Longitudinal Associations of Multimodal Core 1 Alzheimer Disease Biomarkers With Cognition in Aging and Preclinical Alzheimer Disease

Background and objectives: Addressing the association between early-changing Alzheimer disease (AD) biomarkers and cognition is essential for characterizing preclinical AD. However, few studies have explored this relationship longitudinally, especially across multiple biomarker modalities. The aim of this study was to evaluate longitudinal associations of multimodal core 1 AD biomarkers with cognition in a cognitively unimpaired (CU) population at increased risk of AD dementia.

Methods: This prospective observational study included CU individuals from the Alzheimer's and Families+ cohort, based in Barcelona, Spain. Individuals had available baseline CSF biomarker measurements (normal or AD continuum profiles) and longitudinal neuropsychological assessments (2 time points, 3-year follow-up). The primary study outcome was the modified Preclinical Alzheimer's Cognitive Composite (mPACC) score. Study measurements included plasma phosphorylated tau (p-tau) 217, CSF p-tau181/β-amyloid (Aβ) 42, and Aβ PET ([¹⁸F]flutemetamol). Mixed-effects models were used to evaluate the longitudinal associations between fluid biomarkers and mPACC score; voxel-wise models were used to evaluate the longitudinal association between neuroimaging and mPACC score. Sensitivity analyses evaluated these associations stratifying by Aβ status.

Results: In total, 350 individuals were included (mean age: 61 years; 60% female; mean education: 14 years). In the full sample, increases in plasma p-tau217 concentration (βSTD = -0.124, 95% CI -0.172 to -0.076; p < 0.001), CSF p-tau181/Aβ42 ratio (βSTD = -0.059, 95% CI -0.100 to -0.019; p = 0.005), and Aβ PET load in the prefrontal cortex, cingulate cortex, precuneus, and anterior temporal regions were associated with mPACC decline. In the Aβ-positive group (35%), increases in plasma p-tau217 concentration (βSTD = -0.121, 95% CI -0.194 to -0.049; p < 0.001) and Aβ PET load in anterior temporal regions were associated with mPACC decline. In the Aβ-negative group (65%), increases in plasma p-tau217 concentration (βSTD = -0.084, 95% CI -0.157 to -0.011; p = 0.024) and Aβ PET load in frontoparietal regions were associated with mPACC decline.

Discussion: This study demonstrated significant longitudinal associations between multimodal core 1 AD biomarkers and cognitive function over 3 years in CU individuals, including those at the Aβ-negative stage. Distinct biomarker modalities provided complementary insights, emphasizing the potential of blood-based biomarkers for tracking subtle cognitive decline and neuroimaging for delineating vulnerable brain regions in aging and preclinical AD. These findings are crucial for identifying and monitoring high-risk CU individuals, further informing preventive intervention strategies for AD.