Alzheimer's Disease Risk Variants Interact with Amyloid-Beta to Modulate Monocyte Function

Area of Science:

• Neuroimmunology
• Genetics of Alzheimer's Disease
• Innate Immunity

Background:

• Genetics implicate dysregulated innate immunity in Alzheimer's Disease (AD).
• Peripheral myeloid cells, particularly monocytes, are understudied in AD compared to microglia.
• Specific AD risk loci, CD33 and SPI1, are potential targets for investigation.

Purpose of the Study:

• Investigate functional convergence of AD risk variants (rs3865444 in CD33, rs1057233 in SPI1) in monocytes.
• Examine the role of these variants in response to amyloid-beta peptide 1-42 (Aβ1-42) stimulation.
• Determine if these genetic factors impact monocyte immune fitness.

Main Methods:

• Isolated monocytes from peripheral blood mononuclear cells (PBMCs) of healthy individuals.
• Stimulated monocytes with aggregated amyloid-beta peptide 1-42 (Aβ1-42).
• Assessed phagocytosis and TREM2 expression on monocytes.

Main Results:

• Identified functional convergence of CD33 and SPI1 AD risk variants under Aβ stimulation.
• Observed reduced phagocytosis in monocytes carrying these risk variants.
• Found a loss of surface TREM2 expression associated with these variants.

Conclusions:

• AD risk variants in CD33 and SPI1 converge functionally in monocytes exposed to Aβ.
• These variants reduce myeloid cell fitness by impairing phagocytosis and TREM2 expression.
• Peripheral monocytes are genetically and functionally linked to AD risk, highlighting their role in disease susceptibility and progression.