Abstract
Background and Objectives In early Alzheimer disease (AD), β-amyloid (Aβ) deposition is associated with volume loss in the basal forebrain (BF) and cognitive decline. However, the extent to which Aβ-related BF atrophy manifests as cognitive decline is not understood. This study sought to characterize the relationship between BF atrophy and the decline in memory and attention in patients with early AD. Methods Participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study who completed Aβ-PET imaging and repeated MRI and cognitive assessments were included. At baseline, participants were classified based on their clinical dementia stage and Aβ status, yielding groups that were cognitively unimpaired (CU) Aβ-, CU Aβ+, and mild cognitive impairment (MCI) Aβ+. Linear mixed-effects models were used to assess changes in volumetric measures of BF subregions and the hippocampus and changes in AIBL memory and attention composite scores for each group compared with CU Aβ- participants. Associations between Aβ burden, brain atrophy, and cognitive decline were evaluated and explored further using mediation analyses. Results The cohort included 476 participants (72.6 ± 5.9 years, 55.0% female) with longitudinal data from a median follow-up period of 6.1 years. Compared with the CU Aβ- group (n = 308), both CU Aβ+ (n = 107) and MCI Aβ+ (n = 61) adults showed faster decline in BF and hippocampal volumes and in memory and attention (Cohen d = 0.73-1.74). Rates of atrophy in BF subregions and the hippocampus correlated with cognitive decline, and each individually mediated the impact of Aβ burden on memory and attention decline. When all mediators were considered simultaneously, hippocampal atrophy primarily influenced the effect of Aβ burden on memory decline (β [SE] = -0.139 [0.032], proportion mediated [PM] = 28.0%) while the atrophy of the posterior nucleus basalis of Meynert in the BF (β [SE] = -0.068 [0.029], PM = 13.1%) and hippocampus (β [SE] = -0.121 [0.033], PM = 23.4%) distinctively influenced Aβ-related attention decline. Discussion These findings highlight the significant role of BF atrophy in the complex pathway linking Aβ to cognitive impairment in early stages of AD. Volumetric assessment of BF subregions could be essential in elucidating the relationships between the brain structure and behavior in AD.
Document Type
Journal Article
Date of Publication
6-17-2024
Volume
103
Issue
2
PubMed ID
38885444
Publication Title
Neurology
Publisher
Wolters Kluwer Health
School
Centre for Precision Health / School of Medical and Health Sciences
RAS ID
70390
Funders
Alzheimer's Association / Alzheimer's Drug Discovery Foundation / Science and Industry Endowment Fund / Dementia Collaborative Research Centres / Victorian Government’s Operational Infrastructure Support / Australian Alzheimer’s Research Foundation / National Health and Medical Research Council / Yulgilbar Foundation
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Comments
Xia, Y., Dore, V., Fripp, J., Bourgeat, P., Laws, S. M., Fowler, C. J., ... & Maruff, P. (2024). Association of basal forebrain atrophy with cognitive decline in Eearly Alzheimer disease. Neurology, 103(2), e209626. https://doi.org/10.1212/WNL.0000000000209626