Early Amyloid Accumulation, Worse Executive Function in Adults Without Cognitive Impairment

Researchers sought to examine the independent associations of the hallmarks of Alzheimer disease, including s β-amyloid (Aβ), tau, and neurodegeneration with different cognitive domains in individuals without cognitive impairment.

An independent relationship has been found between early β-amyloid (Aβ) accumulation and worse performance on the executive measure in individuals who are cognitively unimpaired, according to a study published in the journal Neurology.

In AD, neuropathological changes begin to manifest before the tell-tale cognitive symptoms arise. However, it’s unclear how these changes correlate with the subtle differences in seen in cognition early on. The objective of the study was to examine the independent associations of the hallmarks of AD—that is, Aβ, tau, and neurodegeneration—with various cognitive domains in individuals who are cognitively unimpaired. The researchers also sought to explore the relationship between Aβ pathology and cognition in individuals with no signs of abnormal tau or atrophy observed, to identify the initial cognitive deficits that are linked to pathologic changes in patients with AD.

The cross-sectional analysis included individuals who are cognitively unimpaired from the ongoing prospective Swedish BioFINDER-2 study (ClinicalTrials.gov identifier: NCT03174938). The current study enrolled only participants who are cognitively unimpaired from the BioFINDER-2 study. All of the participants in the present analysis exhibited cerebrospinal (CSF) biomarkers (Aβ42 and P-tau181); magnetic resonance imaging (MRI) indicative of cortical thickness in AD-susceptible regions; Aβ-positron emission tomography (PET) for neocortical uptake; tau-PET for entorhinal uptake; and cognitive test data to evaluate memory, executive function, verbal function, and visuospatial function.

A total of 316 participants who are cognitively impaired from the BioFINDER-2 study were included in the current analysis. Abnormal Aβ status was significantly associated with the executive measure, regardless of modality (CSF Aβ42 [β=0.128; P =.024]; Aβ-PET [β=0.124; P =.049]), whereas tau was significantly associated with memory (CSF P-tau181 [β=0.132; P =.018]; tau-PET [β=0.189; P =.002]). Additionally, cortical thickness was independently associated with the executive measure (P =.005) and verbal fluency (P =.018) in both of the CSF-based and the PET-based models.

With respect to relationships in the earliest stage of preclinical AD, only those individuals who had normal biomarkers of tau and neurodegeneration were included in the subanalysis (217 participants in the CSF-based model and 246 participants in the PET-based model). Once again, although Aβ status was significantly associated with executive function (CSF Aβ42 [β=0.189; P =.005]; Aβ-PET [β=0.146; P =.023], it was not associated with any other cognitive domains. Results from this study were replicated in the Alzheimer’s Disease Neuroimaging Initiative cohort.

The study had several limitations, the researchers acknowledged. In the ADNI cohort, PET-based results were not validated. In addition, the study’s design did not allow for a casual interference of Aβ accumulation and worse executive function. Lastly, the observed association between Aβ and executive function was modest, potentially limiting its clinical use.

The findings from the present study suggest that Aβ is significantly associated with worse performance on an executive measure but not with memory performance, which is instead linked to tau pathology, the researchers stated. “Although the reported associations between Aβ and the TMT B-A difference score is modest, this finding could contribute to the understanding of how cognitive deficits are manifested in asymptomatic individuals with early Aβ accumulation and more sensitive measures of this cognitive ability might be useful for screening for Aβ pathology or used as an outcome measure in clinical trials targeting Aβ,” they concluded.

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Tideman P, Stomrud E, Leuzy A, Mattsson-Carlgren N, Palmqvist S, Hansson O; Alzheimer’s Disease Neuroimaging Initiative. Association of β-amyloid accumulation with executive function in adults with unimpaired cognition. Neurology. Published online January 12, 2022. doi:10.1212/WNL.0000000000013299