Rethinking early Alzheimer's disease: An impaired internal model updating disorder?

Area of Science:

• Neuroscience
• Systems Biology
• Gerontology

Background:

• Sporadic Alzheimer's disease (AD) is traditionally viewed through a molecular lens (amyloid-β, tau).
• This molecular focus doesn't fully explain early network vulnerability or non-cognitive symptoms preceding memory decline.

Purpose of the Study:

• Propose an integrative, systems-level framework for early AD pathogenesis.
• Link age-related sensory dysfunction, particularly olfactory impairment, to internal model failure and network instability.

Main Methods:

• Review and synthesize existing research on sensory processing, internal models, and AD.
• Propose a mechanistic link between sensory dysfunction and neurobiological changes in AD.

Main Results:

• Age-related sensory deficits, like olfactory impairment, may trigger prediction-error mismatches.
• Sustained compensatory demands on neuromodulatory hubs (locus coeruleus, cerebellum) can lead to maladaptive plasticity and neuroinflammation.
• This process may facilitate AD hallmark accumulation across interconnected brain networks.

Conclusions:

• Non-cognitive AD symptoms (olfactory dysfunction, sleep issues, autonomic dysregulation, affective symptoms) arise from a systems-level failure.
• These early symptoms offer potential for preclinical risk stratification.
• Interventions targeting sensory processing, neuromodulation, and sleep may modify early AD progression.