Charting the Ageing Brain: Insights from 46,000 MRI Scans
What happens inside our brains as we age? In a collaborative research study recently published in Mechanisms of Ageing and Development, researchers used UK Biobank data to create an unprecedented map of brain ageing—discovering why some regions are more vulnerable than others.
When we think about ageing, we often picture outward signs such as wrinkles, slower movement, and greying hair. Yet the most profound changes occur invisibly, within the brain. Understanding the mechanisms of brain ageing is essential not only for differentiating normal trajectories from disease-related alterations, but also for informing the development of interventions that protect cognitive health.
My research, using one of the largest imaging datasets from the UK Biobank, set out to map these changes in unprecedented detail. We analysed high-resolution MRI scans from 46,111 cognitively healthy individuals aged 44 to 83. This scale allowed us to trace volumetric alterations in subcortical grey matter with exceptional statistical power. Our central questions were: which regions are most vulnerable to ageing, and how does biological sex influence these trajectories?
What we found
Our results revealed that ageing exerts its strongest effects on the brainstem, hippocampus, and amygdala in terms of shrinkage of the grey matter. These regions are fundamental: the brainstem regulates vital autonomic functions, the hippocampus underpins memory consolidation, and the amygdala orchestrates emotional processing, among other functions. Their susceptibility to shrinkage underscores why age-related decline often manifests in memory lapses, emotional changes, and reduced resilience in basic physiological regulation.
Importantly, the trajectories were not uniform across sexes. Males exhibited steeper linear declines in the grey matter volume of the hippocampus, amygdala, and putamen compared to females, suggesting greater vulnerability in regions linked to memory and affect. Conversely, in the brainstem and thalamus, females showed sharper declines.
Beyond these linear effects, we observed non-linear patterns: in the brainstem, hippocampus, amygdala, and right thalamus, males displayed a more gradual volumetric decline in later life, whereas females experienced a more accelerated trajectory.
Ageing was not solely characterised by shrinkage. In the pallidum and caudate, we observed volumetric increases consistent with inflammatory processes. These changes accelerated in older age and occurred similarly across sexes, highlighting that ageing encompasses both atrophy and neuroinflammation.
Why sex plays a role
The differential trajectories can be explained by the functional and hormonal sensitivity of specific subcortical regions. The hippocampus, amygdala, and thalamus are deeply involved in memory and cognition, domains known to be modulated by sex hormones. Prior evidence indicates that oestrogen and testosterone influence synaptic density and neuroplasticity, thereby shaping volumetric resilience or vulnerability.
In contrast, regions such as the pallidum, primarily responsible for motor coordination, are less hormonally regulated and thus show minimal sex-related differences. This explains why sex effects are pronounced in memory- and emotion-related structures but negligible in motor-related nuclei.
What this means
The atlas we've created provides several advances. By mapping typical ageing trajectories, it enables clinicians to distinguish normal decline from pathological neurodegeneration. It strengthens diagnostic precision by accounting for biological variability between sexes, and identifies regions most vulnerable to atrophy and inflammation, informing regenerative medicine and neuroprotective strategies.
It also establishes a foundation for longitudinal monitoring, comparative studies, and personalised interventions.
Looking forward
Ageing is not a uniform process but rather a dynamic interplay of structural shrinkage, neuroinflammation, and compensatory adaptation. By charting sex- and region-specific trajectories of subcortical grey matter, this atlas advances the establishment of normative reference models in neuroscience and clinical neurology.
The next step is to translate these insights into interventions that can preserve brain health and delay the onset of neurodegenerative disease. Our findings are helping to shape the future of dementia research and detection, and we look forward to seeing what discoveries lie ahead.
Read the full research paper here.