Cerebral cortical Aβ42 and PHF-τ in 325 consecutive brain autopsies stratified by diagnosis, location, and APOE

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Alzheimer disease is a leading cause of dementia, characterized by amyloid β (Aβ) and tau pathology.
• Genetic factors, such as APOE ε4, are known risk factors for Alzheimer disease.
• Understanding the molecular underpinnings of dementia is crucial for developing effective treatments.

Purpose of the Study:

• To quantify amyloid β 42 (Aβ(42)) and paired helical filament-τ (PHF-τ) in brain tissue using a novel molecular quantification approach.
• To investigate the effects of APOE ε4 on Aβ(42) and PHF-τ levels in different brain regions and disease stages.
• To explore the relationship between Aβ(42), PHF-τ, and dementia, including comorbid conditions.

Main Methods:

• Utilized a novel molecular quantification technique on standard fixed and embedded brain tissue.
• Analyzed frontal, temporal, and parietal cortices from 325 consecutive brain autopsies.
• Correlated molecular findings with diagnostic groups, disease stage, APOE ε4 status, and neuropathologic indices.

Main Results:

• Observed significant effects of APOE ε4 on Aβ(42) levels across diagnostic groups, disease stages, and brain regions.
• Found no significant effect of APOE ε4 on PHF-τ levels.
• Demonstrated stronger correlations between Aβ(42) and PHF-τ in the dementia group, with independent explanatory power for dementia.
• Suggested comorbid Lewy body disease and microvascular injury enhance Alzheimer disease penetrance.

Conclusions:

• The novel molecular quantification approach provides valuable insights into dementia pathogenesis.
• APOE ε4 influences Aβ(42) but not PHF-τ levels in the context of aging and dementia.
• Aβ(42) and PHF-τ levels are strongly correlated in dementia and contribute independently to disease.
• Comorbidities may modulate Alzheimer disease progression and penetrance.