Digital pathology analysis reveals TDP‐43 pathology as a strong predictor of glial activation in Alzheimer’s disease

Abstract

AbstractBackgroundGlial activation plays a critical role in Alzheimer’s disease (AD) pathogenesis and is associated with amyloid‐β plaques and neurofibrillary tangles composed of phosphorylated tau (phospho‐tau). With approximately 40%‐60% of AD cases having limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC), TDP‐43 pathology has become more the rule than the exception in AD brains. However, the effect of LATE‐NC in AD‐related glial activation is unknown.MethodWe analyzed the effect of TDP‐43 pathology on glial activation in three AD subtypes: hippocampal sparing (HpSp) AD, typical AD, and limbic predominant AD. Twenty cases of each subtype (n = 60 total) were selected from the FLorida Autopsied Multi‐Ethnic (FLAME) cohort. Cases were immunohistochemically evaluated on serial sections of the hippocampus in the CA1 and subiculum subsectors, and superior temporal, inferior parietal, and mid‐frontal cortices with antibodies to CD68 (phagocytosis), GFAP (astrogliosis), GT‐38 (conformation‐specific AD‐type tau), 6F/3D (amyloid‐β), and phospho‐Serine 409/410 of TDP‐43 (pTDP‐43). Digital pathology was employed to quantify immunohistochemical staining. Multivariable regression modeling was utilized to understand the relationship between glial activation and AD pathologies.ResultThe level of glial activation, defined as % of immunoreactive surface area for CD68 and GFAP, was lowest in HpSp AD (0.54%, 13%), whereas typical AD (1.3%, 33%) and limbic predominant AD (1.3%, 30%) had similar levels suggesting a ceiling effect, or plateau, of gliosis levels (both p<0.001). HpSp AD was more often male (p<0.001) and younger at disease onset (p<0.001) compared to both typical AD and limbic predominant AD. Multivariable regression modeling of CD68 (subiculum R2 = 0.60) identified advanced tau to be a significant predictor of CD68 in all brain regions. LATE‐NC stage predicted increased CD68 levels in limbic brain regions. Multivariable regression modeling of GFAP (CA1 R2 = 0.60) showed that Aβ was the strongest predictor of astrogliosis in CA1 and subiculum (p<0.001). Advanced tau in CA1 and parietal cortex, LATE‐NC in subiculum and temporal cortex, and APOE4 genotype in CA1 predicted a significant increase in GFAP.ConclusionThese findings highlight the significant role TDP‐43 pathology plays in affecting the microenvironment and interplay between neuroinflammation and neurodegeneration and have important implications for therapeutic strategies in AD with co‐morbid LATE‐NC.