Biomarkers of Alzheimer's disease pathophysiology and delirium

EBioMedicine. 2026 Apr 10;127:106252. doi: 10.1016/j.ebiom.2026.106252. Online ahead of print.

ABSTRACT

BACKGROUND: Alzheimer's disease (AD) is characterised by amyloid-beta (A) and tau (T) pathology, and neurodegeneration (N). AT(N) neuropathology precedes the symptomatic presentation of the disease. This asymptomatic phase may present vulnerability towards delirium, but studies are inconclusive. In this cross-sectional study of hip fracture patients, we aimed to explore the association between AD biomarkers for AT(N) neuropathology and delirium, with focus on patients without clinical dementia.

METHODS: The AT(N) biomarkers were analysed in cerebrospinal fluid (CSF) in hip fracture patients (n = 401). Pre-fracture dementia was defined by IQCODE ≥3.44 (n = 164). Delirium was diagnosed according to the DSM-5 criteria. The CSF concentrations of amyloid-beta_1-42 (Aβ42), amyloid-beta_1-40 (Aβ40), phosphorylated tau₁₈₁ (p-tau) and total-tau (t-tau) were quantified by Lumipulse G assays (Fujirebo, Ghent, Belgium). The Aβ42/Aβ40 ratio (cutoff A+ <0.72), p-tau₁₈₁ (T+ >50 pg/ml) and t-tau (N+ >409 pg/ml) were used to determine A, T and N status, respectively.

FINDINGS: Hip fracture patients with delirium had lower CSF Aβ42 concentrations and higher concentrations of CSF p-tau and CSF t-tau than those without delirium (student's t-test, all p-values <0.001). Brain Aβ-deposition, A+ was more common in patients with delirium (χ² p < 0.001). In patients without pre-fracture dementia, delirium was associated with lower CSF Aβ42 concentrations (student's t-test, p = 0.005), and higher CSF concentrations of p-tau (student's t-test p = 0.004) and t-tau (student's t-test p = 0.002). A higher proportion developed delirium among those A+T+ (33%) compared to A-T- (17%, χ² p = 0.02).

INTERPRETATION: These findings support that the AD AT neuropathology is a risk factor for delirium in patients without clinical dementia.

FUNDING: South-Eastern Norway Regional Health Authorities (# 2017095), the Norwegian Health Association (#16149, #19536, #1513) and by Wellcome Leap's Dynamic Resilience Program (jointly funded by Temasek Trust) (#104617).

PMID:41966730 | DOI:10.1016/j.ebiom.2026.106252