HAI Book 2025 - Flipbook - Page 234
Dodge, Hiroko
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Combined impact of plasma phospho-tau 217 and NfL on longitudinal
domain-specific cognitive decline
Hiroko Dodge1, Chao-Yi Wu1, Liu Chen1, Jennifer Gatchel1, Sudeshna Das1, Pia Kivisäkk1,
Steven Arnold1
1
Harvard Medical School, Boston, MA, US
Introduction: Plasma p-tau217, an indicator of tau pathology with strong associations to amyloid-beta pathology,
and NfL, a marker of axonal damage and neurodegeneration, are promising diagnostic and prognostic tools. Their
combined use could offer more accurate diagnostic or prognostic insights than either biomarker alone. To
enhance the clinical utility of these plasma biomarkers, we examined the trajectories of domain-specific
cognitive functions by stratifying participants based on plasma p-tau217 (quantiles) and NfL levels (high/low),
among those with normal cognition (NC) and mild cognitive impairment (MCI).
Methods: Participants from the Massachusetts Alzheimer9s Disease Research Center longitudinal cohort, with
either normal cognition (CN) or MCI and available plasma p-tau217 and NfL samples, were included (Table 1).
Cognitive functions were assessed longitudinally using the National Alzheimer9s Coordinating Center Uniform Data
Set V1, V2, and V3: general cognition (MMSE, MoCA converted to MMSE in V3), memory (Logical Memory), executive
functions (Trail Making B, Log-transformed and reverse-coded) and language-based executive function (Category
Fluency Animals). We used linear mixed-effects models with 8 groups combining p-tau217 (quantiles) and NfL
(low/high) to predict cognitive trajectories over 7 years, controlling for age.
Results: Visual inspection of trajectory plots (Figure 1) shows that among participants with normal cognition,
higher NfL levels are associated with worse cognitive trajectories across all domains, irrespective of p-tau217
levels. On the other hand, in MCI participants, the highest p-tau217 group exhibits the worst cognitive outcomes,
regardless of NfL levels. This pattern persisted across all cognitive domain outcomes. Despite the small sample
size, statistically significant differences were observed between some groups.
Conclusions: NfL levels are linked to cognitive outcomes when p-tau217 is lower. The combination of these
plasma biomarkers provides a promising approach for predicting domain-specific cognitive decline. Future
research should focus on identifying the optimal cutpoints for biomarker combinations to enhance prognostic
accuracy.
HAI2025 - 234
