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. 2025 Apr 11;17(1):79.
doi: 10.1186/s13195-025-01713-x.

Atrophy trajectories in Alzheimer's disease: how sex matters

Anna Inguanzo  1 , Konstantinos Poulakis  2 , Javier Oltra  3 , Silvia Maioli  4 , Anna Marseglia  2 , Daniel Ferreira  2   5 , Rosaleena Mohanty  2 , Eric Westman  6 ; Alzheimer’s Disease Neuroimaging Initiative
Affiliations

Atrophy trajectories in Alzheimer's disease: how sex matters

Anna Inguanzo et al. Alzheimers Res Ther. .

Abstract

Introduction: Longitudinal subtypes in Alzheimer's disease (AD) have been identified based on their distinct brain atrophy trajectories, encompassing mediotemporal and cortical pathways. These subtypes include minimal atrophy, limbic predominant, limbic predominant plus, diffuse atrophy and hippocampal sparing. The impact of sex on the progression of these subtypes remains a crucial area of investigation.

Methods: We analysed MRI data from 320 amyloid-β positive individuals with AD from three international cohorts (ADNI, J-ADNI and AIBL). Longitudinal clustering was conducted to identify atrophy trajectories over eight years from the clinical disease onset, with separate trajectories delineated for women and men.

Results: Women consistently exhibited earlier hippocampal atrophy and a higher burden of white matter abnormalities compared to men, yet women displayed less cognitive decline over time. Additionally, specific risk factors and distinct neuropsychiatric symptoms were associated with sex within specific trajectories.

Conclusions: AD subtypes show sex-specific differences in disease progression, highlighting the need to account for these differences from the early disease stages. Integrating imaging biomarkers with sex differences can enable the identification of more precise treatments for each patient, ensuring that both women and men have equal access to tailored care.

Keywords: Alzheimer’s disease; Cognition; Disease progression; MRI; Sex differences; Subtypes.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: All individuals provided written informed consent in accordance with the Helsinki declaration and approval for the studies was obtained by the local ethics committees. Consent for publication: All patients or appropriate surrogates gave written informed consent to their participation in the study. Competing interests: AI, KP, JO, SM, AM, RM and EW report no disclosures relevant to the manuscript. DF consults for BioArctic and has received honoraria from Esteve.

Figures

Fig. 1
Fig. 1
Brain atrophy trajectories for women and men within each AD trajectory The data are W-scores based on atrophy measures adjusted for field strength, cohort, and ageing. Additionally volumetric measures were adjusted for estimated total intracranial volume. Warmer colours indicate increasing cortical thinning and subcortical volume loss in the AD individuals compared to the cognitively unimpaired group. Results represent the average of the left and right hemisphere
Fig. 2
Fig. 2
Global cognitive trajectories (MMSE) of the most prevalent AD trajectories. Abbreviations: MMSE – Mini Mental State Examination scores
Fig. 3
Fig. 3
Cognitive trajectories of women and men of the LPA+ subtype measured with ADAS scale. Abbreviations: ADAS – Alzheimer’s disease assessment scale; LPA+ – Limbic predominant plus subtype
See this image and copyright information in PMC

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