Alzheimer's disease neuropathological change in younger individuals with IDH-mutant glioma

With aging populations, the incidence of brain tumors and neurodegenerative diseases is rising. Recently, Alzheimer's disease neuropathological change (ADNC) has been documented in the tumor-adjacent cortex of 50% of patients with glioblastoma, with isolated hyperphosphorylated tau (pTau) deposits already present in younger individuals. This study extends ADNC screening to younger patients with IDH-mutant glioma, focusing on pTau and amyloid beta (Abeta) deposits, microglial activation, and amyloid precursor protein (APP) expression in the context of cortical tumor cell infiltration.

We included 85 patients with IDH-mutant gliomas (37 astrocytomas, median age: 39; 48 oligodendrogliomas, median age: 50) classified as CNS-WHO grades 2-3. Tumor-adjacent cortex was immunohistochemically stained for b-A4, t-AT8, NeuN, APP, Ki67, and Iba1, and cells were quantified using Matlab and QuPath script. Longitudinal samples were available for 15 patients.

The median cell density in the tumor-adjacent cortex was significantly higher in glioma patients (astrocytoma: 1395/mm², oligodendroglioma: 1492/mm²) compared to non-tumor cortex (1098/mm², P < .0001). ADNC, including pTau (36%, N = 31/85) and Abeta (14%, N = 12/85), was observed in 38% (N = 32/85) of individuals. pTau and A beta positively correlated with age (Hazard ratio = 0.1, P = .02), tumor cell infiltration (Kendall's tau = 0.100, P = 4.7*10^-4), and diffuse axonal injury (P = .018). ADNC was commonly found in the temporal cortex (53%, N = 9/17).

Our study reveals an unexpectedly high prevalence of ADNC, particularly isolated pTau deposits, in the tumor-adjacent cortex of younger individuals with IDH-mutant glioma. These findings suggest tumor-driven tau accumulation, prompting further research into potential long-term cognitive effects.