Early detection of neuropathological changes that signal the onset of Alzheimer’s disease (AD) is critical for the early intervention and potential prevention of disease progression.¹ Studies on cerebrospinal fluid (CSF) biomarkers for the early detection of AD are scarce.¹ CSF amyloid beta_1-42 (Aß_1-42), and hyperphosphorylated tau₁₈₁ (p-tau₁₈₁) are well recognized biomarkers for detecting AD in vivo.¹ A recent study indicated that CSF Aß_1-42, p-tau₁₈₁, p-tau₁₈₁/Aß_1-42 ratio, and total-tau (t-tau) were strong predictors of cognitive impairment and correctly predicted AD neuropathology at autopsy, and was likely the only CSF-to-autopsy study in people with normal cognition at baseline.¹ The data on CSF biomarkers for early detection of AD were presented at the 75^th AAN 2023 Annual Meeting.¹

The study validated the reliability of these biomarkers for early AD detection.¹ The goal of the study was to find out whether these ante-mortem CSF indicators were associated with neuropathology at the time of death in brain donors who had normal cognition at the time CSF was taken.¹ Specifically, this study also investigated whether early neuropathological changes, termed “low AD” could be predicted by these biomarkers. 

Receiver operating characteristic (ROC) curve analysis was done for each biomarker after doing multivariable logistic regression; and the covariates included sex, age at lumbar puncture (LP), the time between LP and death, and apolipoprotein E (ApoE) e4 status.¹ The National Alzheimer’s Coordinating Center (NACC) database was used for data collection.¹ A total of 49 brain donors who had normal cognition at the time of LP and had CSF biomarker data analyzed via Lumipulse were included in the study.¹ The clinical dementia rating scale of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) score ≥2 and a Braak staging ≥3 were used to define AD as per the National Institute on Aging (NIA)-Reagan criteria.¹ Low AD was defined as Braak <5 and CERAD=1 or Braak 1 or 2 and CERAD >0.¹

A total of 15 participants were AD-positive (AD+) and had similar characteristics as that of the 34 AD-negative (AD-) participants, and the population was predominantly white.¹ The Low AD group (n=24), in which the average age of death was 87 years, had a significantly higher percentage of participants with ApoE e4 carrier status than the AD- group (41.7% vs. 16%, respectively; p=0.05).¹

The ROC curve of high AD showed that all tested biomarkers (i.e., CSF Aß_1-42, p-tau₁₈₁, p-tau₁₈₁/Aß_1-42 ratio, and t-tau) were associated with increased odds of AD status.¹ Of these, p-tau₁₈₁/Aß_1-42 ratio was the best predictor of late-onset AD followed by p-tau₁₈₁, Aß_1-42, and t-tau.¹ Furthermore, results showed that these 4 core biomarkers were also able to predict low AD, and that high levels of these biomarkers were associated with early AD neuropathology.¹ Besides, similar to accurately predicting high AD, p-tau₁₈₁/Aß_1-42 ratio was the strongest predictor of low AD.¹

Of note, higher amounts of p‐tau₁₈₁/Aβ_1-42 ratio were found in participants with higher Braak and CERAD scores, confirming that higher levels of this biomarker at normal cognition are indicative of advanced AD neuropathology at the time of death.¹ 

This study not only confirmed the results of the previous study highlighting the significance of these core biomarkers in predicting AD neuropathology at autopsy, but also unveiled an important novel finding that these biomarkers can also detect early-onset AD neuropathological changes, opening the doorway for early therapeutic intervention.¹ The results have significant implications for the early diagnosis of AD, treatment, and future drug trials.¹