Feature

Discovery, in science, usually comes only after months--or years--of patient drudge work. Every now and then, however, scientific discovery occurs suddenly, detouring research from its expected painstaking course.

Such was the case, recently, for a group of Scottish researchers led by University of Aberdeen psychiatrist Lawrence J. Whalley, MD, and University of Edinburgh psychologist Ian J. Deary, PhD. Their discovery: a trove of records, long presumed lost, from a 1932 test that measured the mental ability of nearly every 11-year-old in Scotland.

The records, matched with present-day health and psychiatric data, provide a singular opportunity for scientists to examine connections between early intelligence and later cognitive functioning.

"Scotland is unique in the world, in that the mental abilities of two birth cohorts have been comprehensively tested," says Whalley, referring to the 1932 testing and a similar test administered in the 1940s.

Already, the 1932 data have yielded the best evidence yet of a long-suspected link between higher mental ability in childhood and a lower risk for dementia in old age. Whalley, Deary and colleagues published the findings in the Nov. 28 issue of Neurology (Vol. 55, No. 10).

Finding such an association "forces us to consider whether [Alzheimer's disease] is a developmental process beginning at conception or whether it is a disease acquired en route to old age," writes Columbia University neurologist Richard Mayeux, MD, in an editorial accompanying the study.

Fortuitous find

Deary had read that in 1932, almost 90,000 Scottish schoolchildren born in 1921 had been administered the Moray House Test--an intelligence measure that correlates closely with the Stanford-Binet test. But no one at the Scottish Council for Research in Education, who had sponsored the test, seemed to know anything about the records.

As it turned out, the forgotten data were under their feet. Whalley's wife, Patricia, found them, after hours of hunting in the council's musty basement one spring afternoon in 1997.

"My wife and I had been given permission to search the store area," Whalley remembers. "Just when they were hurrying us along at about 5:10 p.m., she pulled out a brown paper sack containing the first of the 16 ledgers we eventually recovered. It was quite an exciting moment."

In their Neurology article, the Scottish researchers reported the results of two analyses that used the 1932 data and contemporary health and psychiatric records. First, using hospital records, they identified 59 people from around Scotland who had taken the 1932 test and who had Alzheimer's disease or vascular dementia that began before age 64. A control group of Scots who had taken the 1932 test but did not have dementia was matched with patients by age, sex, paternal occupation and birth district.

Second, the researchers found 50 1932 test-takers living in Aberdeen who met criteria for late-onset dementia--that is, dementia beginning after age 64. Aberdeen residents who had taken the test at age 11 and who showed no signs of dementia were included in a control group.

Study results showed that participants with early-onset dementia did not differ from control participants on the childhood intelligence test. But late-onset dementia was associated with lower intelligence at age 11. Specifically, among study participants who had dementia after age 64, the average score on the 1932 intelligence test was 32.1, compared with 36.2 for participants in the control group. The test-score difference between people with and without dementia became statistically significant at age 72.

In a related study published in December in the journal Age and Ageing, the Scottish team also found that children who scored highest on the test of mental ability at age 11 were most likely to remain "functionally independent" at age 77.

Welcome confirmation

Researchers have long theorized that mental ability may be linked to cognitive function and dementia during aging. Several studies have indicated that factors such as years of education, occupation or performance on military entrance tests are linked to dementia progression.

In a 1996 examination known as the Nun Study, a team led by University of Kentucky epidemiologist David A. Snowdon, PhD, analyzed autobiographical essays written by 93 young women as they entered a religious convent more than 60 years ago. Results showed that women whose essays revealed lower "idea density" tended to score more poorly on a dementia screening test, after age 75, than did women whose essays were more linguistically sophisticated. In addition, autopsies of 14 nuns who had died showed that all of the women who had demonstrated low linguistic ability as young women had brain pathology consistent with Alzheimer's disease, whereas none of the women whose essays revealed higher idea density had such pathology.

Until now, the Nun Study has provided the strongest evidence of a direct link between early mental ability and dementia. But the measure of mental ability used in that study is regarded as only a proxy for intelligence. The Scottish study, in contrast, involves a robust intelligence measure, administered to a very large number of young people for whom information concerning health more than 60 years later is readily available.

"They have a very good measure of intelligence at an early age, and they're showing that there's a relationship between that intelligence and later development of dementia," comments Yaakov Stern, PhD, a neuropsychologist at Columbia University. "Other studies have tried to do similar things, but none have had such a good measure of early mental ability."

Speculative explanations

The Scottish researchers are quick to caution that early intelligence is a relatively small factor in the development of later dementia. Nonetheless, these latest findings renew questions about why the association arises.

One likely explanation, many researchers believe, is that intelligence produces a "cognitive reserve" in the brain, helping people cope for longer with brain changes that would normally cause dementia. Whether this cognitive reserve is literally a collection of surplus brain cells or is the result of more efficient programming--perhaps derived from greater practice in using alternative brain networks for solving problems--remains unknown.

These new findings provide further evidence that Alzheimer's disease may be "a long-term chronic disease that may have underpinnings in early life," suggests Brenda Plassman, PhD, a cognitive neuroscientist at Duke University. "There may be a long silent phase of the disease, when changes are occurring in the brain but there are no obvious cognitive or behavioral symptoms that appear in individuals' ability to function."

If that's the case, Plassman says, "The challenge to the scientific world will be to identify these early pathophysiological changes and to develop treatments to target the early pathology of the disease."

At this stage, however, ideas about what causes the link between early mental ability and risk for dementia are only tentative.

"We hypothesize about what the cognitive reserve might be, but until these questions have been more thoroughly investigated, we're only speculating," says Stern. Whalley, Deary and their colleagues in Scotland are following up on their findings with a broader sample of 1932 test-takers diagnosed with late-onset dementia, moving beyond those living in the Aberdeen area. They also hope to gain a more complete understanding of additional health and behavioral factors throughout the life span that contribute to dementia.

"Right now, at age 11, we have a snapshot," says Deary. "Then we don't have anything else until the end of life." Understanding what happens in between, he suggests, will help clarify what combination of genetic and environmental risk factors might underlie the association between early intelligence and later dementia.