As Aβ accumulates in a person’s brain during the long preclinical stage of Alzheimer’s disease, deficits in learning emerge prior to impairments in episodic memory, according to a study published in Neurology on September 4. Cognitively normal people who tested positive for brain amyloid learned fewer Chinese characters over a six-day period than their amyloid-negative peers. Their learning deficit was more pronounced than any form of memory impairment, and it correlated with smaller hippocampi. The researchers, led by Yen Ying Lim at the Florey Institute and Paul Maruff of Cogstate, Ltd., both in Melbourne, Australia, suggest that learning tests could be used to more sensitively detect emerging cognitive deficits in the earliest stages of the disease.
- People with brain amyloid learned Chinese characters more slowly than people without.
- This deficit was greater than any memory impairment.
- It correlated with less hippocampal volume.
In public parlance, memory loss has become almost synonymous with AD. Alas, during the disease’s preclinical stage—which scientists are trying to target for intervention— memory loss creeps up slowly and varies from person to person (Baker et al., 2017; Feb 2018 news; Aug 2018 news). Hence trials enrolling people at those stages struggle to assess clinical efficacy of the drug under investigation. New tests are sorely needed.
In the Australian Imaging, Biomarker, and Lifestyle study, Lim, Maruff, and colleagues had previously reported that cognitively normal, Aβ-positive people performed as well on tests of episodic memory as their Aβ-negative peers (Baker et al., 2019). Curiously, though, after several years of repeated testing, Aβ-positives had not improved, while Aβ-negatives benefitted from practice. Studies of other cohorts also reported this lack of a practice effect in preclinical AD (Hassenstab et al., 2015).
Suspecting that a learning deficit was at play here, the scientists devised a means to tease it out within days, rather than years. Called Online Repeated Cognitive Assessment, aka ORCA, and taken on a home computer, their test taught participants the meaning of 50 Chinese characters (see image below). In daily half-hour sessions, participants viewed two training blocks of 200 Chinese characters paired with a spoken English noun. For each pair, they were asked to guess if the translation was correct or incorrect, but received no feedback on their answers. The ratio of correct to incorrect pairings presented to the participants increased from block to block. On day 1, participants saw two correct pairings and two incorrect pairings. Incorrect pairings were not repeated to avoid off-target learning. On day 2, the correct-to-incorrect pairing ratio doubled, on day three it tripled, etc., so that by day six, there were 24 correct and only two incorrect pairings. In this way, the volunteers increasingly connected each character with its proper meaning. No one in the study previously knew Chinese characters, Maruff said, so at the start of the first day they were blindly guessing, and by the end of the first session, they had started to learn. ORCA was modeled after a previously developed learning test that had used a “nonsense language,” instead of Chinese characters, Maruff said (Breitenstein and Knecht, 2002). The benefit of using Chinese characters instead is that participants felt they were learning something meaningful.
Familiar Words, Novel Characters. Chinese characters paired with spoken English words were presented to participants, who were asked to guess whether each translation was correct. They received no feedback, but each day the number of correct pairings increased, such that volunteers began to recognize correct translations by experience. [Courtesy of Lim et al., Neurology, 2020.]
At AAIC in 2018, co-author Jenalle Baker had presented preliminary findings of this test from a cohort of 50 cognitively normal participants, including 20 whose amyloid-PET scans were positive, and 30 whose scans were negative. She reported that while both groups learned to associate characters with spoken words to some extent, the amyloid-positive volunteers made more mistakes already by the second session and the gap widened over the six-day period (Aug 2018 conference news).
The new study tested 80 cognitively normal participants—42 amyloid-negative, 38 -positive—and included other cognitive and neuroimaging measures. As had been seen in the previous cohort, amyloid-negative participants learned the meaning of Chinese characters faster, with accuracy differences between the groups emerging on day one and growing in each session. The two groups’ average rate of learning over the entire six days differed by more than two standard deviations; as gauged by a Cohen’s d value, this came to an effect size of 2.2.
In contrast, the groups barely differed on their most recent scores on any test of episodic memory, as measured using single and composite scores from the California Verbal Learning Test, Second Edition (CVLT-II), and the Logical Memory (LM) subtest of the Wechsler Memory Scale–Revised (WMS-R). Even though memory scores in the amyloid-positive group declined more than in the amyloid-negative over the previous six years, the Cohen’s d effect size of 0.52 was four times smaller than that of the six-day learning deficit.
Among Aβ-positive participants only, those who learned the Chinese characters more slowly had smaller hippocampi and larger brain ventricles, suggesting less gray-matter volume.
Michael Weiner of the University of California, San Francisco, called the study highly innovative. He called the effect size of the learning deficit substantial. “It will be very interesting to determine the ability of such tests to detect longitudinal cognitive decline,” he wrote, noting that the results need to be replicated.
Nikki Stricker of the Mayo Clinic in Rochester, Minnesota, believes the study highlights the importance of learning deficits in preclinical Alzheimer’s disease and their potential in clinical testing. “The large effect size elicited over a short period of time … illustrates that a well-designed learning paradigm can outperform traditional measures of delayed recall, and brings to light the important role that sensitive cognitive measures play in the early detection of Alzheimer’s disease,” Stricker noted.
The findings mesh with studies led by Kevin Duff at the University of Utah in Salt Lake City, which found that weaker practice effects on memory tests taken over one week correlated with amyloid burden (Duff et al., 2014; Duff et al., 2017). “Taken together, these two sets of results indicate that more amyloid in the brain leads to a failure to benefit from experience with novel stimuli, even over days to weeks,” commented Duff. “Ultimately, deficits in learning, especially repeated exposure to novel information, may be one of the earliest harbingers of eventual Alzheimer’s disease.”
Ironically, scientists view practice effects as a fly in the ointment in clinical studies that track cognition. They have gone to great lengths to minimize them by changing the material between tests. Unexpected practice effects have shown up in the DIAN trial of solanezumab and gantenerumab and the Banner/Novartis trial of umibecestat (Apr 2020 conference news; Aug 2020 conference news). “The findings from Lim et al. suggest that learning rates could instead be considered to screen for early cognitive impairment or even future cognitive decline,” wrote Oskar Hansson and David Berron of Lund University, Sweden.
Maruff told Alzforum that the diminished ability to acquire new information on the basis of experience echoes complaints from patients. “They notice something is wrong when they try to learn something new, yet score normally on memory tests,” Maruff said. While ORCA has a memory dimension, the researchers skewed it toward acquisition of new information by including large amounts of it—too much to learn in a single sitting.
This six-day test is not ready for use in clinical trials, Maruff said. The researchers are exploring different ways to implement it. It could be employed at different times throughout a study, each time using new Chinese characters, or some other form of novel information. Alternatively, the researchers could spread out the single-day sessions—one day spaced every two weeks, for example—then compare learning curves of different groups throughout the trial. Cogstate sells computer-based cognitive assessment tools for clinical trial and research applications.
“Tools such as the ORCA-LLT have the advantage of being scalable and simple to administer, making them good candidate tools for population-level screening and longitudinal monitoring,” commented Michael Gold of AbbVie in Chicago. “One can only hope to see rapid independent replication of this paper in a larger cohort and data looking at the effects of APOE and tau on learning efficiency.”
Michelle Farrell of Massachusetts General Hospital in Charlestown wrote that further pinpointing when the learning deficit arises in preclinical AD, and whether it is driven by amyloid, tau, or both pathologies, will help researchers decide when and if they should shift away from traditional measures of memory recall to learning tests instead.
The findings also raise the question of how amyloid deposition interferes with brain networks involved in learning, Hansson and Berron added. “This is especially true for the posterior-medial recollection network, which is particularly prone to early deposition of Aβ plaques,” they wrote. Colin Masters of the Florey Institute, a co-author on the paper, agreed that in addition to accumulating amyloid early in AD, the posterior parietal cortex/precuneus is critical for learning (Brodt et al., 2018). Aβ-inflicted synaptic damage in that region could lead to learning defects, and also disrupt connections with the medial/temporal lobe, ultimately manifesting in more overt memory impairments as preclinical AD progresses, he wrote.—Jessica Shugart
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- Umibecestat-Driven Cognitive Decline Is Reversible
- Baker JE, Lim YY, Pietrzak RH, Hassenstab J, Snyder PJ, Masters CL, Maruff P. Cognitive impairment and decline in cognitively normal older adults with high amyloid-β: A meta-analysis. Alzheimers Dement (Amst). 2017;6:108-121. Epub 2016 Oct 18 PubMed.
- Baker JE, Pietrzak RH, Laws SM, Ames D, Villemagne VL, Rowe CC, Masters CL, Maruff P, Lim YY. Visual paired associate learning deficits associated with elevated beta-amyloid in cognitively normal older adults. Neuropsychology. 2019 Oct;33(7):964-974. Epub 2019 Aug 1 PubMed.
- Hassenstab J, Ruvolo D, Jasielec M, Xiong C, Grant E, Morris JC. Absence of practice effects in preclinical Alzheimer's disease. Neuropsychology. 2015 Nov;29(6):940-8. Epub 2015 May 25 PubMed.
- Breitenstein C, Knecht S. Development and validation of a language learning model for behavioral and functional-imaging studies. J Neurosci Methods. 2002 Mar 15;114(2):173-9. PubMed.
- Duff K, Foster NL, Hoffman JM. Practice effects and amyloid deposition: preliminary data on a method for enriching samples in clinical trials. Alzheimer Dis Assoc Disord. 2014 Jul-Sep;28(3):247-52. PubMed.
- Duff K, Hammers DB, Dalley BC, Suhrie KR, Atkinson TJ, Rasmussen KM, Horn KP, Beardmore BE, Burrell LD, Foster NL, Hoffman JM. Short-Term Practice Effects and Amyloid Deposition: Providing Information Above and Beyond Baseline Cognition. J Prev Alzheimers Dis. 2017;4(2):87-92. PubMed.
- Brodt S, Gais S, Beck J, Erb M, Scheffler K, Schönauer M. Fast track to the neocortex: A memory engram in the posterior parietal cortex. Science. 2018 Nov 30;362(6418):1045-1048. PubMed.
No Available Further Reading
- Lim YY, Baker JE, Bruns L Jr, Mills A, Fowler C, Fripp J, Rainey-Smith SR, Ames D, Masters CL, Maruff P. Association of deficits in short-term learning and Aβ and hippocampal volume in cognitively normal adults. Neurology. 2020 Nov 3;95(18):e2577-e2585. Epub 2020 Sep 4 PubMed.