Objective: The inhibition deficit hypothesis postulates that inhibitory functioning declines with age, which negatively impacts other cognitive abilities. Yet still, the impact of healthy aging on inhibitory functioning remains unclear, with the multifaceted nature of inhibition often an overlooked factor. Moreover, no prior study has empirically tested whether inhibitory subcomponents explain differential age effects in sustained attention—an open question that this work aimed to address. Method: We cross-sectionally investigated the inhibition deficit hypothesis in 80 healthy older adults (Mage = 67.78 years, 44 female). We utilized the PsyToolkit platform to administer three inhibition tasks (i.e., flanker, Stroop, and go/no-go), each targeting a distinct subcomponent process, along with the Sustained Attention to Response Task. Results: The flanker task had low internal consistency and was deemed unreliable. Semipartial correlations of the remaining inhibition measures with age resulted in significant positive relationships with task performance on the Stroop (errors: ρ = 0.337, p = .014; reaction time: ρ = 0.313, p = .028) and a negative association with the go/no-go (balanced integrated score: ρ = −0.471, p < .001), such that older individuals had more pronounced Stroop effects and worse overall go/no-go performance. Finally, go/no-go performance completely mediated the relationship between aging and sustained attention performance (t = −2.30, 95% CI [−0.05, −0.01]), while Stroop effects partially mediated this association (t = −2.16, 95% CI [−0.03, −0.002]). Conclusions: Age-related declines were observed across reliable inhibition tasks, lending support for the inhibition deficit hypothesis. The mediation findings demonstrate that inhibitory subcomponents account for age-related declines in sustained attention, over and beyond aging itself via an indirect path, representing an important cognitive domain to maintain throughout aging.

Inhibition represents a core executive function which underlies the ability to suppress interfering or distracting stimuli, thereby building resistance against task-irrelevant information. However, the impact of ageing on inhibitory functioning and the role of neuroplasticity - largely driven by predominant excitatory (glutamatergic) and inhibitory (GABAergic) neurochemicals – remains poorly understood. This study investigated age relationships with neurochemical concentrations (GABA + and Glx) and their associations with inhibitory sub-components in healthy ageing. Participants completed three inhibition tasks (flanker, Stroop, go/no-go), each measuring a different sub-component process, via the PsyToolkit platform. MRS data were acquired in the sensorimotor (SM1; n = 71, mean age (SD) = 68.3 (± 9.7) years, 39 females) and prefrontal (PFC; n = 58, mean age (SD) = 67.6 (± 9.6) years, 30 females) regions using a HERMES sequence and analysed using OSPREY’s pipeline. After correcting for gender and education, semi-partial correlations revealed no significant relationships between age and GABA + or Glx concentrations in either the SM1 or PFC. Furthermore, after correcting for age, gender and education, partial correlations identified a significant negative relationship between SM1 Glx concentrations and go/no-go error rates, such that greater concentrations of SM1 Glx were associated with greater go/no-go accuracy. The null age-neurochemical results suggest that GABA + and Glx may not uniformly decline during healthy ageing, indicating a more nuanced relationship than previously reported. In addition, our neurochemical-behavioural findings provide neurochemically-and-spatially specific evidence that SM1 Glx concentrations may be important for response inhibition. This result indicates a role for the glutamatergic system in supporting inhibition, independent of age.

The aim of this study was to advance post-traumatic stress disorder (PTSD) understanding in older adults (48–77 years) by determining if circulating cytokines (IL-1β, IL-2, IL-4, IL-6, IL-12p70, IL17A and TNFα), brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF-A) and neuroanatomical brain volumes (grey and white matter, hippocampus, and amygdala) significantly differed in those with versus without PTSD. While none of the tested cytokines showed a significant difference, serum BDNF and VEGF-A levels were found to be significantly higher in the PTSD cohort. The assay used for BDNF quantification was important, with differences in general BDNF detected, but not when pro- and mature BDNF were measured specifically. Additionally, BDNF genotyping revealed a significant difference in Val66Met genotype distribution by PTSD diagnosis, with Val66Met carriers generally having lower circulating levels of BDNF compared to their Val66Val counterparts, regardless of PTSD diagnosis. Neuroanatomically, an all-female subset was examined to find total grey and white matter volumes and left and right hippocampal volumes were significantly smaller in those with PTSD. Collectively, these results show that both novel (VEGF-A) and established targets (BDNF and neuroimaging) may serve as useful biomarkers for older adults with PTSD.

The 2024 Lancet Commission on Dementia estimates that up to 45% of dementia cases could be prevented by addressing modifiable risk factors, emphasizing both prevention opportunities and the need to understand the biological mechanisms. This study investigated neurophysiological mechanisms underlying modifiable dementia risk factors in cognitively unimpaired older adults. Seventy-nine cognitively unimpaired older adults underwent magnetic resonance imaging brain scans, with spectroscopy measurements taken from the sensorimotor cortex (SMC) and prefrontal cortex (PFC), using a Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy sequence, optimized for measuring GABA+. Modifiable dementia risk scores were calculated using the Assessment for Cognitive Health and Dementia Risk (CogDrisk). Hierarchical linear regression analyses revealed a significant negative relationship within the SMC, with lower GABA+ (β = −0.249, P = 0.009) associated with higher risk scores. In the PFC, lower tNAA and tCho concentrations significantly predicted higher risk scores (β = −0.168 and −0.170, respectively). These findings suggest that GABAergic system alterations may underlie the pathophysiology of modifiable dementia risk in healthy aging, while changes in tNAA and tCho may reflect early alterations in neuronal integrity. These region-specific neurochemical findings may help identify potential early biomarkers for dementia risk and suggest new therapeutic pathways for preventive interventions.

Background

The rising prevalence of dementia necessitates identifying early neurobiological markers of dementia risk. Reduced cerebral white matter volume and flattening of the slope of the electrophysiological 1/f spectral power distribution provide neurobiological markers of brain ageing alongside cognitive decline. However, their association with modifiable dementia risk remains to be understood.

Methods

A cross-sectional sample of 98 healthy older adults (79 females, mean age = 65.44) underwent structural magnetic resonance imaging (sMRI), resting-state electroencephalography (EEG), cognitive assessments and dementia risk scoring using the CogDrisk framework. Univariate and multivariate linear regression models were conducted to investigate the relationships between modifiable dementia risk and sMRI brain volumes, the exponent of EEG 1/f spectral power, and cognition, whilst controlling for non-modifiable factors.

Results

Smaller global white matter volume (F(1,87) = 6.884, R2 = 0.073, P = .010), and not grey (F(1,87) = 0.540, R2 = 0.006, P = .468) or ventricle volume (F(1,87) = 0.087, R2 = 0.001, P = .769), was associated with higher modifiable dementia risk. A lower exponent, reflecting a flatter 1/f spectral power distribution, was associated with higher dementia risk at frontal (F(1,92) = 4.096, R2 = 0.043, P = .046) but not temporal regions. No significant associations were found between cognitive performance and dementia risk. In multivariate analyses, both white matter volume and the exponent of the 1/f spectral power distribution independently associated with dementia risk.

Conclusions

Structural and functional neurobiological markers of early brain ageing, but not cognitive function, are independently associated with modifiable dementia risk in healthy older adults.