Is amyloid beta still considered a primary cause of Alzheimer's disease?

Amyloid Beta's Role in Alzheimer's Disease: Current Understanding

The amyloid beta hypothesis is no longer considered the sole cause of Alzheimer's disease, but rather one component of a complex pathophysiological process involving multiple mechanisms including tau pathology, neuroinflammation, and other factors that interact to cause neurodegeneration and cognitive decline. 1

Evolution of the Amyloid Hypothesis

The amyloid hypothesis has been a dominant theory in Alzheimer's disease (AD) research for decades. This hypothesis proposed that:

• Accumulation of amyloid-beta (Aβ) peptides in the brain is an early initiating factor in AD 1
• Aβ deposition leads to a cascade of events resulting in neurodegeneration and dementia 1

However, recent evidence has challenged this simplified view:

Limitations of the Amyloid-Centric Model

• Many cognitively unimpaired individuals have significant amyloid pathology but don't progress to clinical AD 1
• The relationship between amyloid pathology and cognitive decline remains uncertain at an individual level 1
• Therapeutic attempts targeting amyloid reduction have largely failed to demonstrate significant clinical benefits 1

Current Understanding

The 2021 International Working Group recommendations in The Lancet Neurology 1 highlight several key points:

• Multiple pathogenic mechanisms: Besides amyloid, other models emphasize "endosomal recycling deficiency, immunity, lipid metabolism, endocytosis deficiency, and vascular dysfunction" 1

• Synergistic interactions: Evidence suggests AD results not just from tau and amyloid pathologies individually, but from their synergistic interactions leading to protein accumulation and cognitive decline 1

• Biomarker limitations: Amyloid and tau biomarkers alone cannot confidently predict progression to clinical AD without considering clinical presentation 1

Biomarker Evidence and Disease Progression

Current biomarker models recognize:

1. Sequential but overlapping biomarker evolution: Aβ biomarkers appear early but other markers develop in a predictable pattern 1

2. Different biomarker roles:

   • Amyloid biomarkers are primarily "state markers" (indicating disease presence)
   • Tau biomarkers can reflect both state and stage
   • Neurodegeneration biomarkers correlate more closely with clinical symptoms 1

3. Correlation with clinical features: Tau pathology and neurodegeneration markers correlate more strongly with cognitive impairment than amyloid burden 1

Clinical Implications

The shift from an amyloid-centric view has important implications:

• Diagnostic approach: Current guidelines recommend that AD diagnosis should remain tied to clinical phenotype, not solely based on biomarkers 1

• Treatment focus: Therapeutic strategies may need to target multiple pathways beyond amyloid alone 1, 2

• Risk assessment: Individuals with positive amyloid biomarkers but no symptoms should be considered "at risk" rather than having preclinical AD 1

Caveats and Limitations

Important considerations when interpreting the current understanding:

• Many studies suffer from cohort biases (highly educated volunteers, family history concerns) 1
• Biomarkers are proxies for underlying processes and may not fully reflect brain pathology 1
• The relationship between biomarkers and cognition varies across age groups and genetic profiles 1
• The oldest-old population shows particularly complex relationships between pathology and symptoms 1

Conclusion

While amyloid remains an important component and biomarker of Alzheimer's pathology, current evidence suggests it is neither necessary nor sufficient to fully explain the disease. The field has moved toward a more nuanced understanding where multiple pathological processes interact to cause neurodegeneration and cognitive decline, with individual variations in susceptibility and resilience factors playing important roles in disease manifestation.