Axonal degeneration and amyloid pathology predict cognitive decline beyond cortical atrophy
Svenningsson, Anna Linnéa LU
; Stomrud, Erik
LU
; Palmqvist, Sebastian
LU
; Hansson, Oskar
LU
and Ossenkoppele, Rik
LU
(2022)
In Alzheimer's Research and Therapy
14(1).
- Abstract
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... (More)
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.
(Less)
- author
- Svenningsson, Anna Linnéa
LU
; Stomrud, Erik
LU
; Palmqvist, Sebastian
LU
; Hansson, Oskar
LU
and Ossenkoppele, Rik
LU
- organization
- publishing date
- 2022-12-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Aging, Amyloid, Cognition, Neurodegeneration, Resilience
- in
- Alzheimer's Research and Therapy
- volume
- 14
- issue
- 1
- article number
- 144
- publisher
- BioMed Central (BMC)
- external identifiers
-
- pmid:36192766
- scopus:85139107663
- ISSN
- 1758-9193
- DOI
- 10.1186/s13195-022-01081-w
- language
- English
- LU publication?
- yes
- id
- 54998c61-dae6-4a1d-9854-e3a2b9cb962d
- date added to LUP
- 2022-12-09 13:26:24
- date last changed
- 2024-06-13 12:35:44
@article{54998c61-dae6-4a1d-9854-e3a2b9cb962d,
abstract = {{<p>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.</p>}},
author = {{Svenningsson, Anna Linnéa and Stomrud, Erik and Palmqvist, Sebastian and Hansson, Oskar and Ossenkoppele, Rik}},
issn = {{1758-9193}},
keywords = {{Aging; Amyloid; Cognition; Neurodegeneration; Resilience}},
language = {{eng}},
month = {{12}},
number = {{1}},
publisher = {{BioMed Central (BMC)}},
series = {{Alzheimer's Research and Therapy}},
title = {{Axonal degeneration and amyloid pathology predict cognitive decline beyond cortical atrophy}},
url = {{http://dx.doi.org/10.1186/s13195-022-01081-w}},
doi = {{10.1186/s13195-022-01081-w}},
volume = {{14}},
year = {{2022}},
}