14 November 2008. Just as cash in a rainy day fund can help people weather future economic downturns, extra years of school seem to have a protective effect in Alzheimer disease. This theory—that education builds “cognitive reserve,” which guards against later dementia amid buildup of brain amyloid—now draws support from the largest cohort study to detect AD pathology in living people. Exactly how the more highly educated cope as their brains fill with plaques remains unclear. An intriguing clue comes from another study in which researchers use functional magnetic resonance imaging (fMRI) to reveal neurophysiological differences that might explain in part why some folks have better memory even as young adults. Whether genetics, education, or other factors influence these brain features is not yet known, but the findings could help researchers develop measures that portend future cognitive impairment.
Data linking formal education with enhanced ability to withstand the burden of AD pathology has come primarily from studies assessing brain plaques and tangles at autopsy (e.g., Bennett et al., 2003; Roe et al., 2008). Such investigations are limited by variable lag times between the neuropsychological evaluation during a person’s life and the pathological evaluation after death. This gap closed with the development of positron emission tomography (PET) radiotracers (e.g., Pittsburgh Compound B [PIB]) that detect amyloid in living tissue. Earlier this year, researchers at the University of Turku in Finland published the first, small study using live brain imaging to demonstrate the education effect in 25 patients with mild AD (Kemppainen et al., 2008). Led by Juha Rinne, these investigators found that the most educated among their group of equally cognitively impaired research participants had more amyloid pathology than the least educated. A new study, published in this month’s Archives of Neurology by John Morris and colleagues at Washington University School of Medicine, St. Louis, Missouri, reports a similar trend in 198 seniors (161 non-demented, 37 with mild AD). “We found that for people who did not have Alzheimer’s plaques in the brain, there was no association [between education and cognitive test performance],” first author Catherine Roe told ARF. “But for people who did have amyloid plaques, they showed fewer dementia symptoms the more years of education they had.”
Drawn from community volunteers in ongoing memory and aging studies at the university, participants underwent all clinical and cognitive tests over a period of several weeks, with PIB-PET scans being done on average within seven to eight months. Fifty-nine people came up PIB-positive, the remaining 139 PIB-negative. This study differs from the Finnish study in how it was done, though not in the overall finding. The Finnish work related PIB load to education in equally impaired people; the St. Louis study related performance to education in subjects with mild AD or no dementia. On three measures of global cognitive function (Clinical Dementia Rating Sum of Boxes, Mini-Mental State Examination, Short Blessed Test), the WashU team found no influence of formal schooling on test performance among PIB-negative individuals. But in the PIB-positive group, the education effect jumped out: those with more than 16 years of education had the highest mean cognitive scores, followed by the group with 13-16 years and then those with 12 or fewer years of school. Roe and colleagues saw this in all three outcome measures, and got similar results when PIB uptake was considered as a continuous variable (as opposed to the dichotomous PIB-positive and PIB-negative categories used in the main analysis).
“It's a very nice study,” said Bill Klunk of the University of Pittsburgh School of Medicine. “And it follows a very nice study by the Finnish group.” Because PET-PIB imaging is costly and technology-intensive, “no one group can go and study hundreds and hundreds of subjects,” noted Klunk, who co-developed PIB with radiochemist Chester Mathis, also at Pittsburgh. “Everybody is putting pieces of preliminary data into the puzzle, and we will see if it holds up across a bunch of studies.”
Interestingly, no education effect showed up in a small PIB-PET study that found significant amyloid deposition in about a fifth of cognitively normal seniors. Klunk and colleagues published this study (Aizenstein et al., 2008) in the same current issue of the Archives of Neurology after having presented some of its data this past April at the Human Amyloid Imaging conference in Chicago (see ARF related news story). Among the nine of 43 healthy volunteers who came up amyloid-positive in this group, education appeared not to affect performance on cognitive tests. In the Washington University investigation, Roe and colleagues picked up an education effect in a PIB-positive group of 59 subjects, more than half of whom presumably had mild AD. By pooling non-demented and AD patients, Klunk said, the data could not reveal whether the presence or absence of dementia contributed to the education phenomenon.
Nevertheless, this PIB-PET study clearly supports the idea that more education helps people sustain higher brain Aβ loads before succumbing to AD. Similar support for the cognitive reserve theory came from a 21 October Neurology paper, in which Italian researchers assessed neurodegeneration not by amyloid imaging but by using fluorodeoxyglucose (FDG)-PET to measure brain glucose activity in 458 people (242 with probable AD, 72 with amnestic mild cognitive impairment (aMCI), 144 healthy controls). Among those with probable AD and those with amnestic MCI that progressed to AD during the study, Daniela Perani and colleagues at Vita Salute San Raffaele University in Milan, found that those with higher education and mentally demanding jobs had lower glucose metabolism in their posterior temporoparietal cortex and precuneus given a comparable cognitive impairment (Garibotto et al., 2008). In other words, the extra mental stimulation from school and vocation seemed to have helped delay onset of cognitive symptoms in people with AD-related changes in the brain.
These studies do not address what it is that might mediate the protective effect of education in seniors with amyloid and other tissue damage in their brain. (For a review of possible mechanisms of cognitive reserve, see Stern, 2006). “We don't know if there's a causal relationship between education and being able to withstand more AD pathology,” Roe said. “It could be some third variable that we're not measuring that causes you to stay in school longer and also causes you to do better on these cognitive tests.”
For instance, what if certain people’s brains are wired to remember things more efficiently? This possibility might not be so far-fetched in light of a paper published online on 10 November in PNAS Early Edition. Led by William Kelley of Dartmouth College, Hanover, New Hampshire, researchers used fMRI to measure brain activity in healthy young adults taking computerized tests that alternate between simple cognitive tasks and rest periods. They found that people with greater task-induced deactivation of blood-oxygen-level dependent (BOLD) activity in the medial temporal lobe (MTL) performed better on memory tests given during a separate visit.
AD researchers should perk up at the mention of the medial temporal lobe, as it houses several brain areas affected earliest in AD, such as the hippocampus and entorhinal cortex (see ARF related news story). The MTL forms a large part of the “default network”—brain areas that rev up when the mind is at rest and tone down during focused mental tasks. Resting-state activity is reduced in the MTL of AD patients (see ARF related news story) and of seniors with memory decline (Small et al., 2000; Small et al., 2002). Earlier this year, researchers reported that memory in older adults hinges upon their ability to turn down activity in the medial parietal area while firing up the hippocampus (see ARF related news story). This series of findings in older people led first author Gagan Wig to consider whether brain deactivation differences might correlate with memory ability at younger ages.
To address this question, Wig and colleagues recruited 45 healthy volunteers, mostly college students (mean age 20 years), from the Dartmouth area. Each participant underwent two fMRI scans coinciding with cognitive batteries involving different task-rest transitions. In the first test, subjects spent 30 seconds making odd/even judgments on a random set of numbers, followed by 30 seconds of rest, and so forth. Their memory performance correlated with resting-state BOLD activity in two MTL regions—one in the left hippocampus, another in the right hippocampus extending into the right parahippocampal gyrus. Those who did better on the memory tests were the people who deactivated their MTL most strongly during the task periods of the fMRI procedure.
To see if the results would hold across a modified experimental design, the subjects took a second test. This time, the task—pressing buttons to indicate when a flickering checkerboard comes on or off—was alternated between variable, shorter (0-10 sec.) rest periods. “The actual task was unimportant,” said Wig, now at Harvard University. “We just wanted to get that contrast between task and rest.” In the second test, resting activity in the right MTL once again correlated with memory scores. Effects in the left MTL did not replicate, but Wig and colleagues found correlations with other nearby brain areas, suggesting that the relationships on both sides of the MTL were meaningful, he told ARF.
As for why certain people had greater task-induced deactivation in the MTL, the authors could only speculate. “I don't think these people were doing anything intentionally different in the scanner. I don't think they were sitting there actively memorizing anything,” Wig said, noting studies showing that active encoding of recent experiences helps later recollection (e.g., Otten et al., 2006). One possibility, the authors suggest, is that the BOLD signal variability could reflect inherent differences in neuronal firing rates or metabolic activity that do not result from conscious information processing. Supporting the notion that such differences may be inborn, a recent investigation unveiled a set of genetic variants that boost memory and hippocampal activity in people (see ARF related news story).
Putting his work into context with the cognitive reserve study, Wig said, “The Morris paper is demonstrating how environmental factors might influence one's ability to sustain pathological burden, whereas we might be coming at it from the other end of the spectrum. We're saying it might be the case that certain individuals have tools that allow them to engage brain regions that are important for memory at a higher level.” Given that neurophysiological differences showed up in his study at such an early age, Wig said, “If one were to go ahead and follow these individuals into aging, you might potentially have a metric by which to predict who will suffer from mnemonic deficits.” In future studies, Wig and colleagues hope to test whether the correlation between memory and MTL activity holds up in older people (age 65 and up) lacking overt memory problems.—Esther Landhuis.
Roe CM, Mintun MA, D’Angelo G, Xiong C, Grant EA, Morris JC. Alzheimer Disease and Cognitive Reserve: Variation of Education Effect With Carbon 11–Labeled Pittsburgh Compound B Uptake. Arch Neurol. Nov 2008;65(11):1467-1471. Abstract
Wig GS. Grafton ST, Demos KE, Wolford GL, Petersen SE, Kelley WM. Medial temporal lobe BOLD activity at rest predicts individual differences in memory ability in healthy young adults. PNAS Early Edition. 2008 Nov 10. Abstract
Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, Ziolko SK, James JA, Snitz BE, Houck PR, Bi W, Cohen AD, Lopresti BJ, DeKosky ST, Halligan EM, Klunk WE. Frequent Amyloid Deposition Without Significant Cognitive Impairment Among the Elderly. Arch Neurol. Nov 2008; 65: 1509-1517. Abstract
Kemppainen NM, Aalto S, Karrasch M, Någren K, Savisto N, Oikonen V, Viitanen M, Parkkola R, Rinne JO. Cognitive reserve hypothesis: Pittsburgh Compound B and fluorodeoxyglucose positron emission tomography in relation to education in mild Alzheimer's disease. Ann Neurol. 2008 Jan;63(1):112-8.
Garibotto V, Borroni B, Kalbe E, Herholz K, Salmon E, Holtoff V, Sorbi S, Cappa SF, Padovani A, Fazio F, Perani D. Education and occupation as proxies for reserve in aMCI converters and AD: FDG-PET evidence. Neurology. 2008 Oct 21;71(17):1342-9. Abstract