Kalpouzos, G. | bioRxiv Science

bioRxiv2025

Global brain maintenance predicts well-preserved cognitive function: A pooled analysis of three longitudinal population-based Swedish cohorts

Substantial heterogeneity in cognitive ageing is well documented. Such heterogeneity has been attributed to individual differences in brain maintenance - i.e., the relative preservation of neural resources in ageing. However, large-scale longitudinal evidence is lacking. We pooled data from three population-based Swedish cohorts (Betula, N = 196; SNAC-K, N = 472; H70, N = 688; aged 60-93 years at baseline, follow-up duration up to 7 years) to assess whether global brain maintenance is associated with better preserved cognition in ageing, and to identify lifestyle predictors of brain maintenance. In each cohort, global brain integrity was indexed by the volume of the lateral ventricles (adjusted for total intracranial volume), and general cognitive function based on a principal component analysis of four age-sensitive cognitive domains. Participants were classified into subgroups of low (i.e., aged) versus high (i.e., youth-like) brain integrity based on ventricular volume estimates available for a younger reference sample in one of the cohorts (Betula, 25-55 years, N = 60). Subgroup differences in cognition at baseline and over the follow-up were assessed with ANCOVAs and linear mixed effects models. Logistic regressions were used to examine lifestyle predictors of brain maintenance. Across cohorts, 881 individuals (64.97%) were classified into the high brain integrity subgroup at baseline and 409 individuals (49.82%) over the follow-up. Maintenance of more youth-like brain integrity was associated with better baseline cognition (p < .001) and less cognitive decline longitudinally (p < .001). Moreover, lower cardiovascular disease (CVD) risk and the absence of diabetes predicted brain maintenance at baseline (CVD risk, OR = 0.80, 95% CI [0.68, 0.93]; diabetes, OR = 0.39, 95% CI [0.26, 0.59]) and over the follow-up (CVD risk, OR = 0.79, 95% CI [0.64, 0.96]; diabetes, OR = 0.53, 95% CI [0.29, 0.94]). These findings underscore brain maintenance as a key determinant of cognitive ageing and highlight the importance of managing cardiovascular and metabolic disease risk factors for promotion of brain and cognitive health in later life.

neuroscience↗

bioRxiv2023

The iron-dopamine D1 coupling modulates neural signatures of working memory across adulthood

Brain iron overload and decreased integrity of the dopaminergic system have been independently reported as brain substrates of cognitive decline in aging. Dopamine (DA), and iron are co-localized in high concentrations in the striatum and prefrontal cortex (PFC), but follow opposing age-related trajectories across the lifespan. DA contributes to cellular iron homeostasis and the activation of D1-like DA receptors (D1DR) alleviates oxidative stress-induced inflammatory responses, suggesting a mutual interaction between these two fundamental components. Still, a direct in-vivo study testing the iron-D1DR relationship and their interactions on brain function and cognition across the lifespan is rare. Using PET and MRI data from the DyNAMiC study (n=180, age=20-79, %50 female), we showed that elevated iron content was related to lower D1DRs in DLPFC, but not in striatum, suggesting that dopamine-rich regions are less susceptible to elevated iron. Critically, older individuals with elevated iron and lower D1DR exhibited less frontoparietal activations during the most demanding task, which in turn was related to poorer working-memory performance. Together, our findings suggest that the combination of elevated iron load and reduced D1DR contribute to disturbed PFC-related circuits in older age, and thus may be targeted as two modifiable factors for future intervention. HighlightsO_LIFirst study demonstrating the association between regional iron and dopamine D1DR in adult humans. C_LIO_LIThe interplay between age-related elevated iron and diminished D1DR explained lower task-related brain activity, which in turn was related to poorer task performance. C_LIO_LIOur findings iron-DA coupling can help progress the understanding of the mechanisms behind DA-related neurodegeneration. C_LI

neuroscience↗