Basic Science and Pathogenesis.

Area of Science:

• Neuropathology
• Neuroscience
• Aging Research

Background:

• Alzheimer's disease neuropathologic change (ADNC) and primary age-related tauopathy (PART) exhibit distinct hippocampal pathology patterns.
• PART is an amyloid-beta (Aβ)-independent tauopathy with higher CA2/CA1 hyperphosphorylated tau (pTau) ratios compared to ADNC.
• The persistence of these distinct patterns in extreme ages and their correlation with cognition in centenarians remain unclear.

Purpose of the Study:

• To investigate whether distinct hippocampal pTau distributions persist into extreme ages.
• To examine the correlation between hippocampal Aβ- and pTau-distributions and cognitive function in centenarians.
• To compare neuropathologic patterns in centenarians with ADNC versus PART.

Main Methods:

• Quantified Aβ- and pTau-burdens in eight hippocampal and parahippocampal subregions in 112 centenarians, 11 AD, and 7 PART cases.
• Compared CA2/CA1-pTau-ratios in centenarians meeting PART versus ADNC criteria.
• Assessed cognitive performance using 13 neuropsychological tests and employed robust linear regression to associate pathologies with cognition.

Main Results:

• CA2/CA1-pTau-ratios in centenarians with PART were comparable to those with ADNC, unlike in younger individuals.
• In centenarians, CA2/CA1-pTau-ratio was unrelated to Aβ-burden, Thal phase, or Braak stage.
• Higher hippocampal Aβ-burden and parahippocampal pTau-burden were associated with lower cognitive performance.

Conclusions:

• In the oldest-old, PART and ADNC are less distinguishable by traditional determinants.
• Centenarians with ADNC may exhibit Aβ accumulation with PART-like pTau patterns, while PART cases may not always show PART-like pTau patterns.
• Hippocampal Aβ-burden and parahippocampal pTau-burden are linked to cognitive decline, indicating subregional vulnerability.