Plasma proteomic associations with Alzheimer's disease endophenotypes

Area of Science:

• Neuroscience
• Biochemistry
• Genomics

Background:

• Alzheimer's disease (AD) is clinically defined by cerebral β-amyloidosis and cognitive decline.
• Autopsy studies reveal most AD cases involve multiple neuropathologies beyond amyloid.
• The role of peripheral protein alterations in AD endophenotypes remains unclear.

Purpose of the Study:

• To identify plasma proteins and pathways associated with cerebral β-amyloidosis and other neuropathologies in Alzheimer's disease.
• To investigate the relationship between peripheral proteomes, neuropathologies, and cognitive function.
• To explore the potential contribution of peripheral factors to AD pathogenesis.

Main Methods:

• Plasma proteome analysis of 2,139 participants across four cohorts.
• Correlation analysis between plasma proteins, neuropathologies (tau, Lewy bodies, TDP43, etc.), and cognitive function.
• Comparison of plasma protein levels with brain tissue data in a subset of participants.

Main Results:

• Identified numerous plasma proteins linked to cerebral β-amyloidosis and diverse neuropathologies.
• Found that established neuropathologies explained only half of the proteins associated with cognitive function.
• Observed weak correlations between many plasma proteins and their brain counterparts, suggesting peripheral influence.

Conclusions:

• Peripheral protein alterations are associated with Alzheimer's disease endophenotypes and cognitive function.
• Plasma proteomic signatures may reflect neuropathologies not fully captured by brain pathology alone.
• Targeting identified peripheral protein pathways could represent a novel strategy for Alzheimer's disease risk reduction and progression management.