Alzheimer’s disease (AD) is the most common neurodegenerative disorder and a leading cause of dementia. One major challenge for clinicians is accurately assessing the rate of disease progression (RoP) early in the diagnostic process, which is crucial for patient management and clinical trial stratification. This study evaluated the role of cerebrospinal fluid biomarkers—Aβ42, t-Tau, pTau, Neurogranin (Ng), and Neurofilament light-chain (NF-L)—in predicting RoP at the time of AD diagnosis. We included 56 AD patients and monitored cognitive impairment using MMSE scores at diagnosis and during six-month follow-up visits. RoP scores were calculated based on these assessments. Our correlation analyses revealed significant associations between RoP and pTau, Aβ42/Ng ratio, and NF-L levels. When patients were stratified by median RoP values into low-to-moderate (L-M: 2) groups, those in the U-M group had notably higher CSF NF-L levels compared to the L-M group. Logistic regression analysis further demonstrated that elevated CSF NF-L levels were predictive of a faster RoP. These findings highlight the potential of CSF NF-L as a prognostic biomarker for rapid disease progression in AD. By identifying patients at risk for accelerated cognitive decline, CSF NF-L could significantly enhance early intervention strategies and improve patient management in clinical settings.

Background/Objectives: Amyloid-PET is accurate but costly and capacity-limited. Blood-based biomarkers (BBMs), particularly plasma p-tau217, offer a scalable alternative for triaging patients. Objective of this study is to evaluate the diagnostic accuracy and clinical utility of plasma p-tau217 as a pre-screening tool for amyloid-PET positivity, identifying operating thresholds for rule-out and rule-in strategies. Methods: We analyzed 1681 participants from the ADNI cohort with concurrent plasma biomarkers (Fujirebio Lumipulse assays) and ¹⁸F-florbetapir PET. The primary outcome was discrimination of amyloid-PET positivity (Centiloid > 20). We compared p-tau217 alone against multivariable models (including Aβ42/40, GFAP, NfL, APOE) using Area Under the Curve (AUC) and Decision Curve Analysis (DCA). Two clinical thresholds were defined: a high-sensitivity “rule-out” cut-off (≥95% sensitivity) and a Youden-optimal “balanced” cut-off. These were validated using stratified bootstrap resampling. Results: Of 1681 participants, 679 (40.4%) were amyloid-positive. In the full sample, plasma p-tau217 alone achieved an AUC of 0.902 (95% CI 0.885–0.918). Operating thresholds were derived on a development split and applied to an independent validation split (N = 505). In the validation cohort, the high-sensitivity threshold (0.106 pg/mL) yielded 94.6% sensitivity and 93.7% NPV, effectively ruling out amyloid pathology. The Youden threshold (0.177 pg/mL) offered 78.9% sensitivity and 86.0% specificity. DCA demonstrated net benefit for p-tau217 screening over “PET all” strategies across clinically relevant probability ranges. Conclusions: Plasma p-tau217 provides high discrimination and clinically interpretable operating points for prioritizing confirmatory PET. Implementing a p-tau217-first strategy could significantly reduce unnecessary imaging without compromising diagnostic safety.