Microglial Activation, Tau Pathology, and Neurodegeneration Biomarkers Predict Longitudinal Cognitive Decline in Alzheimer’s Disease Continuum

Abstract

PurposeBiomarkers used for predicting longitudinal cognitive change in Alzheimer’s disease (AD) continuum are still elusive. Tau pathology, neuroinflammation, and neurodegeneration are the leading candidate predictors. We aimed to determine these three aspects of biomarkers in cerebrospinal fluid (CSF) and plasma to predict longitudinal cognition status using Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.Patients and MethodsA total of 430 subjects including, 96 cognitive normal (CN) with amyloid β (Aβ)-negative, 54 CN with Aβ-positive, 195 mild cognitive impairment (MCI) with Aβ-positive, and 85 AD with amyloid-positive (Aβ-positive are identified by CSF Aβ42/Aβ40 < 0.138). Aβ burden was evaluated by CSF and plasma Aβ42/Aβ40 ratio; tau pathology was evaluated by CSF and plasma phosphorylated-tau (p-tau181); microglial activation was measured by CSF soluble TREM2 (sTREM2) and progranulin (PGRN); neurodegeneration was measured by CSF and plasma t-tau and structural magnetic resonance imaging (MRI); cognition was examined annually over the subsequent 8 years using the Alzheimer’s Disease Assessment Scale Cognition 13-item scale (ADAS13) and Mini-Mental State Exam (MMSE). Linear mixed-effects models (LME) were applied to assess the correlation between biomarkers and longitudinal cognition decline, as well as their effect size on the prediction of longitudinal cognitive decline.ResultsBaseline CSF Aβ42/Aβ40 ratio was decreased in MCI and AD compared to CN, while CSF p-tau181 and t-tau increased. Baseline CSF sTREM2 and PGRN did not show any differences in MCI and AD compared to CN. Baseline brain volumes (including the hippocampal, entorhinal, middle temporal lobe, and whole-brain) decreased in MCI and AD groups. For the longitudinal study, there were significant interaction effects of CSF p-tau181 × time, plasma p-tau181 × time, CSF sTREM2 × time, and brain volumes × time, indicating CSF, and plasma p-tau181, CSF sTREM2, and brain volumes could predict longitudinal cognition deterioration rate. CSF sTREM2, CSF, and plasma p-tau181 had similar medium prediction effects, while brain volumes showed stronger effects in predicting cognition decline.ConclusionOur study reported that baseline CSF sTREM2, CSF, and plasma p-tau181, as well as structural MRI, could predict longitudinal cognitive decline in subjects with positive AD pathology. Plasma p-tau181 can be used as a relatively noninvasive reliable biomarker for AD longitudinal cognition decline prediction.

Association between hippocampal microglia, AD and LATE‐NC, and cognitive decline in older adults

“…This important finding highlights that microglia inflammation, particularly in the hippocampus, is a separate and distinct biological process that contributes to cognitive decline in older adults that is not fully explained by the presence of other neurodegenerative and cerebrovascular pathologies. Supporting this, other studies demonstrated that neuroinflammation in the anterior temporal brain structurers measured by positron emission tomography 24 and soluble TREM2 evaluated by cerebrospinal fluid 25 was associated with longitudinal cognitive change. Surprisingly, we found no association between stage 2/3 microglia with level or decline in global cognition or any cognitive domain, a finding that may be the result of having relatively lower amounts of stage 2/3 microglial cells.…”

The innate immune response in tauopathies

“…These TREM2 expression patterns were further shown to positively correlate with intraneuronal p‐tau levels [150]. This relates to work that highlights TREM2 as a correlative biomarker for heightened p‐tau levels and lowered cognition in AD [151, 152] but not in FTD [153].…”

The Alzheimer's Disease Neuroimaging Initiative in the era of Alzheimer's disease treatment: A review of ADNI studies from 2021 to 2022

“…In ADNI participants across the AD spectrum, elevated sTREM2 was associated with old age and CSF AD biomarkers (Aβ42, p‐Tau181, and t‐tau) as well as cytokines related to inflammation (chitinase‐3‐like protein 1 [YKL‐40], progranulin, interleukin [IL]‐10, transforming growth factor [TGF]‐β1, tumor necrosis factor alpha [TNF‐α], C3, factor H) and neurodegeneration (NfL, synaptosomal‐associated protein 25, neurogranin, growth‐associated protein 43) but not with brain metabolism, MRI volumes, or cognition 175 . In contrast, in another study, elevated CSF sTREM2 predicted cognitive decline in A+ but not A– MCI and AD ADNI participants with an effect size comparable to that of CSF p‐tau181 but less than MRI volumes 176 …”

“…161 In 175 In contrast, in another study, elevated CSF sTREM2 predicted cognitive decline in A+ but not A-MCI and AD ADNI participants with an effect size comparable to that of CSF p-tau181 but less than MRI volumes. 176 The disparity between these results may reflect a stage-dependent effect of microglial activation. GWAS have identified TREM2 as a protective gene in AD (reviewed in Veitch et al 8,9 and Weiner et al 13 ) that promotes anti-inflammatory cytokine expression and reduces pro-inflammatory cytokine release, activating microglia to surround and endocytose Aβ plaques.…”