Learning deficit in cognitively normal APOE ε4 carriers with LOW ß-amyloid.

INTRODUCTION: In cognitively normal (CN) adults, increased rates of amyloid beta (Aß) accumulation can be detected in low Aß (Aß-) apolipoprotein E (APOE) ε4 carriers. We aimed to determine the effect of ε4 on the ability to benefit from experience (ie, learn) in Aß- CNs. METHODS: Aß- 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: Aß- 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 Aß- ε4 carriers compared to non-carriers (d = 1.2). DISCUSSION: In Aß- 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.

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

OBJECTIVE: To determine the extent to which deficits in learning over 6 days are associated with ß-amyloid-positive (Aß+) and hippocampal volume in cognitively normal (CN) adults. METHODS: Eighty CN older adults who had undergone PET neuroimaging to determine Aß status (n = 42 Aß- and 38 Aß+), 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 Aß+ CN participants were significantly worse than those in matched Aß- CN participants, with the magnitude of this difference very large (d [95% confidence interval (CI)] 2.22 [1.64-2.75], p < 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 Aß+ CN adults, slower rates of learning were associated with smaller hippocampal and larger ventricular volumes. CONCLUSIONS: These results suggest that in CN participants, Aß+ is associated more strongly with a deficit in learning than any aspect of memory dysfunction. Slower rates of learning in Aß+ CN participants were associated with hippocampal volume loss. Considered together, these data suggest that the primary cognitive consequence of Aß+ is a failure to benefit from experience when exposed to novel stimuli, even over very short periods.

Use of an experimental language acquisition paradigm for standardized neuropsychological assessment of learning: A pilot study in young and older adults.

Introduction: Despite the numerous episodic memory tasks used in neuropsychological assessment, relatively few learning tasks are available, with methods lacking the complexity and sophistication to capture very subtle changes in information acquisition.Method: We adapted a previously validated associative learning task for use within an online framework, utilizing real-world stimuli, in which learning of audio-visual pairs of Chinese characters and English words occurs over 5 days. The aim of this study was to validate our adaptation to the task, provide estimates of rates of learning in both young and older adults, as well as provide a methodological framework for further adaptation and development of the paradigm. A total of 30 young adults and 30 older adults completed 5 days of the Chinese Characters Learning Task (CCLT).Results: Results indicated that rates of learning on the adapted task were comparable to the original paradigm and consistent across variations to testing frequency and duration. Our results also indicate the presence of a significant age-related impairment in the rate and accuracy of learning, with young adults aged 18-45 years performing significantly better than older adults aged 65-85 years, that was not due to differences in reaction time.Conclusions: These findings suggest that daily measurement of cognition via an online platform can detect age-related impairments in learning and is therefore applicable for use within the context of age-related disorders of memory and learning.

Visual paired associate learning deficits associated with elevated beta-amyloid in cognitively normal older adults.

OBJECTIVE: Previous studies have shown that paired associate learning (PAL), a type of episodic memory, is impaired in early Alzheimer's disease (AD). Such tasks require that a set of associations (e.g., pattern-location) be learned over several trials, and the objective is to reduce errors with each trial. Currently, the nature and magnitude of impairment and decline on PAL measures in cognitively normal (CN) older adults with elevated levels of beta-amyloid (Aß+) is unknown. METHOD: This study examined PAL errors in Aß+ and Aß - CN older adults, both within a single assessment and over time. Participants (210 Aß - CN, 146 Aß + CN) from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study underwent three assessments over 36-months (baseline, and 18- and 36-month follow-ups) using a computerized paired associate learning task (CPAL). Aß status was determined by positron emission tomography (PET) neuroimaging. RESULTS: No significant group differences in PAL were evident at baseline. Significant groupxtime interactions were observed, with the Aß - CN group, but not the Aß + CN group, evidencing improvement over time (Cohen's d = 0.30 [0.08, 0.51]). Despite this, no group differences were evident at 36-months. CONCLUSIONS: Results suggest that PAL dysfunction is evident over time in Aß + CNs. This indicates a lack of benefit from repeated exposure to the task over time associated with Aß+, which is not the case for Aß - CNs. Further, results suggest that assessing change in Aß+ related cognition over time, rather than at a single assessment, provides greater understanding of dysfunction in early AD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Episodic Memory and Learning Dysfunction Over an 18-Month Period in Preclinical and Prodromal Alzheimer's Disease.

Recent meta-analyses suggest that episodic memory impairment associated with preclinical Alzheimer's disease (AD) equates to 0.15-0.24 standard deviations below that of cognitively healthy older adults. The current study aimed to characterize impairments in verbal acquisition and recall detectable at a single assessment, and investigate how verbal learning and episodic memory deteriorates in preclinical AD. A verbal list-learning task, the International Shopping List Test (ISLT), was administered multiple times over an 18-month period, to three groups of participants: amyloid-beta negative healthy older adults (Aß- CN; n = 50); Aß+ positive healthy older adults (preclinical AD; n = 25); and Aß+ positive individuals diagnosed with mild cognitive impairment (prodromal AD; n = 22). At baseline, there was no significant difference between the preclinical AD and control groups rate of acquisition, or total and delayed recall, however all indices were impaired in prodromal AD. Performance on ISLT total score improved in the control group over the 18-month period, but showed a moderate magnitude decline in the preclinical AD group (Cohen's d = - 0.63, [- 1.12, - 0.14]) and the prodromal AD group (Cohen's d = - 0.36, [- 0.94, 0.22]). No significant impairment in acquisition associated with preclinical AD was seen at baseline. Individuals with preclinical AD showed a significantly different performance on the ISLT total score over an 18-month period, compared to those without abnormal Aß. Individuals with prodromal AD showed substantial impairment on the ISLT at baseline and declined to a greater extent over time.

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

INTRODUCTION: This meta-analysis aimed to characterize the nature and magnitude of amyloid (Aß)-related cognitive impairment and decline in cognitively normal (CN) older individuals. METHOD: MEDLINE Ovid was searched from 2012 to June 2016 for studies reporting relationships between cerebrospinal fluid or positron emission tomography (PET) Aß 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 Aß measure, how Aß 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. RESULTS: A total of 38 studies met inclusion criteria contributing 30 cross-sectional (N = 5005) and 14 longitudinal (N = 2584) samples. Aß-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). Aß-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. DISCUSSION: CN older adults with high Aß show a small general cognitive impairment and small to moderate decline in episodic memory, visuospatial function, semantic memory, and global cognition.