Alzheimer's disease clinical variants show distinct regional patterns of neurofibrillary tangle accumulation

Background: Neurofibrillary tangle (NFT) pathology in Alzheimer9s disease (AD) follows a stereotypic progression well-characterized by Braak staging. However, some AD cases show deviations from the Braak staging scheme. In this study, we tested the hypothesis that these variations in the regional distribution of tau pathology are linked to heterogeneity in the clinical phenotypes of AD. Methods: We included a clinicopathological cohort of ninety-four AD cases enriched for atypical clinical presentations. Subjects underwent apolipoprotein E (APOE) genotyping and neuropsychological testing. Main cognitive domains (executive, visuospatial, language, and memory function) were assessed using an established composite z-score. We assessed NFT density and distribution from thioflavin S fluorescent microscopy throughout four neocortical and two hippocampal regions. A mathematical algorithm classifying AD cases into typical, hippocampal sparing (HpSp), and limbic predominant (LP) subtypes based on regional NFT burden was compared to unbiased hierarchical clustering for cases with Braak stage > IV. Results: Patients diagnosed with logopenic primary progressive aphasia showed significantly higher NFT density in the superior temporal gyrus relative to patients diagnosed with Alzheimer-type dementia (p = 0.0091), while patients with corticobasal syndrome showed significantly higher NFT density in the primary motor cortex (p = 0.0205). Hierarchical clustering identified three discrete clusters of patients characterized respectively by low overall NFT burden (n = 18), high overall burden (n = 30), and cortical-predominant burden (n = 24). A regionally specific effect was observed for visuospatial ability; higher NFT density in the angular gyrus (β = -0.0921, p = 0.0099) and in the CA1 sector of the hippocampus (β = -0.0735, p = 0.0380) was significantly associated with more severe visuospatial dysfunction, modulated by age of death. Conclusions: Our results suggest domain-specific functional consequences of regional NFT accumulation. In particular, we observed focal aggregation of NFT density in clinically relevant regions among different clinical AD variants. Continued work to map the regionally specific clinical consequences of tau accumulation presents an opportunity to increase understanding of disease mechanisms underlying atypical clinical manifestations.