Can white matter changes in the brain determine our ageing trajectory?

Ageing is a major risk factor for most neurological and psychiatric disorders. As populations worldwide continue to grow older, the burden of brain- and cognition-related disorders is expected to rise substantially. There is, therefore, an urgent need to understand the normal trajectory of brain ageing and to develop scientific methods that can determine and predict whether an individual is following a healthy ageing path or is at risk of developing cognitive disorders later in life.

Normal ageing is associated with well-defined changes in brain structure and behaviour. Accelerated changes in brain structure and function beyond this typical trajectory are believed to increase the risk of age-related disorders and may lead to their earlier onset. Central to brain function are the white-matter regions, which consist of axonal fibre tracts responsible for communication and connectivity between different parts of the brain. These fibre tracts, insulated by myelin, are essential for efficient information transfer.

What our research aimed at

In our research, published in November 2025 in Cerebral Cortex we focused on the health of brain white matter, with an underlying quest to measure the extent of white-matter changes as a quantitative feature that could determine brain health and the ageing trajectory. With the usual ageing process, white matter fibres undergo gradual pruning and degeneration from infarction of the brain’s smallest blood vessels. Brain MRI measurements allow this damage to be detected as white-matter hyperintensities (WMH) in regions near the brain’s ventricles, as well as in deep white matter. These changes accumulate in nearly everyone with age, but not at the same rate. A subset of individuals experiences relatively slow/no accumulation, while others show a much faster deposition of WMHs.

Using a large global ageing consortium, including the U.S.’s National Alzheimer’s Coordinating Center, the multi-centre Alzheimer’s Disease Neuroimaging Initiative, and an Indian meta-cohort of Indian Institute of Science Education and Research, Berhampur, we conducted comprehensive quantitative brain imaging and cognitive investigations to pinpoint white matter changes as an index to map global brain health and brain age.

The central question was to determine when changes that occur in everyone with age begin to interfere with normal brain function.

What our research found

Our research revealed a clear biological tipping point in the brain aging trajectory, defined by a critical burden of WMH on a brain MRI, beyond which brain tissue loss and cognitive inefficiency increase disproportionately. When WMH volume exceeds approximately 2.5 mL, individuals are more likely to exhibit structural brain loss and impairments in everyday cognitive functions, including reaction time, attention, planning, multitasking, and word retrieval. Importantly, these changes can occur even when standard memory measures and global cognitive tests remain within the normal range.

Brain ageing, therefore, depends on how much white-matter change happens with ageing in an individual. Individuals of the same age can follow very different brain-ageing paths, and significant white-matter injury can accumulate silently even before cognitive problems become apparent, highlighting the importance of early monitoring and preventive strategies.

The study further showed that not all white-matter damage behaves uniformly. Lesions that develop near the brain’s fluid-filled spaces were particularly disruptive because they affect major communication pathways. Using a machine-learning model to estimate ‘Brain Age’ from MRI scans, we found that individuals with greater periventricular white-matter damage had brains that appeared older than their actual age.

The implications

One important implication is that normal brain ageing can be distinguished from accelerated ageing using a clear, quantitative biological threshold. Individuals whose white-matter damage remains below a critical level tend to follow a more typical ageing trajectory. Once this is crossed, the pattern shifts, and that is often the point at which closer monitoring and earlier management of vascular risk factors, such as high blood pressure, become important.

This distinction is particularly significant for India, where vascular risk factors are widespread and rising rapidly. An estimated 77 million Indian adults live with diabetes, and nearly 234 million are affected by hypertension, conditions that directly damage the brain’s small blood vessels and accelerate white-matter injury. At the same time, India is undergoing a profound demographic shift. By 2050, nearly one in five individuals will be 60 years or older, amounting to over 300 million senior citizens. Together, these trends suggest that the burden of cerebrovascular injury and age-related cognitive decline in India is likely to grow beyond what would be expected from ageing alone.

For the field, these results challenge how “healthy brain ageing” is usually defined. Our findings argue for a shift toward quantifying white-matter lesion burden early, before overt cognitive decline, rather than treating such changes as secondary or incidental. This framework can improve how individuals are stratified in ageing studies and clinical trials. It can also refine vascular-based models of neurodegeneration, and support earlier, preventive interventions aimed at protecting brain health.

Overall, our work reframes white-matter injury as a modifiable driver of brain ageing, with implications for public health, prevention strategies, and how societies prepare for cognitive ageing in an era of increasing vascular risks.

(Niraj Kumar Gupta is the first author of the study ‘Brain aging and cognitive decline accelerate beyond a threshold of periventricular white matter hyperintensity’ nirajg20@iiserbpr.ac.in; Dr. Vivek Tiwari is the lead author of the study. Both authors are with the Department of Biological Sciences, IISER, Berhampur vivekt@iiserbpr.ac.in)