Researchers striving to understand the origins of dementia are building the case against a possible culprit: lead exposure early in life. A study spanning 23 years has now revealed that monkeys who drank a lead-rich formula as infants later developed tangles of a key brain protein, called tau, linked to Alzheimer's disease. Though neuroscientists say more work is needed to confirm the connection, the research suggests that people exposed to lead as children—as many in America used to be before it was eliminated from paint, car emissions, water, and soil—could have an increased risk of the common, late-onset form of Alzheimer’s disease.

Even in small doses, lead can wreak havoc on the heart, intestines, kidneys, and nervous system. Children are especially prone to its pernicious effects, as it curbs brain development. Many studies have linked early lead exposure with lower IQs. Researchers estimate that one in 38 children in the United States still have harmful levels of the metal in their systems, but evidence linking this exposure to dementia later in life has been tenuous.

A team led by toxicologist Nasser Zawia, however, has vigorously pursued the lead hypothesis. In one early study, from 2008, the group showed that plaques, insoluble globs of a protein called β-amyloid, marred the brains of five macaques that had consumed a lead-enriched formula as infants. The researchers had compared the preserved brain tissues from those macaques, sacrificed in 2003 at age 23 in a National Institutes of Health lab, with four similarly aged monkeys who had had lead-free formula. The amyloid plaques closely resembled those in the brains of adults with Alzheimer's disease that are thought to contribute to the dementia.

Now, Zawia's team has used brain samples from the same five macaques that received lead-enriched formula to find clear evidence of another structural change strongly linked to Alzheimer's: tangles of tau protein. It’s not certain how, or even if, these tangles promote dementia, but when tau proteins decompose into crumpled strands inside a neuron, the cell’s vital transport system can become blocked. The researchers analyzed frontal cortex tissues to show that the lead-exposed monkeys had three times more irregular tau protein in their brain cells than the monkeys who drank normal formula as infants. Moreover, the genetic instructions that assemble the tau proteins were altered, suggesting that early lead exposure epigenetically reprogrammed the monkeys' DNA .

“This is very strong evidence that early [lead] exposure can determine what happens in old age,” says Zawia, of the University of Rhode Island, Kingston. The team's results appear in the December issue of NeuroToxicology.

The brain physiologies of macaques and humans are close enough that dementia researchers should pay attention to the findings, says neuroscientist Marc Weisskopf of the Harvard School of Public Health in Boston. “This study adds another important piece to this link between early-life lead exposure and Alzheimer's-like pathology.”

While Weisskopf says he is “intrigued” that the researchers could find macaques that lived a full life after infant lead exposure, he is cautious. “As far as I can tell, there’s only one group putting this story out,” he says. “We [would] like to see that this is replicable, but that’s hard. It’s just a difficult study to wait that long and have that kind of data.”

Understanding how lead might interfere with DNA's instructions to promote brain degeneration later in life will take much more work, Weisskopf adds. Correlating the lead exposure of human infants to a disease that doesn’t manifest until people are in their 60s, 70s, and 80s is challenging, he says.

Current lead regulations in the United States should suffice to prevent such long-term neurological harm, Zawia believes. However, children in many other countries still face this hazard—as do adults in the United States who grew up in densely populated areas much more contaminated by lead. “This study is a good indicator to not forget people who were exposed in the past before [lead] awareness and regulations," he says. "Their risk [of developing dementia] might have been increased.”

*Correction, 10 December, 12:40 p.m.: This item has been updated. The original phrase, "While Weisskopf says he is 'intrigued' that the researchers could find macaques that had lifelong exposure to lead …" has been changed to, "While Weisskopf says he is 'intrigued' that the researchers could find macaques that lived a full life after infant lead exposure … ."