Amyloid‐β accumulation is independently related to executive function in cognitively unimpaired adults

Abstract

AbstractBackgroundThe shift from a symptom‐based to a biological definition of Alzheimer’s disease (AD), within the NIA‐AA research framework, has highlighted the importance of biomarkers that are indicative of the neuropathological changes underlying AD. The independent associations of amyloid (Aβ), tau, and neurodegeneration with different cognitive domains in cognitively unimpaired (CU) need to be studied in deeply phenotyped cohorts. In the current study we investigated how the distinctive pathologies and neurodegeneration of AD, according to the AT(N) system, are related to cognition in four cognitive domains in CU adults.MethodWe included 316 CU individuals from the prospective BioFINDER‐2 study. The results were validated in CU participants from the ADNI study (n=376). All cases had CSF biomarkers (Aβ42 and P‐tau181), MRI (cortical thickness of AD‐susceptible regions), Aβ‐PET (neocortical uptake) and tau‐PET (entorhinal cortical uptake) as well as neuropsychological test data (including tests for i) memory, ii) executive function, iii) verbal function, iv) visuospatial function). Multivariable linear regression models, adjusted for age, sex and education, were performed, first using CSF Aβ42, P‐tau181 and cortical thickness and secondly using Aβ‐PET, tau‐PET and cortical thickness.ResultIn BioFINDER‐2, abnormal Aβ‐status was independently associated with executive function, regardless of biomarker (CSF Aβ42 β=0.128, p=0.024; Aβ‐PET β=0.124, p=0.049), but not memory or any other cognitive domains. Tau, on the other hand, was independently related to memory (CSF P‐tau181 β=0.132, p=0.018; tau‐PET β=0.189, p=0.002). Cortical thickness was independently associated with executive function (CSF‐based model, β= ‐0.161, p=0.013; PET‐based model, β= ‐0.186, p=0.005) and verbal function (CSF‐based model, β= 0.163, p=0.011; PET‐based model, β= 0.156, p=0.018). In a second step, only participants without evidence of tau pathology or neurodegeneration were included, again resulting in an association between Aβ and executive function (CSF Aβ42, β=0.189, p=0.005; Aβ‐PET, β=0.146, p=0.023), but not with other cognitive domains. Results were overall replicated in the ADNI cohort.ConclusionThese findings suggest an independent relationship between early Aβ accumulation and worse executive function in CU individuals while tau is associated with memory. This finding contributes to our understanding of how cognitive deficits are manifested in early AD, especially in regard to Aβ accumulation.