Alzheimer's Imaging Consortium.

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Soluble tau phosphorylated at threonine 231 (p-tau₂₃₁) increases in preclinical Alzheimer's disease (AD), preceding amyloid-beta (Aβ) PET positivity.
• The mechanisms linking early tau phosphorylation to Aβ accumulation are unclear, but microglial reactivity is implicated in Aβ dynamics.
• Microglia can either clear Aβ (protective) or promote its buildup via neuroinflammation (detrimental).

Purpose of the Study:

• To investigate the association between CSF p-tau₂₃₁, longitudinal Aβ accumulation, and CSF sTREM2 levels in cognitively unimpaired individuals.
• To determine if microglial reactivity, indicated by sTREM2, mediates the relationship between p-tau₂₃₁ and Aβ accumulation.

Main Methods:

• Studied 187 cognitively unimpaired individuals from the ALFA+ cohort with repeated Aβ-PET imaging.
• Utilized linear regression and mediation analysis to assess relationships between CSF p-tau₂₃₁, Aβ-PET accumulation, and CSF sTREM2.
• Adjusted models for baseline Aβ levels, age, APOE-ε4 status, and sex.

Main Results:

• Higher CSF p-tau₂₃₁ levels correlated with faster Aβ-PET accumulation (p<0.01).
• Elevated p-tau₂₃₁ was associated with increased CSF sTREM2 (p<0.001).
• Higher sTREM2 levels were linked to reduced Aβ accumulation rates (p<0.01), mediating 27% of the p-tau₂₃₁-Aβ relationship.

Conclusions:

• Early-stage soluble tau phosphorylation may enhance TREM2-mediated microglial reactivity.
• This microglial response might act as a protective mechanism against Aβ aggregation in preclinical AD.
• Enhancing microglial function in preclinical AD presents a potential therapeutic strategy to delay Aβ buildup.