To chart how our brains change over the course of our lives, neuroscientists have focused largely on beginnings and endings: the rapid development and pruning of neural connections in childhood and adolescence, and the degeneration associated with old age. “We kind of skipped over middle age,” says Sebastian Dohm-Hansen, a bioinformatician at University College Cork in Ireland.
There are good reasons for that, not least that changes in brain structure and function are easier to spot with neuroimaging when they are at their most extreme. In the case of cognitive decline and dementia, “a lot of what we care about presents most dramatically after the age of 60”, says Dohm-Hansen.
But over the past few years, researchers have started to look more closely at the middle-aged brain, identifying a series of subtle but significant changes between the ages of 40 and 65 that mark it out as a vital time to identify problems that won’t manifest until later in life.
“Think of midlife as the top of an inverted U-curve,” says Ahmad Hariri, a professor of neuroscience at Duke University in North Carolina. You spend the earlier decades on the upward slope, developing and refining your brain. You’ll likely spend decades on the downward slope, slowly losing those gains. “Targeting midlife is like extending that level section at the top of the curve, to delay the downward trajectory.”
Among the most important of these midlife changes, according to a 2024 review by Dohm-Hansen and his colleagues, are changes in connectivity – how well neurons send signals over long distances and how the brain organises its processing across regions. This connectivity peaks in middle age, then rapidly declines.
The extent of the decline correlates with how people’s cognitive abilities fare, too, particularly their capacity to remember everyday events. The brain “undergoes a kind of turning point during middle age,” says Dohm-Hansen, offering a window for the detection of problems down the line. It is not simple to track, though. Connectivity increases across some brain networks to compensate for losses elsewhere, and how all of these changes play out varies among individuals.
The good news is that other ways to spot early signs of cognitive decline and dementia are emerging. One of the most striking is using blood-based biomarker tests, which can detect the presence of the misfolded amyloid-beta and tau proteins thought to cause Alzheimer’s disease – the most common form of dementia – long before symptoms appear.
These tests might one day be used in clinical settings, possibly even as part of routine screenings, and they are already available directly to consumers. Most neurologists urge caution, though, because most studies have been done in older cohorts. More importantly, not everyone with accumulations of these misfolded proteins will go on to develop Alzheimer’s.
Another, broader approach stems from a new way to measure rates of biological ageing, which don’t always tally with rates of chronological ageing. In 2025, a team led by Hariri introduced a tool to estimate a person’s overall rate of biological ageing, at 45, from a single MRI brain scan. When the researchers used the tool to analyse other brain scans, they found that older people deemed to be ageing faster had more shrinkage in the hippocampus, a brain region crucial for memory, and performed worse on cognitive tests. They were also more likely to experience cognitive impairment and develop dementia in the following years. “[Our tool] is foundationally a measure of accelerated aging in midlife,” says Hariri, “but it predicts future dementia for people in their late 60s to 80s.” It is not yet a reliable prediction tool, however, because the associations come from older people with short-term follow-ups.
As with blood-biomarker tests, then, we can’t yet use MRI pace-of-ageing scans to say with any confidence that a 45-year-old, say, will develop dementia at 75. “Knowing how well any midlife biomarkers actually predict later health requires tracking individuals for decades,” says Hariri. What’s more, even if these measures provide clinically reliable predictions, it is difficult to imagine them being available to everyone any time soon, owing to the costs involved.
There are signs anyone can look out for today, though. A study published earlier this year, for example, found a correlation between 6 specific psychological and cognitive symptoms of depression in midlife – including people losing confidence in themselves and feeling “nervous and strung-up all the time” – and an increased risk of dementia in later years. “These symptoms might be very early signs of brain changes, and we’re talking 20 years before dementia [onset],” says Gill Livingston, a professor of psychiatry at University College London and a co-author of the study. “It’s possible that how you think and feel could be as informative, or even more informative, than MRI or biomarkers, but we don’t know yet.”
Livingston also points out that we already have several well-established early indicators of brain health trajectories and dementia risk, including blood pressure and cholesterol, which can be easily checked. “We shouldn’t overlook them,” says Livingston.
Indeed, there is growing evidence that adopting a healthier lifestyle in midlife can boost long-term resilience to cognitive decline and even “prevent” dementia – in the sense that it can be delayed long enough that people don’t develop symptoms in their lifetime. The latest Lancet Commission on dementia, published in 2024, concluded that 45 per cent of dementia cases could be avoided by addressing key lifestyle factors, including high blood pressure, obesity, smoking, excessive alcohol consumption, social isolation, depression and physical inactivity. Doing so in middle age has a particularly significant effect on our risk of getting dementia in our later years.
So, while we await reliable, cheap blood-biomarker tests and genuinely effective treatments for dementia, middle age is a critical window of opportunity to protect your brain before it’s too late.
Livingston draws an analogy with the way we think about pensions: the sooner you start investing in your brain health, by taking steps to reduce your blood pressure, for example, the greater the long-term benefits in terms of resilience to cognitive decline and dementia. “If you wait, you’re going to have less cognitive reserve [in your later years],” she says. “Doing it earlier will make a difference.”
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