What causes Alzheimer's disease?

Causes of Alzheimer's Disease

Alzheimer's disease is primarily caused by the accumulation of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles in the brain, leading to synaptic dysfunction, neuronal loss, and progressive cognitive decline. 1, 2

Primary Pathological Mechanisms

Amyloid Pathway

• Amyloid-beta (Aβ) accumulation is considered a key early event in AD pathophysiology 1
• Aβ is derived from amyloid precursor protein (APP) through proteolytic cleavage by beta and gamma secretases 3
• Genetic evidence strongly supports the amyloid hypothesis:
  • All known autosomal dominant early-onset forms of AD involve alterations in APP production or cleavage 1
  • Trisomy 21 (Down syndrome) invariably results in AD pathology due to three copies of the APP gene on chromosome 21 1
  • APOE, the major genetic risk factor for late-onset AD, is implicated in amyloid trafficking and plaque clearance 1

Tau Pathology

• Hyperphosphorylated tau forms neurofibrillary tangles 2, 4
• Tau pathology correlates better with clinical impairment than amyloid plaque count or total Aβ load 1
• Tau pathology is measured by the Braak NFT (neurofibrillary tangle) stage in neuropathological diagnosis 2

Downstream Effects

• Synaptic depletion and dysfunction 1, 3
• Neuronal loss 1
• Mitochondrial structural and functional changes 3
• Neuroinflammation 5

Risk Factors and Contributing Factors

Genetic Factors

• Early-onset familial AD: Mutations in APP, PSEN1, and PSEN2 genes 3, 6
• Late-onset sporadic AD: APOE ε4 allele is the strongest genetic risk factor 5

Age-Related Factors

• Advanced age is the greatest risk factor for developing AD 1
• Approximately 30% of clinically normal individuals over 65 years have biomarker evidence of amyloid accumulation 1

Vascular Risk Factors

• Hypertension, hypercholesterolemia, and diabetes increase risk of dementia 1
• These factors may contribute directly to the effect of AD pathology on the aging brain 1

Other Contributing Factors

• Frailty increases risk of dementia even in individuals with low neuropathological burden 1
• Psychological factors: Depression, apathy, and chronic psychological distress 1
• Environmental exposures: Head trauma may influence progression 1
• Pure AD pathology is rare; most older adults with dementia have multiple neuropathological markers 1, 2

Pathophysiological Sequence

1. Initial Aβ accumulation occurs years or decades before symptoms appear 1
2. Tau pathology develops, with hyperphosphorylated tau forming neurofibrillary tangles 4
3. Neuronal dysfunction occurs, including synaptic damage and mitochondrial changes 3
4. Progressive neurodegeneration leads to brain atrophy 1
5. Cognitive symptoms emerge when pathology exceeds compensatory mechanisms 1

Modulating Factors

Protective Factors

• Cognitive reserve and brain reserve may delay symptom onset 1
  • Higher education and socioeconomic status associated with lower age-adjusted incidence of AD 1
  • Engagement in cognitive, physical, leisure, and social activities may decrease risk 1

Comorbid Pathologies

• Lewy bodies (alpha-synuclein aggregates) frequently coexist with AD pathology 2
• Vascular pathology often accompanies AD changes 1
• Patients with both synucleinopathy and Aβ deposition have significantly shorter survival 2

Important Considerations

• The distinction between Aβ as a risk factor versus an early detectable stage of AD remains unclear 1
• It remains unproven whether Aβ accumulation alone is sufficient to trigger the full pathological cascade 1
• The neurodegenerative process may involve:
  • Direct synaptic toxicity from oligomeric forms of Aβ
  • Disruption of axonal trajectories from fibrillar Aβ
  • A "second hit" that leads to synaptic dysfunction and neurodegeneration 1

Understanding these complex, interrelated pathological mechanisms is essential for developing effective treatments that target the underlying disease process rather than just symptoms.