Middle age is a tipping point for the brain and can offer clues about the risk of cognitive decline and dementia, emerging scientific evidence shows.

Why it matters: The decades between 40 and 60 years old could be a key time for early interventions and provide a knowledge base for new therapies to prevent disease.

• "The fifth and sixth decades of human life are emerging as being more than a mere interlude between adulthood and advanced age," researchers at University College Cork in Ireland write in a paper published this week, calling for more research of this generally understudied time of life.

How it works: People experience cognitive decline at different rates and times but there are a few changes that happen in everyone's brain as they age.

• The brain shrinks beginning in one's 30s and 40s (then more rapidly after the age of 60) as some of the synapses where neurons connect are pruned because they aren't needed anymore.
• The retrieval of memories slows down. It can take longer to come up with a list of words that start with the letter "f" or remember the name of a movie. But, "as long as the memory is there, it is just age-associated," says Keith Vossel, professor of neurology and director of the Alzheimer's Disease Research Center at UCLA.
• That gradual decline in how fast the brain processes information is "probably the most consistent finding," says Jason Hassenstab, a professor of neurology at Washington University in St. Louis.

Driving the news: Those and other changes in the brain and other organs may amount to "a phase of 'middle aging'" in the brain that "shape future cognitive aging," the researchers at University College Cork argue.

• Reviewing studies in humans and rodents, the researchers detail structural, molecular and cellular changes in the brain during middle age.
• There's the shrinking of the hippocampus, which plays a critical role in memory, and a decrease in the white matter that connects some parts of the brain.
• The expression of some genes in the brain also changes in middle age: Inflammation-related genes are increasingly expressed while some genes involved in producing proteins that play a role in neuron synapses are expressed less, they write.

One part of middle age that is a big step-change for half the world's population: menopause.

• Many women report a "brain fog" characterized by difficulty paying attention and forgetfulness.
• That's tied to the drop of estrogen during menopause, which researchers are trying to unravel. The Biden administration is calling for a $12 billion investment in women's health research, including the impact of menopause on brain health.

Zoom in: Studies have found women tend to have higher levels of a protein called tau that is believed to lead to cognitive decline in Alzheimer's disease compared to men in the same stage of disease.

• The underlying biology is unclear but one study found women with early Alzheimer's disease who began menopause early or prematurely — before the age of 45 — tended to have higher tau levels than women who started menopause later.
• The same was true for women who delayed starting hormone replacement therapy.
• That could be because the body has already started to compensate for its natural loss of the hormone and then estrogen acts as an "accelerant" when it is added back in to the system, including for cancer, says Rachel Buckley, a professor of neurology at Massachusetts General Hospital who led the research.
• Other studies find the expression of genes linked to the X-chromosome is associated with higher levels of tau.

The intrigue: Changes in the brain that can lead to dementia can appear in middle age — sometimes two decades before someone develops outward cognitive symptoms, says Vossel.

• The new paper highlights one study that found inflammation-related molecules detected in the blood of middle-aged people could be used to predict cognitive decline 20 years later.
• A study published last year analyzed blood from 1,000 participants — older adults who had a buildup of amyloid plaque that has been linked to an increased risk for Alzheimer's disease and those without it.
• They found that only people who had a biomarker called glial fibrillary acidic protein (GFAP) and amyloid plaques were likely to develop more tau protein.

The big picture: Middle age is a time when some of the biggest risk factors for dementia, including alcohol intake, obesity and hypertension, are especially important, Hassenstab says.

• It's "a sensitive period where, if your lifestyle is not on the healthier side, you're setting yourself up for a lot of problems as you head into late middle age and early old age," he says.
• But it's also a time when those risk factors can be modified.

"We used to think Alzheimer's disease and other dementias are senile diseases," Vossel says.

• "Now we realize there is already organ damage in the brain by the time people have cognitive symptoms so we can try to prevent [disease] as best we can at the earliest stages possible — like heart disease."