Association between amyloid-β deposition and cognitive function in cognitively normal adults: a multilevel meta-analysis

The association between cerebral amyloid-β (Aβ) burden and cognitive performance in cognitively normal (CN) older adults remains uncertain. This meta-analysis aimed to provide an updated and modality-sensitive synthesis of the relationship between Aβ burden and cognitive performance in CN ageing. We searched major electronic databases for observational studies investigating the relationship between Aβ biomarkers (positron emission tomography [PET], cerebrospinal fluid [CSF], or plasma) and cognitive outcomes in CN adults. Effect sizes were transformed to Fisher’s z. To account for within-study dependencies, we applied a multilevel random-effects meta-analytic model, followed by subgroup analyses by biomarker modality, study design, and cognitive domain. Sixty-two studies involving 27,320 CN participants (197 effect sizes) met the inclusion criteria. Overall, higher Aβ burden was modestly but significantly associated with poorer cognition (Fisher’s z = − 0.092, p < 0.001), with substantial heterogeneity. Modality-specific analyses showed significant negative associations for PET (Fisher’s z = − 0.098, p < 0.001) and plasma (Fisher’s z = − 0.103, p = 0.012), but not for CSF. By study design, significant associations were observed in both longitudinal studies (Fisher’s z = − 0.109, p = 0.002) and cross-sectional studies (Fisher’s z = − 0.070, p = 0.002). By cognitive domain, the association appeared to be strongest for episodic memory (Fisher’s z = − 0.156, p < 0.001), with significant associations also noted for global cognition, language, executive function, and attention (Fisher’s z = − 0.130 to − 0.057, p ≤ 0.038). In CN ageing, higher Aβ burden was associated with slightly poorer cognition. Associations were more consistently detected for PET-based measures and were most pronounced for episodic memory. These findings highlight the importance of biomarker modality and domain-targeted outcomes in preclinical AD research. Aβ burden is modestly but significantly associated with cognitive performance in cognitively normal older adults. Significant Aβ–cognition associations were observed in PET- and plasma-based analyses, whereas the association was not significant in CSF-based analyses. Episodic memory is the cognitive domain most strongly associated with Aβ burden in the preclinical stage.