APOE4, the strongest genetic risk factor for sporadic Alzheimer’s disease, has been tied to slightly better memory in the young. Now, researchers led by Sebastian Crutch and Jonathan Schott, University College London, find a similar benefit in older people. In the October 7 Nature Aging, they reported that cognitively intact 70-year-olds carrying the APOE4 allele edged out noncarriers on a short-term visual memory task. The advantage was slight, but showed up even in people who had brain amyloid. “It was surprising that the E4 memory advantage endured in people with Aβ,” Nahid Zokaei, University of Oxford, U.K., wrote to Alzforum.
- APOE4 carriers remembered objects and their whereabouts better than noncarriers.
- Carriers who had brain amyloid maintained this slight edge.
- This advantage may explain why APOE4 persists in the genome despite increasing a person's risk of AD.
Renaud La Joie and Marianne Chapleau, University of California, San Francisco, went one further. “That they could see a cognitive benefit from APOE4 in older people is very surprising,” they said.
APOE4 increases the risk for amyloidosis and dementia (Apr 2009 news; June 2011 news; Morris et al., 2010). Against this uncontested backdrop, some controversial research over the years has been suggesting that throughout early to mid-adulthood APOE4 carriers have a slight cognitive advantage, which then begins to wane (Rusted et al., 2013; Zink et al., 2019; Jochemsen et al., 2011).
To find out, first author Kirsty Lu and colleagues correlated APOE genotype, amyloid PET, structural MRI, and cognitive test data from a subset of the British 1946 Birth Cohort. These volunteers were all born during the same week after World War II and researchers have been following them ever since. Of the 398 cognitively normal participants selected for the present analysis, 30 percent carried an APOE4 allele. One-third of them also had brain amyloid, compared to just 10 percent of noncarriers.
The researchers gauged visual working memory by asking participants to recall an object they had seen on a computer a few seconds earlier, and to remember where it had been on the screen (see image below). Each volunteer repeated this task 24 times. Lu and colleagues adjusted raw data for confounding factors, including hippocampal and white-matter volume, and childhood cognitive abilities. Jennifer Rusted, University of Sussex, U.K., noted that most studies do not have this level of demographic detail, nor the statistical power to isolate multiple confounding factors that influence a specific measure of cognition.
What Was Where? In this test, participants had to recall which object they had seen and where it had been on the screen. The test measures the ability to identify things and place them in space. [Courtesy of Lu et al., Nature Aging, 2021.]
As expected, amyloid-positive volunteers did worse at object recognition, picking the one they had not seen 19 percent more often than did the amyloid-negative group, though both similarly misremembered where the objects had been. In contrast, APOE4 carriers did better than noncarriers. They were 14 percent less likely to recall the wrong object, and dragged the symbols 7 percent closer to their original location, even when the object they selected was the wrong one.
What about in people who harbored both APOE4 and plaques? When push came to shove, E4 prevailed. Among amyloid-positives, APOE carriers still recalled an object’s location more precisely than their non-E4 counterparts (see image below). I certainly thought the impact of the amyloid would swamp the more subtle E4 effect,” Crutch admitted, and Schott agreed. “This study suggests E4-associated compensation may extend into older adulthood and, in high-functioning individuals, could offset the negative impact of low-level Aβ deposits,” wrote Rusted.
The E4 Effect. When recalling which object they had seen before (left), and where it was (right), APOE4 carriers (red) made fewer mistakes than noncarriers (blue), even if they had amyloid in the brain. This effect was more pronounced in people who had plaques (right columns). [Courtesy of Lu et al., Nature Aging, 2021.]
Jacob Raber, Oregon Health & Science University, Portland, emphasized that the E4 enhancement is specific for short-term memory—the allele impairs long-term memory in healthy older people (Zokaei et al., 2019).
Ralph Martins, Edith Cowan University, Joondalup, Australia, cautiously interpreted the results. He noted that the shortened version of the “What was where?” test, which usually involves more than 100 iterations rather than the 24 used here, has not been clinically validated. However, La Joie and Chapleau pointed out that people carrying E4 also performed better on classical verbal memory tests. “Carriers did not just do better on one test by chance, there was a pattern in this cohort,” La Joie told Alzforum.
La Joie and Chapleau were curious how long the cognitive benefits last as E4 carriers age. Rusted said that a full model must include how tangles fit into the E4-Aβ-cognition puzzle. To this end, Schott said that they will continue following up with this cohort subset, collecting tau PET scans on amyloid-positive participants. About one-third of volunteers have given cerebrospinal fluid, in which Schott and colleagues plan to measure phospho-tau species and neurofilament light.
On a final note, the authors suggest that ApoE’s slight boost to working memory may explain why it has persisted in the human gene pool despite being a major risk factor for disease—an example of “antagonistic pleiotropy.” Other commentators agreed. Neill Graff-Radford, Mayo Clinic, Jacksonville, wrote, “This excellent paper convincingly illustrated antagonist pleiotropy for ApoE4 in aging.”—Chelsea Weidman Burke
- More ApoE4 Means More Amyloid in Brains of Middle-Aged
- Paper Alert: ApoE Affects Alzheimer's Risk via Aβ Clearance
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