Journal of Alzheimer's Disease - Volume 94, issue 4

Authors: Belliart-Guérin, Ghislain | Planche, Vincent

Article Type: Research Article

Abstract: Background: Mnemonic discrimination is the behavioral ability stemming from pattern separation, which is the neural process of establishing independent and non-overlapping new memories. Over the past two decades, its assessment in various populations has contributed to a better conceptual understanding of age-related memory decline. Objective: To assess the clinical relevance of mnemonic discrimination in the memory clinics setting. Methods: This retrospective study was performed in 90 patients with a Mini-Mental State Examination (MMSE)>18 who consulted our memory clinic for the first time. All patients were tested with the Mnemonic Similarity Task, a freely available computerized test. …Global cognitive function, executive function, visuoconstructional abilities, and verbal and visual episodic memory were also collected, together with the diagnosis after the initial clinical assessment (subjective cognitive complaint [SCC], mild cognitive impairment [MCI], or mild dementia). Results: Mnemonic discrimination performance was correlated with global cognitive function, executive function, and visual and verbal episodic memory scores, independent of age. It discriminated patients with SCC from those with MCI (amnestic or non-amnestic) with moderate accuracy (AUC = 0.77-0.78), similar to MMSE and the Frontal Assessment Battery (AUC = 0.74-0.84). Mnemonic discrimination performance did not distinguish between amnestic and non-amnestic MCI and the variability of the measure was important within groups. Conclusion: Mnemonic discrimination performance involves many cognitive domains and discriminates between patients with SCC and MCI with performance equivalent to “paper-and-pencil” screening tests. Further dedicated prospective studies will determine whether this task is of interest beyond research purposes, as a diagnostic or screening tool in primary care. Show more

Keywords: Alzheimer’s disease, episodic memory, hippocampus, memory clinic, mild cognitive impairment, mnemonic discrimination, pattern separation, subjective cognitive complaint

DOI: 10.3233/JAD-230221

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1527-1534, 2023

Authors: Emrani, Sheina | Lamar, Melissa | Price, Catherine C. | Swenson, Rod | Libon, David J. | Baliga, Ganesh

Article Type: Research Article

Abstract: Background: The theory of executive attention (Fuster, 2015) suggests considerable plasticity regarding when specific neurocognitive operations are recruited to bring executive tasks to fruition. Objective: We tested the hypothesis that differing neurocognitive operations are recruited upon the initiation of a response, but that other distinct neurocognitive operations are recruited towards the middle or end of a response. Methods: The Backward Digit Span Test (BDST) was administered to 58 memory clinic patients (MCI, n = 22; no-MCI, n = 36). Latency to generate all correct 5-span responses was obtained. Statistical analyses found that optimal group …classification was achieved using the first and third digit backward. First and third response latencies were analyzed in relation to verbal working memory (WM), visual WM, processing speed, visuospatial operations, naming/lexical access, and verbal episodic memory tests. Results: For the first response, slower latencies were associated with better performance in relation to verbal WM and visuospatial test performance. For the third response, faster latencies were associated with better processing speed and visuospatial test performance. Conclusion: Consistent with the theory of executive attention, these data show that the neurocognitive operations underlying successful executive test performance are not monolithic but can be quite nuanced with differing neurocognitive operations associated with specific time epochs. Results support the efficacy of obtaining time-based latency parameters to help disambiguate successful executive neurocognitive operations in memory clinic patients. Show more

Keywords: Alzheimer’s disease, Boston Process Approach, digit span, executive control, intra-component latency, mild cognitive impairment, temporal organization

DOI: 10.3233/JAD-230288

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1535-1547, 2023

Authors: Tio, Earvin S. | Hohman, Timothy J. | Milic, Milos | Bennett, David A. | Felsky, Daniel

Article Type: Research Article

Abstract: Background: Neuroinflammation and the activation of microglial cells are among the earliest events in Alzheimer’s disease (AD). However, direct observation of microglia in living people is not currently possible. Here, we indexed the heritable propensity for neuroinflammation with polygenic risk scores (PRS), using results from a recent genome-wide analysis of a validated post-mortem measure of morphological microglial activation. Objective: We sought to determine whether a PRS for microglial activation (PRSmic ) could augment the predictive performance of existing AD PRSs for late-life cognitive impairment. Methods: First, PRSmic were calculated and optimized in a calibration cohort …(Alzheimer’s Disease Neuroimaging Initiative (ADNI), n  = 450), with resampling. Second, predictive performance of optimal PRSmic was assessed in two independent, population-based cohorts (total n  = 212,237). Finally, we explored associations of PRSmic with a comprehensive set of imaging and fluid AD biomarkers in ADNI. Results: Our PRSmic showed no significant improvement in predictive power for either AD diagnosis or cognitive performance in either external cohort. Some nominal associations were found in ADNI, but with inconsistent effect directions. Conclusion: While genetic scores capable of indexing risk for neuroinflammatory processes in aging are highly desirable, more well-powered genome-wide studies of microglial activation are required. Further, biobank-scale studies would benefit from phenotyping of proximal neuroinflammatory processes to improve the PRS development phase. Show more

Keywords: Alzheimer’s disease, Canadian Longitudinal Study on Aging, computational modelling, microglial cell, neuroinflammation, polygenic traits, statistical data analysis

DOI: 10.3233/JAD-230434

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1549-1561, 2023

Authors: Gottschalk, William K | Mahon, Scott | Hodgson, Dellila | Barrera, Julio | Hill, Delaney | Wei, Angela | Kumar, Manish | Dai, Kathy | Anderson, Lauren | Mihovilovic, Mirta | Lutz, Michael W. | Chiba-Falek, Ornit

Article Type: Research Article

Abstract: Background: The human chromosome 19q13.32 is a gene rich region and has been associated with multiple phenotypes, including late onset Alzheimer’s disease (LOAD) and other age-related conditions. Objective: Here we developed the first humanized mouse model that contains the entire TOMM40 and APOE genes with all intronic and intergenic sequences including the upstream and downstream regions. Thus, the mouse model carries the human TOMM40 and APOE genes and their intact regulatory sequences. Methods: We generated the APOE -TOMM40 humanized mouse model in which the entire mouse region was replaced with the …human (h)APOE -TOMM40 loci including their upstream and downstream flanking regulatory sequences using recombineering technologies. We then measured the expression of the human TOMM40 and APOE genes in the mice brain, liver, and spleen tissues using TaqMan based mRNA expression assays. Results: We investigated the effects of the ‘523’ polyT genotype (S/S or VL/VL), sex, and age on the human TOMM40- and APOE- mRNAs expression levels using our new humanized mouse model. The analysis revealed tissue specific and shared effects of the ‘523’ polyT genotype, sex, and age on the regulation of the human TOMM40 and APOE genes. Noteworthy, the regulatory effect of the ‘523’ polyT genotype was observed for all studied organs. Conclusion: The model offers new opportunities for basic science, translational, and preclinical drug discovery studies focused on the APOE genomic region in relation to LOAD and other conditions in adulthood. Show more

Keywords: Age, Alzheimer’s disease, Alzheimer’s mouse model, APOE , gene expression, sex, TOMM40

DOI: 10.3233/JAD-230451

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1563-1576, 2023

Authors: Wang, Mengxue | Zhao, Guofeng | Jiang, Ying | Lu, Tong | Wang, Yanjuan | Zhu, Yixin | Zhang, Zhengsheng | Xie, Chunming | Wang, Zan | Ren, Qingguo

Article Type: Research Article

Abstract: Background: Cognitive impairment is the most common clinical manifestation of ischemic leukoaraiosis (ILA), but the underlying neurobiological pathways have not been well elucidated. Recently, it was thought that ILA is a “disconnection syndrome”. Disorganized brain connectome were considered the key neuropathology underlying cognitive deficits in ILA patients. Objective: We aimed to detect the disruption of network hubs in ILA patients using a new analytical method called voxel-based eigenvector centrality (EC) mapping. Methods: Subjects with moderate to severe white matters hyperintensities (Fazekas score ≥3) and healthy controls (HCs) (Fazekas score = 0) were included in the study. The resting-state …functional magnetic resonance imaging and the EC mapping approach were performed to explore the alteration of whole-brain network connectivity in ILA patients. Results: Relative to the HCs, the ILA patients exhibited poorer cognitive performance in episodic memory, information processing speed, and executive function (all ps  < 0.0125). Additionally, compared with HCs, the ILA patients had lower functional connectivity (i.e., EC values) in the medial parts of default-mode network (i.e., bilateral posterior cingulate gyrus and ventral medial prefrontal cortex [vMPFC]). Intriguingly, the functional connectivity strength at the right vMPFC was positively correlated with executive function deficit in the ILA patients. Conclusion: The findings suggested disorganization of the hierarchy of the default-mode regions within the whole-brain network in patients with ILA and advanced our understanding of the neurobiological mechanism underlying executive function deficit in ILA. Show more

Keywords: Brain connectome, default-mode network, eigenvector centrality mapping, executive function, ischemic leukoaraiosis, resting-state fMRI

DOI: 10.3233/JAD-230048

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1577-1586, 2023

Authors: Xu, Yuexuan | Vasiljevic, Eva | Deming, Yuetiva K. | Jonaitis, Erin M. | Koscik, Rebecca L. | Van Hulle, Carol A. | Lu, Qiongshi | Carboni, Margherita | Kollmorgen, Gwendlyn | Wild, Norbert | Carlsson, Cynthia M. | Johnson, Sterling C. | Zetterberg, Henrik | Blennow, Kaj | Engelman, Corinne D.

Article Type: Research Article

Abstract: Background: Genetic scores for late-onset Alzheimer’s disease (LOAD) have been associated with preclinical cognitive decline and biomarker variations. Compared with an overall polygenic risk score (PRS), a pathway-specific PRS (p-PRS) may be more appropriate in predicting a specific biomarker or cognitive component underlying LOAD pathology earlier in the lifespan. Objective: In this study, we leveraged longitudinal data from the Wisconsin Registry for Alzheimer’s Prevention and explored changing patterns in cognition and biomarkers at various age points along six biological pathways. Methods: PRS and p-PRSs with and without APOE were constructed separately based on the significant …SNPs associated with LOAD in a recent genome-wide association study meta-analysis and compared to APOE alone. We used a linear mixed-effects model to assess the association between PRS/p-PRSs and cognitive trajectories among 1,175 individuals. We also applied the model to the outcomes of cerebrospinal fluid biomarkers in a subset. Replication analyses were performed in an independent sample. Results: We found p-PRSs and the overall PRS can predict preclinical changes in cognition and biomarkers. The effects of PRS/p-PRSs on rate of change in cognition, amyloid-β, and tau outcomes are dependent on age and appear earlier in the lifespan when APOE is included in these risk scores compared to when APOE is excluded. Conclusion: In addition to APOE , the p-PRSs can predict age-dependent changes in amyloid-β, tau, and cognition. Once validated, they could be used to identify individuals with an elevated genetic risk of accumulating amyloid-β and tau, long before the onset of clinical symptoms. Show more

Keywords: Aging, Alzheimer’s disease, ApoE, biomarkers, cognition, longitudinal studies

DOI: 10.3233/JAD-230097

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1587-1605, 2023

Authors: Fenton, Laura | Han, S. Duke | DiGuiseppi, Carolyn G. | Fowler, Nicole R. | Hill, Linda | Johnson, Rachel L. | Peterson, Ryan A. | Knoepke, Christopher E. | Matlock, Daniel D. | Moran, Ryan | Karlawish, Jason | Betz, Marian E.

Article Type: Research Article

Abstract: Background: Older adults are faced with many unique and highly consequential decisions such as those related to finances, healthcare, and everyday functioning (e.g., driving cessation). Given the significant impact of these decisions on independence, wellbeing, and safety, an understanding of how cognitive impairment may impact decision making in older age is important. Objective: To examine the impact of mild cognitive impairment (MCI) on responses to a modified version of the Short Portable Assessment of Capacity for Everyday Decision making (SPACED). Methods: Participants were community-dwelling, actively driving older adults (N = 301; M age = 77.1 years, SD = 5.1; 69.4% with …a college degree or higher; 51.2% female; 95.3% White) enrolled in the Advancing Understanding of Transportation Options (AUTO) study. A generalized linear model adjusted for age, education, sex, randomization group, cognitive assessment method, and study site was used to examine the relationship between MCI status and decision making. Results: MCI status was associated with poorer decision making; participants with MCI missed an average of 2.17 times more points on the SPACED than those without MCI (adjusted mean ratio: 2.17, 95% CI: 1.02, 4.61, p  = 0.044). Conclusion: This finding supports the idea that older adults with MCI exhibit poorer decision-making abilities than cognitively normal older adults. It also suggests that older adults with MCI may exhibit poorer decision making across a wide range of decision contexts. Show more

Keywords: Alzheimer’s disease, cognition, decision making, mild cognitive impairment, older adults

DOI: 10.3233/JAD-230222

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1607-1615, 2023

Authors: Cai, Hong-Yan | Yang, Dan | Qiao, Jing | Yang, Jun-Ting | Wang, Zhao-Jun | Wu, Mei-Na | Qi, Jin-Shun | Holscher, Christian

Article Type: Correction

DOI: 10.3233/JAD-239006

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1617-1618, 2023

Authors: Yang, Heyun | Wang, Wei | Jia, Longfei | Qin, Wei | Hou, Tingting | Wu, Qiaoqi | Li, Haitao | Tian, Yuanruhua | Jia, Jianping

Article Type: Correction

DOI: 10.3233/JAD-239007

Citation: Journal of Alzheimer's Disease, vol. 94, no. 4, pp. 1619-1622, 2023