Abstract Body

RACIAL DIFFERENCES IN MOLECULAR BIOMARKERS FOR AD

John C. Morris, MD; Suzanne Schindler, MD; Chengjie Xiong, PhD; on behalf of the Knight ADRC, Washington University School of Medicine, St. Louis, Missouri, USA

Objectives:

The possibility of racial differences in molecular biomarkers for Alzheimer disease (AD) has been minimally explored, in part because few research participants from under-represented groups are included in biomarker studies.

Methods:

Using a cohort of 1255 community living adults (including 173 self-identified Blacks), both those who were cognitively normal and those with symptomatic AD, who had completed at least 1 brain magnetic resonance imaging (MRI) study, and/or amyloid positron emission tomography (PET) scan, and/or 1 lumbar puncture to obtain cerebrospinal fluid (CSF), we compared cross-sectional biomarker modalities in Black versus White participants.

Results:

There were no racial differences in mean cortical standardized uptake value ratios for Pittsburgh Compound B or for CSF Aβ42. However, mean CSF concentrations of tau and p-tau₁₈₁ were lower in Black versus White participants; there was a race by APOE ε4 interaction. Moreover, Black participants had more coding variants for TREM2 that were associated with lower CSF soluble TREM2 concentrations than were found for Whites.

Conclusions:

Identifying racial differences in molecular biomarkers for AD is important for the understanding of AD pathophysiology, diagnosis, and treatment. Interpreting these differences will require the appreciation of the effects of systemic racism and other social determinants of health as they relate to observed biomarker disparities in AD.

Aims

Therapeutic modulation of microglial functions may provide an additional strategy to slow progression of Alzheimer disease (AD). Although animal models suggest that TREM2 function is protective, we do not know if that is the case in AD patients. We therefore studied the dynamics of soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) as a surrogate marker of TREM2 signalling and its relationship with AD evolution.

Methods

We measured sTREM2 in longitudinal CSF samples from 261 participants in the Dominantly Inherited Alzheimer Network (DIAN) study, including 161 mutation carriers (MC) and 100 non-carriers (NC). We assessed the association between the CSF sTREM2 dynamics and the longitudinal changes in amyloid-β (Aβ), tau and neuronal damage markers along with the cognitive decline (cognitive composite).

Results

Higher Aβ burden at baseline (lower CSF Aβ42) was associated with a higher subsequent rate of sTREM2 increase (β=-3.704x10^-2, p=0.004) in MC. This increase was independent of tau-related pathology at baseline (CSF t-tau and p-tau). A higher rate of sTREM2 increase was associated with slower Aβ deposition either measured by CSF Aβ42 (r=0.56, p=0.01, presymptomatic MC) or PIB-PET (r=-0.38, p=0.05, all MC). Furthermore, higher sTREM2/p-tau at baseline predicted slower hippocampal volume and precuneus cortical shrinkage (β=1716.05, p=0.004; β=2.032x10^-2, p=0.03, respectively). Strikingly, we found a strong association between higher rate of sTREM2 increase and slower cognitive decline (r=0.62, p=0.003) in presymptomatic MC.

Conclusions

CSF sTREM2 increase in autosomal-dominant AD is mainly driven by Aβ accumulation. Increased TREM2 expression and signalling appears to protect against Aβ deposition and cognitive decline.