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.

Background
Many types of dementia have high heritability, which creates opportunities for DNA diagnostics. Clinicians sporadically test for causal genetic variants. However, in addition to causal genetic mutations, an increasing number of both common and rare risk factors are being identified, especially for Alzheimer’s disease (AD). Here, we describe and evaluate diagnostic performance of combining genetic risk factors for AD to assist memory clinic clinicians.

Methods
A retrospective analysis of 998 consecutive patients (mean age 62.1, 40.3% females, 63.3% dementia) was conducted over 2.5 years in a Dutch memory clinic. The patients underwent a complete genetic risk assessment, including whole-exome sequencing and array genotyping. We examined known pathogenic genetic variants for all dementia types and their correlation with clinical diagnoses. We evaluated a combined genetic score (GS) based on all genetic risk factors for AD - namely APOE genotypes, candidate risk rare variants in 11 genes, and a polygenic risk score (PRS) based on 82 common variants. Then, we analyzed the discriminatory characteristics of the GS.

Results
Causal pathogenic variants were rare, present in 3.4% of individuals, but genetic testing would have altered the diagnosis in over half of the carriers. Candidate rare risk variants were more common, identified in 31.6% of patients. Both APOE genotypes and the PRS were independently associated with AD, and gene-specific interaction was found between TREM2 and AD-PRS (β = -1.16, p = 0.015). Patients with a high GS were 7 times more likely receive an AD diagnosis compared to those with a low GS (p = 2.5E-07).

Conclusion
Overall, this study highlights the potential of integrating genetic risk factors into clinical practice to enhance AD diagnosis, though the improvement in diagnostic accuracy was moderate. The findings underscore the importance of genetic testing in diagnosis while also recognizing its limitations.