Mounting evidence points to Aβ accumulation as a harbinger of Alzheimer’s disease, but can subtle slippage on memory tests also raise a red flag? Not according to a massive meta-analysis of cross-sectional studies. In the January issue of JAMA Psychiatry, a large collaboration of international research groups, led by Pieter Jelle Visser at Maastricht University in the Netherlands, reported that among cognitively normal people, or people with mild cognitive impairment (MCI), those with brain Aβ accumulation were more likely to perform poorly on memory tests. However, some Aβ-negative people also faltered on the tests, making the tests a poor screening measure for preclinical AD. Even so, the researchers used the data to estimate a 10–15 year lag between Aβ accumulation and the first signs of fuzzy memory, and this many years again between early memory loss and AD dementia, in keeping with previous data.
- In large cross-sectional meta-analysis of cognitively normal and mildly impaired people, memory was likely to slip when Aβ accumulated.
- By itself, low memory in cognitively normal people did not predict amyloid accumulation, and was useless for trial enrollment.
- The data confirm a 10–15 year lag between Aβ positivity and low memory scores, and 10–15 years between poor memory and AD.
While multiple cross-sectional and longitudinal studies have revealed a strong correlation between Aβ accumulation and future development of AD, the relationship between Aβ and early memory problems in otherwise cognitively normal people has proven trickier to demonstrate. Cross-sectional studies have reached contrasting conclusions, with some finding a link but others coming up short (Sperling et al., 2013; Petersen et al., 2016; Rowe et al., 2010). However, a recent longitudinal study reported that having Aβ accumulation at baseline significantly boosted a person’s chance of showing signs of memory loss within a decade (Jun 2017 news).
In an effort to settle the question using as much data as possible, first author Willemijn Jansen and colleagues looked to the Amyloid Biomarker Study, a meta-analysis of cross-sectional data on biomarkers, cognition, and other metrics from 53 studies. An initial report from the project predicted a 20–30 year lag between testing positive for elevated Aβ—as assessed by thresholds set for PET scans or CSF Aβ42 concentration in each study—and reaching symptom severity that meets the definition of AD dementia (May 2015 news).
For the current study, the researchers investigated the connection between testing positive for Aβ accumulation in the brain and low memory scores, as well as the contributions of age, ApoE4 status, and educational attainment to memory performance. Verbal word learning tests were used to assess episodic memory, though the exact tests differed between individual studies used in the meta-analysis. The researchers used z-scores to normalize the data between studies, and categorized people in the lowest 10th percentile as having “low memory scores.”
Among 2,908 cognitively normal people included in the meta-analysis, low memory scores were more frequent in people with Aβ accumulation, but only in those 70 years or older. The correlation strengthened with age, and by 80 years, cognitively normal people with elevated Aβ were almost twice as likely to perform poorly on memory tests. A higher proportion of people with MCI had poor memory compared to cognitively normal people at any age, and Aβ also played a hand in this group. Among 4,133 people with MCI, Aβ positivity correlated with low memory scores, but the strength of this association decreased with advancing age.
Why would age have the opposite effect in cognitively normal versus cognitively impaired people? The researchers speculate that as cognitively normal people age, increasing amounts of Aβ and/or other comorbid pathologies, along with increased vulnerability to Aβ, bring on cognitive decline. In people with MCI, those who do not have brain amyloid are likely to suffer from a non-AD pathology as they age. As these non-AD pathologies ramp up, the incidence of low memory scores among Aβ-positive and -negative groups converges, the researchers proposed.
Might other factors, such as sex, ApoE4, and educational attainment, sway the relationship between Aβ and low memory scores? No, it turns out. The researchers found that associations between Aβ positivity and the incidence of low memory scores held steady regardless of any of these. However, each factor associated with low memory independently of Aβ—being male, having an ApoE4 allele, or low educational attainment—all increased the odds of poor memory scores by 8 percent.
In their previous study, the researchers reported that an age-related rise in the prevalence of AD dementia occurred 20–30 years after a similar rise in cases of elevated Aβ. In the current study, they placed low memory scores at roughly the halfway point along this disease trajectory, cropping up about 10–15 years after Aβ turned abnormal, but 10–15 years before AD dementia set in (see image below).
Ultimately, the researchers found that while Aβ positivity correlates with low memory scores, the latter could not be used to predict the former: Low scores on memory tests in cognitively normal people or those with MCI did not add to the estimation of Aβ positivity above what could already be surmised by age and ApoE4 status.
The data confirms consistent trends in the literature, commented co-author William Jagust of the University of California, Berkeley. “There is a relationship between Aβ and memory, but this relationship is relatively weak. For this reason, many smaller studies have conflicted about this relationship, although larger studies and meta-analyses have confirmed a small association,” he said. “The size of this association makes memory an unreliable screening method for the detection of amyloid,” he added.
Rachel Buckley of Massachusetts General Hospital in Boston also commended the study for its size. “The strength of this type of study is the ability to have the statistical power to detect relatively small effects, which is arguably the case with the cross-sectional relationship between amyloid and cognition,” she wrote to Alzforum. While Buckley found the lack of predictive power of low memory scores on amyloid positivity disheartening, she noted that the very nature of a meta-analysis limits its conclusions. For example, different memory tests were used across the studies, whereas performance on a single task might better predict Aβ. “More sophisticated data harmonization techniques will need to be applied in order to better align cognitive test performance across studies,” she added.—Jessica Shugart
- At Risk, or Already Alzheimer’s? Elevated Aβ Predicts Cognitive Decline
- Meta-Analyses Deliver Most Definitive Data Yet on Amyloid Prevalence
- Sperling RA, Johnson KA, Doraiswamy PM, Reiman EM, Fleisher AS, Sabbagh MN, Sadowsky CH, Carpenter A, Davis MD, Lu M, Flitter M, Joshi AD, Clark CM, Grundman M, Mintun MA, Skovronsky DM, Pontecorvo MJ, . Amyloid deposition detected with florbetapir F 18 ((18)F-AV-45) is related to lower episodic memory performance in clinically normal older individuals. Neurobiol Aging. 2013 Mar;34(3):822-31. PubMed.
- Petersen RC, Wiste HJ, Weigand SD, Rocca WA, Roberts RO, Mielke MM, Lowe VJ, Knopman DS, Pankratz VS, Machulda MM, Geda YE, Jack CR Jr. Association of Elevated Amyloid Levels With Cognition and Biomarkers in Cognitively Normal People From the Community. JAMA Neurol. 2016 Jan;73(1):85-92. PubMed.
- Rowe CC, Ellis KA, Rimajova M, Bourgeat P, Pike KE, Jones G, Fripp J, Tochon-Danguy H, Morandeau L, O'Keefe G, Price R, Raniga P, Robins P, Acosta O, Lenzo N, Szoeke C, Salvado O, Head R, Martins R, Masters CL, Ames D, Villemagne VL. Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol Aging. 2010 Aug;31(8):1275-83. PubMed.
- Jack CR Jr, Therneau TM, Wiste HJ, Weigand SD, Knopman DS, Lowe VJ, Mielke MM, Vemuri P, Roberts RO, Machulda MM, Senjem ML, Gunter JL, Rocca WA, Petersen RC. Transition rates between amyloid and neurodegeneration biomarker states and to dementia: a population-based, longitudinal cohort study. Lancet Neurol. 2016 Jan;15(1):56-64. Epub 2015 Nov 18 PubMed.
- Insel PS, Donohue MC, Mackin RS, Aisen PS, Hansson O, Weiner MW, Mattsson N, Alzheimer's Disease Neuroimaging Initiative. Cognitive and functional changes associated with Aβ pathology and the progression to mild cognitive impairment. Neurobiol Aging. 2016 Dec;48:172-181. Epub 2016 Aug 26 PubMed.
- Jansen WJ, Ossenkoppele R, Tijms BM, Fagan AM, Hansson O, Klunk WE, van der Flier WM, Villemagne VL, Frisoni GB, Fleisher AS, Lleó A, Mintun MA, Wallin A, Engelborghs S, Na DL, Chételat G, Molinuevo JL, Landau SM, Mattsson N, Kornhuber J, Sabri O, Rowe CC, Parnetti L, Popp J, Fladby T, Jagust WJ, Aalten P, Lee DY, Vandenberghe R, Resende de Oliveira C, Kapaki E, Froelich L, Ivanoiu A, Gabryelewicz T, Verbeek MM, Sanchez-Juan P, Hildebrandt H, Camus V, Zboch M, Brooks DJ, Drzezga A, Rinne JO, Newberg A, de Mendonça A, Sarazin M, Rabinovici GD, Madsen K, Kramberger MG, Nordberg A, Mok V, Mroczko B, Wolk DA, Meyer PT, Tsolaki M, Scheltens P, Verhey FR, Visser PJ, Amyloid Biomarker Study Group, Aarsland D, Alcolea D, Alexander M, Almdahl IS, Arnold SE, Baldeiras I, Barthel H, van Berckel BN, Blennow K, van Buchem MA, Cavedo E, Chen K, Chipi E, Cohen AD, Förster S, Fortea J, Frederiksen KS, Freund-Levi Y, Gkatzima O, Gordon MF, Grimmer T, Hampel H, Hausner L, Hellwig S, Herukka SK, Johannsen P, Klimkowicz-Mrowiec A, Köhler S, Koglin N, van Laere K, de Leon M, Lisetti V, Maier W, Marcusson J, Meulenbroek O, Møllergård HM, Morris JC, Nordlund A, Novak GP, Paraskevas GP, Perera G, Peters O, Ramakers IH, Rami L, Rodríguez-Rodríguez E, Roe CM, Rot U, Rüther E, Santana I, Schröder J, Seo SW, Soininen H, Spiru L, Stomrud E, Struyfs H, Teunissen CE, Vos SJ, van Waalwijk van Doorn LJ, Waldemar G, Wallin ÅK, Wiltfang J, Zetterberg H. Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia. JAMA Psychiatry. 2018 Jan 1;75(1):84-95. PubMed.