Basic Science and Pathogenesis

BACKGROUND: The hippocampus is differentially affected in Alzheimer's disease neuropathologic change (ADNC) versus primary age-related tauopathy (PART), an amyloid-beta (Aβ)-independent tauopathy: the CA2/CA1 hyperphosphorylated tau (pTau)-ratio is higher in PART, which inversely correlates with Aβ-burden. However, as the aging brain often presents mixed rather than uniform pathologies, we questioned whether these distinct hippocampal pTau distributions persist into extreme ages and how hippocampal Aβ- and pTau-distributions correlate with cognition in centenarians.

METHOD: We quantified Aβ- (6F/3D) and pTau (AT8)-burdens across eight hippocampal and parahippocampal subregions in 112 centenarians (median age 104, IQR 102-105), alongside 11 AD (median age 84, IQR 72-86) and 7 PART cases for comparison (median age 88, IQR 78-92; Figure 1). We compared CA2/CA1-pTau-ratio in centenarians who met PART criteria (Thal phase ≤2, Braak stage I-IV; n = 49) with centenarians who met ADNC criteria (intermediate/high according to NIA-AA guidelines; Thal phase ≥3, Braak stage III-VI; n = 50). Cognitive performance was assessed using 13 neuropsychological tests shortly before brain donation (median 10 months, IQR5-14, n = 72). Robust linear regression models were used to associate subregional Aβ- and pTau-burdens with cognitive performance, while adjusting for age, sex, and education.

RESULT: In line with previous findings, CA2/CA1-pTau-ratios were higher in younger PART cases compared to AD patients (median 3.0, IQR 2.1-3.6, min-max 1.6-4.2 vs. median 1.2, IQR 0.9-1.4, min-max 0.8-1.4; p <0.001). Surprisingly, CA2/CA1-pTau-ratios in centenarians with PART were comparable to centenarians with ADNC (median 1.3, IQR 1.1-2.0, min-max 0.3-10.8 vs. median 1.2, IQR 1.0-1.8, min-max 0.2-6.2; p = 0.684). Accordingly, CA2/CA1-pTau-ratio in centenarians was unrelated to Aβ-burden, Thal phase or Braak stage. Higher Aβ- and pTau-burdens associated with lower cognition, though through different subregions: cognition associated with Aβ-burden in the hippocampus (CA4, CA3, CA2, CA1/subiculum), whereas pTau-burden in the parahippocampus (presubiculum, entorhinal cortex, fusiform gyrus) associated with cognition.

CONCLUSION: In the oldest-old, PART and ADNC are less distinguishable by determinants observed in younger individuals: centenarians with ADNC may show age-related Aβ accumulation alongside PART-like pTau patterns, while centenarians meeting PART criteria do not always show PART-like pTau patterns. However, hippocampal Aβ-burden and parahippocampal pTau-burden associate with cognitive decline, highlighting subregional-specific vulnerability to pathology-driven cognitive decline.