TY - JOUR
T1 - Axonal degeneration and amyloid pathology predict cognitive decline beyond cortical atrophy
AU - Svenningsson, Anna Linnéa
AU - Stomrud, Erik
AU - Palmqvist, Sebastian
AU - Hansson, Oskar
AU - Ossenkoppele, Rik
N1 - Funding Information: Open access funding provided by Lund University. Work at the authors’ research centre was supported by the Swedish Research Council (2016-00906), the Knut and Alice Wallenberg foundation (2017-0383), the Marianne and Marcus Wallenberg foundation (2015.0125), the Strategic Research Area MultiPark (Multidisciplinary Research in Parkinson’s disease) at Lund University, the Swedish Alzheimer Foundation (AF-939932), the Swedish Brain Foundation (FO2021-0293), The Parkinson foundation of Sweden (1280/20), the Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, the Skåne University Hospital Foundation (2020-O000028), Regionalt Forskningsstöd (2020-0314), and the Swedish federal government under the ALF agreement (2018-Projekt0279). Publisher Copyright: © 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - Background: Cortical atrophy is associated with cognitive decline, but the association is not perfect. We aimed to identify factors explaining the discrepancy between the degree of cortical atrophy and cognitive decline in cognitively unimpaired elderly. Methods: The discrepancy between atrophy and cognitive decline was measured using the residuals from a linear regression analysis between change in whole brain cortical thickness over time and change in a cognitive composite measure over time in 395 cognitively unimpaired participants from the Swedish BioFINDER study. We tested for bivariate associations of this residual measure with demographic, imaging, and fluid biomarker variables using Pearson correlations and independent-samples t-tests, and for multivariate associations using linear regression models. Mediation analyses were performed to explore possible paths between the included variables. Results: In bivariate analyses, older age (r = −0.11, p = 0.029), male sex (t = −3.00, p = 0.003), larger intracranial volume (r = −0.17, p < 0.001), carrying an APOEe4 allele (t = −2.71, p = 0.007), larger white matter lesion volume (r = −0.16, p = 0.002), lower cerebrospinal fluid (CSF) β-amyloid (Aβ) 42/40 ratio (t = −4.05, p < 0.001), and higher CSF levels of phosphorylated tau (p-tau) 181 (r = −0.22, p < 0.001), glial fibrillary acidic protein (GFAP; r = −0.15, p = 0.003), and neurofilament light (NfL; r = −0.34, p < 0.001) were negatively associated with the residual measure, i.e., associated with worse than expected cognitive trajectory given the level of atrophy. In a multivariate analysis, only lower CSF Aβ42/40 ratio and higher CSF NfL levels explained cognition beyond brain atrophy. Mediation analyses showed that associations between the residual measure and APOEe4 allele, CSF Aβ42/40 ratio, and CSF GFAP and p-tau181 levels were mediated by levels of CSF NfL, as were the associations with the residual measure for age, sex, and WML volume. Conclusions: Our results suggest that axonal degeneration and amyloid pathology independently affect the rate of cognitive decline beyond the degree of cortical atrophy. Furthermore, axonal degeneration mediated the negative effects of old age, male sex, and white matter lesions, and in part also amyloid and tau pathology, on cognition over time when accounting for cortical atrophy.
AB - Background: Cortical atrophy is associated with cognitive decline, but the association is not perfect. We aimed to identify factors explaining the discrepancy between the degree of cortical atrophy and cognitive decline in cognitively unimpaired elderly. Methods: The discrepancy between atrophy and cognitive decline was measured using the residuals from a linear regression analysis between change in whole brain cortical thickness over time and change in a cognitive composite measure over time in 395 cognitively unimpaired participants from the Swedish BioFINDER study. We tested for bivariate associations of this residual measure with demographic, imaging, and fluid biomarker variables using Pearson correlations and independent-samples t-tests, and for multivariate associations using linear regression models. Mediation analyses were performed to explore possible paths between the included variables. Results: In bivariate analyses, older age (r = −0.11, p = 0.029), male sex (t = −3.00, p = 0.003), larger intracranial volume (r = −0.17, p < 0.001), carrying an APOEe4 allele (t = −2.71, p = 0.007), larger white matter lesion volume (r = −0.16, p = 0.002), lower cerebrospinal fluid (CSF) β-amyloid (Aβ) 42/40 ratio (t = −4.05, p < 0.001), and higher CSF levels of phosphorylated tau (p-tau) 181 (r = −0.22, p < 0.001), glial fibrillary acidic protein (GFAP; r = −0.15, p = 0.003), and neurofilament light (NfL; r = −0.34, p < 0.001) were negatively associated with the residual measure, i.e., associated with worse than expected cognitive trajectory given the level of atrophy. In a multivariate analysis, only lower CSF Aβ42/40 ratio and higher CSF NfL levels explained cognition beyond brain atrophy. Mediation analyses showed that associations between the residual measure and APOEe4 allele, CSF Aβ42/40 ratio, and CSF GFAP and p-tau181 levels were mediated by levels of CSF NfL, as were the associations with the residual measure for age, sex, and WML volume. Conclusions: Our results suggest that axonal degeneration and amyloid pathology independently affect the rate of cognitive decline beyond the degree of cortical atrophy. Furthermore, axonal degeneration mediated the negative effects of old age, male sex, and white matter lesions, and in part also amyloid and tau pathology, on cognition over time when accounting for cortical atrophy.
KW - Aging
KW - Amyloid
KW - Cognition
KW - Neurodegeneration
KW - Resilience
UR - http://www.scopus.com/inward/record.url?scp=85139107663&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s13195-022-01081-w
DO - https://doi.org/10.1186/s13195-022-01081-w
M3 - Article
C2 - 36192766
SN - 1758-9193
VL - 14
JO - ALZHEIMERS RESEARCH & THERAPY
JF - ALZHEIMERS RESEARCH & THERAPY
IS - 1
M1 - 144
ER -