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.

IMPORTANCE Older individuals without dementia often have amyloid-beta (Aβ) Thal phases similar to patients with Alzheimer disease (AD), suggesting that Aβ pathology may be a benign consequence of aging. OBJECTIVE To explore whether Aβ pathology in centenarians is associated with cognitive performance. DESIGN, SETTING, AND PARTICIPANTS This longitudinal cohort study used cross-sectional data on antemortem cognitive performance and postmortem neuropathology of participants in the Dutch 100-plus Study. Cognitive performance was measured a median of 10 (IQR, 3-13) months before postmortem brain donation. From January 2013 to July 2022, 1187 centenarians who self-reported being cognitively healthy, confirmed by proxy, were approached: 406 were included and 95 donated their brain. Centenarians were compared with patients with clinicopathologically confirmed AD from the Netherlands Brain Bank. Data were analyzed from June 2022 to October 2024. MAIN OUTCOMES AND MEASURES Aβ pathology was assessed with the Thal phase for Aβ progression and by determining quantitative Aβ loads (percentage positive area) in the frontal, parietal, temporal, and occipital neocortices, 3 parahippocampal, and 5 hippocampal subregions. Aβ pathology was associated with performance on 13 neuropsychological tests assessing memory, fluency, attention/processing speed, and executive functioning, as well as 4 measures of global cognition. RESULTS This study evaluated Aβ pathology in 95 centenarians (median age at brain donation, 103.5 [IQR, 102.3-104.7] years; 71 female [75%] and 24 male [25%]) and 38 patients with AD (median age, 84 [IQR, 78-90] years; 18 female [47%] and 20 male [53%]). Global cognition parameters were available for all 95 centenarians and complete cognitive assessment for 72 centenarians (76%). A fraction of the centenarians had no Aβ load (9 of 95 [9%]), most had low Aβ load (53 of 95 [56%]) and, despite high Thal phases, about one-third (33 of 95 [35%]) had high Aβ load comparable with patients with AD. Centenarians with no or low Aβ load had significantly higher cognitive performance than centenarians with high Aβ loads. Higher Aβ loads across all 4 neocortical regions, cornu ammonis 3, cornu ammonis 1/subiculum, and the entorhinal cortex specifically affected executive functioning. Interestingly, 5 resilient centenarians maintained high cognitive performance despite having high Aβ loads; they had significantly less tau pathology compared with centenarians with high Aβ loads and low cognitive performance. CONCLUSIONS AND RELEVANCE These results indicate that Aβ pathology is not a benign consequence of aging. Even in the oldest individuals, Aβ and tau pathology interaction was consistent with the amyloid cascade hypothesis.

INTRODUCTION: Neuropathological substrates associated with neurodegeneration occur in brains of the oldest old. How does this affect cognitive performance?. METHODS: The 100-plus Study is an ongoing longitudinal cohort study of centenarians who self-report to be cognitively healthy; post mortem brain donation is optional. In 85 centenarian brains, we explored the correlations between the levels of 11 neuropathological substrates with ante mortem performance on 12 neuropsychological tests. RESULTS: Levels of neuropathological substrates varied: we observed levels up to Thal-amyloid beta phase 5, Braak-neurofibrillary tangle (NFT) stage V, Consortium to Establish a Registry for Alzheimer's Disease (CERAD)-neuritic plaque score 3, Thal-cerebral amyloid angiopathy stage 3, Tar-DNA binding protein 43 (TDP-43) stage 3, hippocampal sclerosis stage 1, Braak-Lewy bodies stage 6, atherosclerosis stage 3, cerebral infarcts stage 1, and cerebral atrophy stage 2. Granulovacuolar degeneration occurred in all centenarians. Some high performers had the highest neuropathology scores. DISCUSSION: Only Braak-NFT stage and limbic-predominant age-related TDP-43 encephalopathy (LATE) pathology associated significantly with performance across multiple cognitive domains. Of all cognitive tests, the clock-drawing test was particularly sensitive to levels of multiple neuropathologies.

Introduction: With increasing age, neuropathological substrates associated with Alzheimer's disease (AD) accumulate in brains of cognitively healthy individuals—are they resilient, or resistant to AD-associated neuropathologies?. Methods: In 85 centenarian brains, we correlated NIA (amyloid) stages, Braak (neurofibrillary tangle) stages, and CERAD (neuritic plaque) scores with cognitive performance close to death as determined by Mini-Mental State Examination (MMSE) scores. We assessed centenarian brains against 2131 brains from AD patients, non-AD demented, and non-demented individuals in an age continuum ranging from 16 to 100+ years. Results: With age, brains from non-demented individuals reached the NIA and Braak stages observed in AD patients, while CERAD scores remained lower. In centenarians, NIA stages varied (22.4% were the highest stage 3), Braak stages rarely exceeded stage IV (5.9% were V), and CERAD scores rarely exceeded 2 (4.7% were 3); within these distributions, we observed no correlation with the MMSE (NIA: P = 0.60; Braak: P = 0.08; CERAD: P = 0.16). Discussion: Cognitive health can be maintained despite the accumulation of high levels of AD-related neuropathological substrates. Highlights: Cognitively healthy elderly have AD neuropathology levels similar to AD patients. AD neuropathology loads do not correlate with cognitive performance in centenarians. Some centenarians are resilient to the highest levels of AD neuropathology.