Atrophy trajectories in Alzheimer's disease: how sex matters
Poster No:
140
Submission Type:
Abstract Submission
Authors:
Anna Inguanzo1, Konstantinos Poulakis1, Javier Oltra2, Silvia Maioli3, Anna Marseglia1, Daniel Ferreira1, Rosaleena Mohanty1, Eric Westman1
Institutions:
1Division of Clinical Geriatrics, Centre for Alzheimer Research, NVS, Karolinska Institutet, Stockholm, Sweden, 2Aging Research Center (ARC), Centre for Alzheimer Research, NVS, Stockholm, Sweden, 3Division of Neurogeriatrics, Centre for Alzheimer Research, NVS, Stockholm, Sweden
First Author:
Anna Inguanzo
Division of Clinical Geriatrics, Centre for Alzheimer Research, NVS, Karolinska Institutet
Stockholm, Sweden
Division of Clinical Geriatrics, Centre for Alzheimer Research, NVS, Karolinska Institutet
Stockholm, Sweden
Co-Author(s):
Konstantinos Poulakis
Division of Clinical Geriatrics, Centre for Alzheimer Research, NVS, Karolinska Institutet
Stockholm, Sweden
Division of Clinical Geriatrics, Centre for Alzheimer Research, NVS, Karolinska Institutet
Stockholm, Sweden
Anna Marseglia
Division of Clinical Geriatrics, Centre for Alzheimer Research, NVS, Karolinska Institutet
Stockholm, Sweden
Division of Clinical Geriatrics, Centre for Alzheimer Research, NVS, Karolinska Institutet
Stockholm, Sweden
Daniel Ferreira
Division of Clinical Geriatrics, Centre for Alzheimer Research, NVS, Karolinska Institutet
Stockholm, Sweden
Division of Clinical Geriatrics, Centre for Alzheimer Research, NVS, Karolinska Institutet
Stockholm, Sweden
Rosaleena Mohanty
Division of Clinical Geriatrics, Centre for Alzheimer Research, NVS, Karolinska Institutet
Stockholm, Sweden
Division of Clinical Geriatrics, Centre for Alzheimer Research, NVS, Karolinska Institutet
Stockholm, Sweden
Eric Westman
Division of Clinical Geriatrics, Centre for Alzheimer Research, NVS, Karolinska Institutet
Stockholm, Sweden
Division of Clinical Geriatrics, Centre for Alzheimer Research, NVS, Karolinska Institutet
Stockholm, Sweden
Introduction:
Longitudinal subtypes in Alzheimer's disease (AD) have been recently identified based on their distinct brain atrophy trajectories (Poulakis et al., 2022), which follow either a mediotemporal or a cortical atrophy pathway. The most prevalent, the mediotemporal, included three longitudinal subtypes: the limbic predominant (LPA), the limbic predominant plus (LPA+), and the minimal atrophy (MA). LPA+ is characterised by the fastest rate of atrophy, beginning in the entorhinal cortex, later involving the temporal lobe and the rest of the cortex, while LPA is confined to atrophy in temporal regions. In contrast, the MA subtype is characterised by minimal atrophy in mediotemporal areas. Within the cortical pathway, there are two less common subtypes, the hippocampal sparing (HS) subtype, characterised by parietal atrophy but preserved medial-temporal cortex at AD diagnosis, and the diffuse atrophy (DA) subtype with temporal and frontal atrophy already at AD diagnosis, as well as a rapid progression. Although the discovery of distinct brain atrophy trajectories in AD represents a significant contribution to advancing precision medicine, the impact of sex – a major risk factor for AD – on these trajectories has yet to be explored. This study aims to investigate sex-specific effects within these trajectories.
Methods:
We analysed MRI from three international AD cohorts (ADNI, J-ADNI and AIBL; N=320). All participants with AD were amyloid-β positive and were classified into one of the following longitudinal subtypes using a longitudinal clustering approach (Poulakis et al., 2022): LPA+, LPA, MA, HS or DA. Clustering was based on W-scores of atrophy measures over 8 years, including grey matter volumes from seven subcortical regions and thickness from 34 cortical regions, which were adjusted for cohort and normal brain ageing relative to an amyloid-β negative cognitively normal control group (N=305). The W-scores were also adjusted for field strength, and additionally, in the case of volumetric measures, for intracranial volume. The W-scores represented standard deviations of atrophy below the control group. To address the main goal of our study, we subsequently stratified each atrophy trajectory by sex to delineate atrophy trajectories for women and men within each longitudinal subtype. We compared women and men within each subtype in relation to socio-demographic information and changes in global cognition (assessed with the Mini Mental State Examination test, MMSE) using linear mixed-effects models.
Results:
The frequency of women in each subtype was as follows: LPA+ (N=23, 61% women), LPA (N=93, 48% women), MA subtype (N=189, 48% women), HS subtype (N=10, 40% women) and DA subtype (N=5, 60% women). For all AD subtypes, women consistently exhibited hippocampal atrophy at earlier disease stages than men (Figure 1). Regarding the mediotemporal pathway, LPA+ women showed greater atrophy over time compared to LPA+ men in frontal regions, while LPA+ men experienced precentral atrophy sooner. LPA+ men had an older age of onset (U=20.5, p=0.008), and showed a faster cognitive decline compared to women (χ2(1)=5.19, p=0.023). In contrast, in the LPA subtype, women presented with precentral atrophy earlier than men. MA women showed lateral temporal atrophy earlier compared to MA men. In the cortical pathway, HS women showed frontal atrophy earlier compared to men. Within the DA subtype, both men and women exhibited a widespread pattern of atrophy over time.
Conclusions:
Our findings revealed unique atrophy trajectories in women and men within longitudinal AD subtypes, emphasizing the importance of investigating sex-related differences in AD heterogeneity. This highlights the need for future research to consider sex differences in order to develop tailored monitoring and treatment approaches in both sexes.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
Segmentation and Parcellation 2
Keywords:
Aging
Cognition
STRUCTURAL MRI
1|2Indicates the priority used for review