The entorhinal cortex (EC) is the first cortical region affected by tau pathology in Alzheimer’s disease (AD), but its functions remain unclear. The EC is thought to support memory binding, which can be tested using the Visual Short-Term Memory Binding Test (VSTMBT). We aimed to test whether VSTMBT performance can identify individuals with preclinical AD before noticeable episodic memory impairment and whether these performances are related to amyloid (Aβ) pathology and/or EC tau burden.

Ninety-four participants underwent the VSTMBT (including a shape-only condition (SOC) and a shape-color binding condition (SCBC)), standard neuropsychological assessment including the Preclinical Alzheimer Cognitive Composite (PACC5), an Aβ status examination, a 3D-T1 MRI and a [18F]-MK-6240 tau-PET scan. Participants were classified as follows: 54 Aβ-negative cognitively normal (Aβ − CN), 22 Aβ-positive CN (Aβ + CN, preclinical AD), and 18 Aβ + individuals with Mild Cognitive Impairment (Aβ + MCI, prodromal AD).

Aβ + CN individuals performed worse than Aβ-CN participants in the SCBC while the SOC only distinguished Aβ − CN from MCI participants. The SCBC performance was predicted by tau burden in the EC after adjusting for Aβ, white matter hypointensities, inferior temporal cortex (ITC) tau burden, age, sex, and education. The SCBC was more sensitive than the PACC5 in identifying CN individuals with a positive tau-PET scan.

Impaired visual short-term memory binding performance was evident from the preclinical stage of sporadic AD and related to tau pathology in the EC, suggesting that SCBC performance could detect early tau pathology in the EC among CN individuals.