Aβ-induced vulnerability propagates via the brain's default mode network.

Area of Science:

• Neuroscience
• Alzheimer's Disease Research
• Metabolic Imaging

Background:

• The relationship between brain amyloid-β (Aβ) deposition, glucose metabolism, and dementia symptoms is crucial for understanding Alzheimer's disease (AD).
• Existing research highlights Aβ plaques and neurofibrillary tangles as key pathological hallmarks of AD.
• The precise mechanisms linking Aβ pathology to metabolic dysfunction and cognitive decline require further elucidation.

Purpose of the Study:

• To investigate the causal link between amyloid-β aggregation in the default mode network and regional brain hypometabolism.
• To determine if the interaction between hypometabolism and local Aβ aggregation predicts cognitive decline in Alzheimer's disease.
• To validate these findings in an animal model lacking neurofibrillary tangles.

Main Methods:

• Positron emission tomography (PET) imaging using [18F]florbetapir for Aβ and [18F]FDG for glucose metabolism.
• Application of a novel analytical framework to assess Aβ-induced hypometabolism and its functional connectivity.
• Utilized transgenic Aβ rats as a model to study Aβ-related pathology independent of tau.

Main Results:

• Aβ aggregation in the default mode network was found to induce hypometabolism in functionally connected, distant brain regions.
• An interaction between regional hypometabolism and overlapping Aβ deposition significantly correlated with subsequent cognitive decline.
• These Aβ-dependent effects on metabolism and cognition were confirmed in Aβ rats, irrespective of neurofibrillary tangle formation.

Conclusions:

• Aβ pathology can induce remote metabolic dysfunction through interconnected brain networks.
• The interplay between Aβ-driven metabolic vulnerability and local Aβ accumulation accelerates dementia progression.
• This study proposes a novel mechanism for cognitive deterioration in Alzheimer's disease, independent of neurofibrillary tangles.