Genetic Drivers of Atypical Alzheimer’s Disease Neuropathologic Change

Abstract

AbstractBackgroundQuantitative differences in neurofibrillary tangle density are not well captured by more global measures such as Braak staging. Indeed, amongst cases with high Alzheimer’s disease neuropathologic change (ADNC), quantitative differences in the distribution of neurofibrillary tangle density is associated with atypical, non‐amnestic clinical presentations. We sought here to study the effect of TREM2 and APOE risk genotypes on neuropathologically and clinically defined atypical Alzheimer’s disease.MethodsTREM2 variant versus wild‐type autopsy cases with an intermediate to high level of ADNC were identified from the Center for Neurodegenerative Disease Research Brain Bank at the University of Pennsylvania. Archived clinical records were used to classify cases into typical versus atypical AD. Neuropathologic classification of cases into typical versus atypical AD was based on quantification of neurofibrillary tangle density using PHF1 stained sections from neocortical and hippocampal regions. Morphology from Iba1 stained sections was used to quantify microglial reactivity.Results31 AD cases with TREM2 risk genotypes were compared to wild‐type TREM2 AD cases (n = 119). TREM2 variants were associated with a significantly higher proportion of atypical AD clinical phenotypes including behavioral/dysexecutive variants, primary progressive aphasias, posterior cortical atrophy, and others (19.33% versus 48.39%, Fisher’s exact test p = 0.002). These clinical phenotypes were associated with a significantly higher proportion of TREM2 variant cases with neuropathologically defined atypical AD, namely hippocampal sparing AD (8.7% versus 28.57%, Fisher’s exact test p = 0.046). Moreover, the proportion of microglia with a dystrophic morphology correlated with neurofibrillary tangle density and not amyloid burden. Finally, to get a sense of the magnitude of this TREM2 association relative to other genetic risk factors, we observed a non‐significant trend towards the absence of the APOE E4 risk genotype being associated with hippocampal sparing AD.ConclusionsThis clinicopathologic correlation study suggests that TREM2 risk variants are associated with clinically and neuropathologically defined atypical AD. Given that both TREM2 and APOE affect microglial reactivity to amyloid, the observed tendency towards TREM2 variant cases exhibiting hippocampal sparing AD suggests that altered microglial reactivity to amyloid may change downstream tauopathy patterns leading to atypical AD clinical phenotypes.