Gray matter hypoperfusion is a late pathological event in the course of Alzheimer's disease

Area of Science:

• Neuroimaging
• Neurodegenerative Diseases
• Biomarkers

Background:

• Alzheimer's disease (AD) is characterized by decreased cerebral blood flow (CBF), but its role in pathogenesis is unclear.
• Investigating the link between hypoperfusion and AD pathologies like amyloid-beta (Aβ) and tau is crucial for understanding disease progression.

Purpose of the Study:

• To examine the association between gray matter CBF (GM-CBF) and AD pathologies (Aβ, tau), synaptic/axonal degeneration, and neurodegeneration.
• To model the temporal sequence of AD biomarker abnormalities, including GM-CBF.

Main Methods:

• Utilized arterial spin labeling MRI, PET, and cerebrospinal fluid (CSF) biomarkers.
• Applied disease progression modeling to a cohort across the AD spectrum.
• Analyzed associations between GM-CBF and Aβ, tau, synaptic/axonal markers in specific cortical regions.

Main Results:

• Lower GM-CBF was observed in the temporo-occipito-parietal cortex of Aβ-positive cognitively impaired individuals.
• GM-CBF correlated with tau, synaptic, and axonal dysfunction, but not Aβ, in participants along the AD spectrum.
• Disease progression modeling indicated GM-CBF disruption followed Aβ, tau, and atrophy biomarker abnormalities.

Conclusions:

• Tau pathology and neurodegeneration are more closely associated with GM-CBF changes than Aβ pathology in AD.
• Hypoperfusion may not be an early event in AD pathogenesis, potentially occurring after Aβ accumulation and preceding significant tau pathology.
• Findings highlight the complex interplay between vascular factors and core AD pathologies, suggesting hypoperfusion is a later manifestation.