Cortical thickness signature of early-onset Alzheimer’s disease across clinical stages and A/T1 biomarker profiles

Abstract Background The cortical thinning signature of early-onset Alzheimer’s disease (EOAD) is well established in dementia, but its emergence during earlier disease stages remains unclear. We investigated when it becomes detectable and whether it differs according to fluid amyloid and phosphorylated-tau (A/T1) biomarker profiles. Methods We studied 292 individuals <65 years who underwent 3T structural MRI and cerebrospinal fluid assessment of Aβ42/40 and p -tau181. Participants were classified as A−T1− subjective cognitive decline (SCD; reference group), A+T1−, or A+T1+. Cortical thickness and hippocampal volume were measured using FreeSurfer. EOAD signature regions were defined by comparing biomarker-confirmed AD dementia with the reference group and subsequently examined across A/T1 profiles in SCD and mild cognitive impairment (MCI). Brain–cognition associations were assessed. Results The cohort comprised 107 reference and 185 amyloid-positive participants (76 A+T1− and 109 A+T1+). EOAD dementia was characterized by marked cortical thinning in posterior parietal and lateral temporal regions. In MCI, cortical thinning was focal in A+T1−, but more extensive in A+T1+ who also showed hippocampal atrophy. At the SCD stage, focal thinning of the EOAD signature, precuneus, and banks of the superior temporal sulcus was observed in A+T1+, whereas no structural alterations were detected in A+T1−. Cortical thinning was associated with episodic and visuospatial memory performance in MCI, while no brain–cognition associations were observed in SCD. Conclusion EOAD-related cortical thinning is detectable before dementia and varies across A/T1 profiles, with combined amyloid and p -tau181 positivity associated with earlier and more extensive structural involvement.