (particularly in women)
  
  

• Possible infections (e.g., herpes viruses)
  
  

• Oxidative DNA damage
  
  

• Loss of cholinergic neurons
  
  

• Sleep disturbances
  
  

• Chronic inflammation and metal imbalance
  
  

• Smoking and air pollution exposure
  
  

• Age-related decline of myelin and oligodendrocyte function
  
  

• Viral infections, including possible associations with COVID-19
  
  

Pathophysiology

Macroscopically, the Alzheimer’s brain often shows widespread cortical shrinkage, particularly in the hippocampus, amygdala, and certain cortical regions, along with enlarged ventricles. Microscopic analysis reveals two hallmark features: amyloid plaques and tau tangles. These abnormalities appear first in specific brain regions and spread throughout the brain as the disease advances.

Other pathological features include amyloid deposition in blood vessels, chronic inflammation, and significant loss of neurons and synapses—which correlates most strongly with dementia severity. Many patients also show overlapping pathologies, such as vascular disease or Lewy bodies, complicating diagnosis.

Biochemistry of Alzheimer’s Disease

Alzheimer’s disease (AD) is mainly a protein misfolding disorder involving:

A. Amyloid-β (Aβ) Pathology

• Aβ is a peptide fragment (39–43 amino acids) produced from amyloid precursor protein (APP).
  
  

• APP is normally involved in:
  
  

  • Neuronal growth
    
    

  • Survival
    
    

  • Repair
    
    

• In AD, two enzymes β-secretase and γ-secretase abnormally cut APP → produce Aβ.
  
  

• The Aβ peptide misfolds → aggregates → forms oligomers & amyloid plaques.
  
  

• Excitatory neurons are major producers of Aβ.
  
  

• Toxic Aβ oligomers:
  
  

  • Disrupt synapses
    
    

  • Cause inflammation
    
    

  • Impair mitochondria & glucose use
    
    

B. Tau Protein Abnormality

• Tau stabilizes microtubules inside neurons.
  
  

• In AD:
  
  

  • Tau becomes hyperphosphorylated
    
    

  • Forms neurofibrillary tangles (NFTs)
    
    

  • Microtubules collapse → nutrient transport stops → neuron dies
    
    

• Tau can cause:
  
  

  • Transposable element dysregulation
    
    

  • Necroptosis (regulated cell death)
    
    

2. Disease Mechanism – Amyloid Cascade Hypothesis

The classical model suggests:

1. Aβ accumulation is the initiating event.
   
   

2. Misfolded Aβ spreads in a prion-like seeding mechanism.
   
   

3. Toxic oligomers damage neurons.
   
   

4. Leads to:
   
   

   • Tau hyperphosphorylation
     
     

   • Inflammation
     
     

   • Oxidative stress
     
     

   • Mitochondrial failure
     
     

   • Calcium imbalance
     
     

   • Autophagy failure
     
     

   • Lipid and metal dyshomeostasis (iron → ferroptosis)
     
     

Overall: AD = complex cascade of Aβ + tau + inflammation + neuronal metabolic failure.

3. Microglia & Inflammation

Microglia (brain immune cells):

• Recognize & clear Aβ
  
  

• BUT chronic activation → releases inflammatory cytokines
  
  

• Early microglial activation can occur before visible plaques
  
  

• Associated with:
  
  

  • Aberrant tau
    
    

  • Aβ deposition
    
    

  • Neuronal injury
    
    

Astrocytes, oligodendrocytes, and lymphocytes also contribute.

4. Neurotrophic Factors

• Reduced BDNF and receptor imbalance contribute to:
  
  

  • Synaptic dysfunction
    
    

  • Memory impairment
    
    

5. Diagnosis of Alzheimer’s Disease

A. Definitive diagnosis only at autopsy

• Detection of:
  
  

  • Amyloid plaques
    
    

  • Neurofibrillary tangles
    
    

B. Clinical Diagnosis (Probable AD)

Based on:

• Patient history
  
  

• Cognitive decline in ≥2 domains:
  
  

  • Memory
    
    

  • Language
    
    

  • Executive function
    
    

  • Visuospatial skills
    
    

  • Attention
    
    

C. Imaging Findings

• MRI/CT shows:
  
  

  • Hippocampal atrophy (most specific)
    
    

  • Cortical atrophy
    
    

  • Cerebrovascular disease (common co-factor)
    
    

• FDG-PET:
  
  

  • Reduced metabolism in temporal & parietal lobes
    
    

• PET amyloid/tau scans (using radiotracers):
  
  

  • Florbetapir, Flutemetamol, Florbetaben, Flortaucipir
    
    

D. Cognitive Tests

• MMSE
  
  

• MoCA
  
  

• Mini-Cog
  (But these can be less sensitive in early disease.)
  
  

E. Blood Test Breakthrough (2025)

• Fujirebio Lumipulse pTau217/Aβ42 ratio
  
  

• First FDA-approved blood test for early detection (age ≥55).