Cognitive impairment and decline in cognitively normal older adults with high amyloid-β: A meta-analysis

AbstractIntroductionThis meta-analysis aimed to characterize the nature and magnitude of amyloid (Aβ)-related cognitive impairment and decline in cognitively normal (CN) older individuals.MethodMEDLINE Ovid was searched from 2012 to June 2016 for studies reporting relationships between cerebrospinal fluid or positron emission tomography (PET) Aβ levels and cognitive impairment (cross-sectional) and decline (longitudinal) in CN older adults. Neuropsychological data were classified into domains of episodic memory, executive function, working memory, processing speed, visuospatial function, semantic memory, and global cognition. Type of Aβ measure, how Aβ burden was analyzed, inclusion of control variables, and clinical criteria used to exclude participants, were considered as moderators. Random-effects models were used for analyses with effect sizes expressed as Cohen's d.ResultsA total of 38 studies met inclusion criteria contributing 30 cross-sectional (N = 5005) and 14 longitudinal (N = 2584) samples. Aβ-related cognitive impairment was observed for global cognition (d = 0.32), visuospatial function (d = 0.25), processing speed (d = 0.18), episodic memory, and executive function (both d's = 0.15), with decline observed for global cognition (d = 0.30), semantic memory (d = 0.28), visuospatial function (d = 0.25), and episodic memory (d = 0.24). Aβ-related impairment was moderated by age, amyloid measure, type of analysis, and inclusion of control variables and decline moderated by amyloid measure, type of analysis, inclusion of control variables, and exclusion criteria used.DiscussionCN older adults with high Aβ show a small general cognitive impairment and small to moderate decline in episodic memory, visuospatial function, semantic memory, and global cognition

Learning deficit in cognitively normal apoe ε4 carriers with low β-amyloid

Introduction: In cognitively normal (CN) adults, increased rates of amyloid beta (Aβ) accumulation can be detected in low Aβ (Aβ–) apolipoprotein E (APOE) ε4 carriers. We aimed to determine the effect of ε4 on the ability to benefit from experience (ie, learn) in Aβ–CNs. Methods: Aβ– CNs(n= 333) underwent episodic memory assessments every 18 months for 108 months. A subset (n = 48) completed the Online Repeatable Cognitive Assessment-Language Learning Test (ORCA-LLT) over 6 days. Results: Aβ– ε4 carriers showed significantly lower rates of improvement on episodic memory over 108 months compared to non-carriers (d = 0.3). Rates of learning on the ORCA-LLT were significantly slower in Aβ– ε4 carriers compared to non-carriers (d = 1.2). Discussion: In Aβ– CNs,ε4 is associated with a reduced ability to benefit from experience. This manifested as reduced practice effects (small to moderate in magnitude) over 108 months on the episodic memory composite, and a learning deficit (large in magnitude) over 6 days on the ORCA-LLT. Alzheimer’s disease (AD)–related cognitive abnormalities can manifest before preclinical AD thresholds

The nature of memory decline and learning dysfunction in preclinical Alzheimer’s disease

© 2019 Jenalle Edwina BakerBackground: In cognitively normal (CN) older adults, abnormal levels of amyloid-beta indicates that the pathophysiological process of Alzheimer’s disease (AD) has begun, although it may be up to 20 years before these individuals meet clinical criteria for dementia Measurement of episodic memory is a cornerstone of neuropsychological assessment in AD, which is consistent with clinicopathological studies showing that the earliest neuronal loss begins within the medial temporal lobe (MTL), a brain region crucial for learning and memory. Neuropsychological compendia detail many tests of episodic memory well validated for use in AD, however, there are fewer standardized neuropsychological tests of learning validated for use in AD. The overarching aim of this thesis was to investigate the relationship between AD pathological markers such as beta-amyloid, and trajectories of neuropsychological performance on memory and learning tasks in CN older adults. Methods: The nature and magnitude of cognitive impairment and decline associated with abnormal levels of amyloid beta in CN older adults was determined via meta-analysis of studies published from 2012 to 2016. Indices of memory and learning on computerised cognitive tests were examined in amyloid negative and amyloid positive CN older adults, with estimates of impairment and decline reported over periods of 18 and 36 months. Finally, a novel web-based learning task was designed and validated to enable the modelling of learning and memory in amyloid negative and amyloid positive CN older adults. Results: Meta-analytic estimates showed significant impairments of small to moderate magnitude (Cohen’s d’s 0.15-0.32) associated with abnormal amyloid in CN older adults in the domains of visuospatial function, processing speed, episodic memory, executive function, and global cognition. Significant decline of small-to-moderate magnitude associated with abnormal amyloid in CN older adults were found for semantic memory, visuospatial function, episodic memory, and global cognition (Cohen’s d’s 0.24-0.30). Rates of learning on the computerised cognitive tests at baseline were equivalent between the amyloid negative and amyloid positive CN groups, while significant differences in longitudinal trajectory of performance was evident. The amyloid negative group showed significant practice effects over time, which were absent in the amyloid positive group, suggesting an inability to learn from repeated exposure. Daily measurement of cognition via a remote, online assessment was sensitive to both age and pathology related changes in ability to learn new information over one week in CN older adults. The magnitude of this effect was very large (Cohen’s d = 1.50), approximately three times larger than current longitudinal estimates of cognitive decline in amyloid positive CN individuals over a year or more. Conclusions: Results indicated that the presence of abnormal amyloid in CN older adults has a significant, negative effect on a range of cognitive domains, although the magnitude of this effect is only small-to-moderate and is largest for memory. Furthermore, amyloid positive CN older adults display aberrant performance on memory and learning tasks over time in the form of a lack of practice effects. This suggests that in amyloid positive CN individuals, the processes by which learning occurs as a function of repeated exposure and presentation to stimuli may be compromised. The large magnitude of impairment in daily learning on the web-based task highlights that the ability to learn new information is dysfunctional in the preclinical stage of AD, and that a sensitive way of measuring cognition in very early disease stages is via repeatable learning assessments. This suggests the need for a paradigm shift towards understanding cognitive dysfunction in preclinical AD as dysfunctional learning, rather than memory

Association of deficits in short-term learning and Aβ and hippocampal volume in cognitively normal adults

© 2020 American Academy of Neurology. OBJECTIVE: To determine the extent to which deficits in learning over 6 days are associated with β-amyloid-positive (Aβ+) and hippocampal volume in cognitively normal (CN) adults. METHODS: Eighty CN older adults who had undergone PET neuroimaging to determine Aβ status (n = 42 Aβ- and 38 Aβ+), MRI to determine hippocampal and ventricular volume, and repeated assessment of memory were recruited from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Participants completed the Online Repeatable Cognitive Assessment-Language Learning Test (ORCA-LLT), which required they learn associations between 50 Chinese characters and their English language equivalents over 6 days. ORCA-LLT assessments were supervised on the first day and were completed remotely online for all remaining days. RESULTS: Learning curves in the Aβ+ CN participants were significantly worse than those in matched Aβ- CN participants, with the magnitude of this difference very large (d [95% confidence interval (CI)] 2.22 [1.64-2.75], p \u3c 0.001), and greater than differences between these groups for memory decline since their enrollment in AIBL (d [95% CI] 0.52 [0.07-0.96], p = 0.021), or memory impairment at their most recent visit. In Aβ+ CN adults, slower rates of learning were associated with smaller hippocampal and larger ventricular volumes. CONCLUSIONS: These results suggest that in CN participants, Aβ+ is associated more strongly with a deficit in learning than any aspect of memory dysfunction. Slower rates of learning in Aβ+ CN participants were associated with hippocampal volume loss. Considered together, these data suggest that the primary cognitive consequence of Aβ+ is a failure to benefit from experience when exposed to novel stimuli, even over very short periods

A blood-based biomarker panel indicates IL-10 and IL-12/23p40 are jointly associated as predictors of β-amyloid load in an AD cohort

Alzheimer's Disease (AD) is the most common form of dementia, characterised by extracellular amyloid deposition as plaques and intracellular neurofibrillary tangles of tau protein. As no current clinical test can diagnose individuals at risk of developing AD, the aim of this project is to evaluate a blood-based biomarker panel to identify individuals who carry this risk. We analysed the levels of 22 biomarkers in clinically classified healthy controls (HC), mild cognitive impairment (MCI) and Alzheimer's participants from the well characterised Australian Imaging, Biomarker and Lifestyle (AIBL) study of aging. High levels of IL-10 and IL-12/23p40 were significantly associated with amyloid deposition in HC, suggesting that these two biomarkers might be used to detect at risk individuals. Additionally, other biomarkers (Eotaxin-3, Leptin, PYY) exhibited altered levels in AD participants possessing the APOE ϵ4 allele. This suggests that the physiology of some potential biomarkers may be altered in AD due to the APOE ϵ4 allele, a major risk factor for AD. Taken together, these data highlight several potential biomarkers that can be used in a blood-based panel to allow earlier identification of individuals at risk of developing AD and/or early stage AD for which current therapies may be more beneficial