Journal of Alzheimer's Disease - Volume 89, issue 1

Authors: Clark, Kaylyn | Leung, Yuk Yee | Lee, Wan-Ping | Voight, Benjamin | Wang, Li-San

Article Type: Review Article

Abstract: The success of genome-wide association studies (GWAS) completed in the last 15 years has reinforced a key fact: polygenic architecture makes a substantial contribution to variation of susceptibility to complex disease, including Alzheimer’s disease. One straight-forward way to capture this architecture and predict which individuals in a population are most at risk is to calculate a polygenic risk score (PRS). This score aggregates the risk conferred across multiple genetic variants, ultimately representing an individual’s predicted genetic susceptibility for a disease. PRS have received increasing attention after having been successfully used in complex traits. This has brought with it renewed attention …on new methods which improve the accuracy of risk prediction. While these applications are initially informative, their utility is far from equitable: the majority of PRS models use samples heavily if not entirely of individuals of European descent. This basic approach opens concerns of health equity if applied inaccurately to other population groups, or health disparity if we fail to use them at all. In this review we will examine the methods of calculating PRS and some of their previous uses in disease prediction. We also advocate for, with supporting scientific evidence, inclusion of data from diverse populations in these existing and future studies of population risk via PRS. Show more

Keywords: Alzheimer’s disease, diversity, genome-wide association studies, polygenic risk score, statistical genetics

DOI: 10.3233/JAD-220025

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 1-12, 2022

Authors: Leitão, Mariana | Saúde, Alexandra | Bouça-Machado, Raquel | Ferreira, Joaquim J.

Article Type: Systematic Review

Abstract: Background: In addition to cognitive changes, motor impairments have been observed in patients with dementia and are present early in the disease, even at the preclinical stage. Although it is difficult to assess motor function in this population, it is critical for monitoring disease progression and determining the efficacy of therapeutic interventions. However, the best measurement tools for assessing motor function in dementia patients have yet to be determined. Objective: We aimed to summarize and critically evaluate the measurement tools used to assess motor function indementia. Methods: A systematic review was conducted using the databases CENTRAL, …MEDLINE, Embase, and PEDro from their inception to June 2021 to identify all experimental studies conducted in patients with dementia and that included an assessment of motor function. Two reviewers independently screened citations, extracted data, and assessed clinimetric properties. Results: We included 200 studies that assess motor function in dementia patients. Motor function was assessed using a total of 84 different measurement tools. Only nine (12%) were used in over ten studies. The Timed-Up-and-Go test, 6MWT, Berg Balance Scale, and the Short Physical Performance Battery are all suggested. Conclusion: Currently, a wide variety of measurement instruments are used to assess motor performance in people with dementia, most instruments were not designed for this population and have not been validated for this use. We propose the development of an assessment protocol tailored to the different disease stages. We also recommend that future research continues to develop technological devices that can assist with this task. Show more

Keywords: Alzheimer’s disease, dementia, measurement instruments, motor assessment, outcome measures, systematic review

DOI: 10.3233/JAD-220151

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 13-24, 2022

Authors: Sandhu, Gurveen Kaur | Zailan, Fatin Zahra | Vipin, Ashwati | Ann, Soo See | Kumar, Dilip | Ng, Kok Pin | Kandiah, Nagaendran

Article Type: Short Communication

Abstract: Oligomeric amyloid-β (OAβ), an upstream driver of Alzheimer’s disease (AD) neuropathology, correlates with poor cognitive performance and brain volume reduction. Its effect on cognitive performance measured by the language neutral Visual Cognitive Assessment Test (VCAT) remains to be evaluated. We studied the correlation of plasma OAβ with VCAT scores and grey matter volume (GMV) in a Southeast Asian cohort with mild cognitive impairment. Higher plasma OAβ significantly correlated with lower; cognitive scores (VCAT, Mini-Mental State Examination) and GMV/intracranial volume ratio. Such findings reveal the clinical utility of plasma OAβ as a promising biomarker and support validation through longitudinal studies.

Keywords: Alzheimer’s disease, cognitive assessment, cross sectional study, grey matter volume, mild cognitive impairment, Mini-Mental State Examination, multimer detection system, oligomeric amyloid-beta, plasma biomarkers, Visual Cognitive Assessment Test

DOI: 10.3233/JAD-220484

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 25-29, 2022

Authors: Yang, Yulin | Swinnerton, Kaitlin | Portacolone, Elena | Allen, Isabel Elaine | Torres, Jacqueline M. | Duchowny, Kate

Article Type: Short Communication

Abstract: We compared the prevalence of reporting difficulty with basic and instrumental activities of daily living without help received for persons with cognitive impairment living alone versus those living with others. We used data on 13,782 community-dwelling participants aged 55+ with cognitive impairment in the Health and Retirement Study (2000–2016). Models were stratified by gender and race/ethnicity. Among cognitively impaired older adults, those living alone were more likely to report difficulty without help received than those living with others. Results were similar by gender and race/ethnicity. Providers and policymakers might focus their efforts on ensuring the adequate provision of home and …community-based services for older adults living alone with cognitive impairment. Show more

Keywords: Aging in place, cognitive impairment, disability, living arrangement, racial/ethnic disparity

DOI: 10.3233/JAD-220172

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 31-37, 2022

Authors: Vlegels, Naomi | Ossenkoppele, Rik | van der Flier, Wiesje M. | Koek, Huiberdina L. | Reijmer, Yael D. | Wisse, Laura EM | Biessels, Geert Jan

Article Type: Research Article

Abstract: Background: Alzheimer’s disease is characterized by the accumulation of amyloid-β (Aβ) into plaques, aggregation of tau into neurofibrillary tangles, and neurodegenerative processes including atrophy. However, there is a poorly understood spatial discordance between initial Aβ deposition and local neurodegeneration. Objective: Here, we test the hypothesis that the cingulum bundle links Aβ deposition in the cingulate cortex to medial temporal lobe (MTL) atrophy. Methods: 21 participants with mild cognitive impairment (MCI) from the UMC Utrecht memory clinic (UMCU, discovery sample) and 37 participants with MCI from Alzheimer’s Disease Neuroimaging Initiative (ADNI, replication sample) with available Aβ-PET scan, …T1-weighted and diffusion-weighted MRI were included. Aβ load of the cingulate cortex was measured by the standardized uptake value ratio (SUVR), white matter integrity of the cingulum bundle was assessed by mean diffusivity and atrophy of the MTL by normalized MTL volume. Relationships were tested with linear mixed models, to accommodate multiple measures for each participant. Results: We found at most a weak association between cingulate Aβ and MTL volume (added R2 <0.06), primarily for the posterior hippocampus. In neither sample, white matter integrity of the cingulum bundle was associated with cingulate Aβ or MTL volume (added R2 <0.01). Various sensitivity analyses (Aβ-positive individuals only, posterior cingulate SUVR, MTL sub region volume) provided similar results. Conclusion: These findings, consistent in two independent cohorts, do not support our hypothesis that loss of white matter integrity of the cingulum is a connecting factor between cingulate gyrus Aβ deposition and MTL atrophy. Show more

Keywords: Alzheimer’s disease, amyloid-β, diffusion tensor imaging, medial temporal lobe, neurodegeneration, PET, white matter integrity

DOI: 10.3233/JAD-220024

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 39-49, 2022

Authors: Carnemolla, Sarah E. | Kumfor, Fiona | Liang, Cheng Tao | Foxe, David | Ahmed, Rebekah M. | Piguet, Olivier

Article Type: Research Article

Abstract: Background: Olfactory dysfunction is highly prevalent in dementia syndromes, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The structural integrity of the olfactory bulb (OB) is thought to play a critical role in odor detection and identification, but no MRI study has measured OB volume in FTD, or measured OB volume longitudinally in AD. Objective: To measure OB volume in FTD and AD patients longitudinally using MRI. Methods: This study measured OB volumes using MRI in patients diagnosed with behavioral-variant FTD (n  = 55), semantic dementia (n  = 34), progressive non-fluent aphasia (n  = 30), AD (n  = 50), and …healthy age-matched controls (n  = 55) at their first visit to a dementia research clinic (‘baseline’). Imaging data in patients 12-months later were analyzed where available (n  = 84) for longitudinal assessment. Volumes of subcortical and cortical olfactory regions (‘olfactory network’) were obtained via surface-based morphometry. Results: Results revealed that in AD and FTD at baseline, OB volumes were similar to controls, whereas volumes of olfactory network regions were significantly reduced in all patient groups except in progressive non-fluent aphasia. Longitudinal data revealed that OB volume became significantly reduced (10–25% volume reduction) in all dementia groups with disease progression. Conclusion: Olfactory dysfunction is common in patients diagnosed with AD or FTD, but our results indicate that there is no detectable volume loss to the OBs upon first presentation to the clinic. Our findings indicate that the OBs become detectably atrophied later in the disease process. OB atrophy indicates the potential usefulness for OBs to be targeted in interventions to improve olfactory function. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, magnetic resonance imaging, neurodegeneration, olfaction, olfactory bulb

DOI: 10.3233/JAD-220080

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 51-66, 2022

Authors: Xue, Feng | Gao, Luyan | Chen, TingTing | Chen, Hongyuan | Zhang, Haihua | Wang, Tao | Han, Zhifa | Gao, Shan | Wang, Longcai | Hu, Yang | Tang, Jiangwei | Huang, Lei | Liu, Guiyou | Zhang, Yan

Article Type: Research Article

Abstract: Background: Both INPP5D and INPP5F are members of INPP5 family. INPP5F rs117896735 variant was associated with Parkinson’s disease (PD) risk, and INPP5D was an Alzheimer’s disease (AD) risk gene. However, it remains unclear about the roles of INPP5F rs117896735 variant in AD. Objective: We aim to investigate the roles of rs117896735 in AD. Methods: First, we conducted a candidate variant study to evaluate the association of rs117896735 variant with AD risk using the large-scale AD GWAS dataset. Second, we conducted a gene expression analysis of INPP5F to investigate the …expression difference of INPP5F in different human tissues using two large-scale gene expression datasets. Third, we conducted an expression quantitative trait loci analysis to evaluate whether rs117896735 variant regulate the expression of INPP5F . Fourth, we explore the potentially differential expression of INPP5F in AD and control using multiple AD-control gene expression datasets in human brain tissues and whole blood. Results: We found that 1) rs117896735 A allele was associated with the increased risk of AD with OR = 1.15, 95% CI 1.005–1.315, p  = 0.042; 2) rs117896735 A allele could increase INPP5F expression in multiple human tissues; 3) INPP5F showed different expression in different human tissues, especially in brain tissues; 4) INPP5F showed significant expression dysregulation in AD compared with controls in human brain tissues. Conclusion: Conclusion: We demonstrate that PD rs117896735 variant could regulate INPP5F expression in brain tissues and increase the risk of AD. These finding may provide important information about the role of rs117896735 in AD. Show more

Keywords: Alzheimer’s disease, eQTLs, genome-wide association study, INPP5F, Parkinson’s disease

DOI: 10.3233/JAD-220086

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 67-77, 2022

Authors: Zhou, Kai | Wu, Peng

Article Type: Research Article

Abstract: Background: The question that whether the presence of osteoarthritis (OA) can modify the effects of apolipoprotein E4 (APOE4 ) genotype on longitudinal change in cognitive performance among non-demented older people remains unclear. Objective: To examine whether the association of APOE4 genotype with change in verbal episodic memory over time is modified by the presence of OA among non-demented older people. Methods: Longitudinal data from 1,400 non-demented older people were obtained from the Alzheimer’s Disease Neuroimaging Initiative database. The sample included 466 healthy individuals and 934 mild cognitive impairment. The effects of the OA×APOE4 genotype …interaction term on longitudinal change in cognitive performance were examined using linear mixed-effects regression models. Global cognition was assessed by the Mini-Mental State Examination score and Clinical Dementia Rating–Sum of Boxes. Verbal episodic memory was evaluated by the Rey Auditory Verbal Learning Test (RAVLT) immediate recall and delayed recall score. Results: We found that OA interacted with APOE4 genotype to influence longitudinal change in verbal episodic memory (as assessed by RAVLT immediate recall score) but not global cognition. Specifically, the OA–/APOE4+ group had a steeper decline in RAVLT immediate recall score compared with the OA+/APOE4+ group. However, there was no difference in RAVLT immediate recall score between OA–/APOE4 –and OA+/APOE4 –individuals. Conclusion: Our study suggested that the association of APOE4 genotype with change in RAVLT immediate recall score over time is modified by the presence of OA at earliest stages of the disease. Show more

Keywords: APOE , Alzheimer’ disease, cognitive decline, mild cognitive impairment, osteoarthritis

DOI: 10.3233/JAD-220138

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 79-86, 2022

Authors: Aschwanden, Damaris | Sutin, Angelina R. | Ledermann, Thomas | Luchetti, Martina | Stephan, Yannick | Sesker, Amanda A. | Zhu, Xianghe | Terracciano, Antonio

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is related to personality functioning and risk of subsequent objective cognitive impairment. Objective: The aim of this study was to examine whether lower neuroticism and higher conscientiousness—resilient personality traits—protect against conversion from SCD to objective cognitive impairment in two longitudinal community-based cohorts. Methods: Data from the Health and Retirement Study (N = 1,741, Mean age = 68.64 years, Follow-up mean = 7.34 years) and the National Health and Aging Trends Survey (N = 258, Mean age = 79.34 years, Follow-up mean = 4.31 years) were analyzed using Cox regression analysis, controlling for sociodemographic covariates, symptoms of anxiety and depression, and apolipoprotein ɛ4. …Results: The pooled results showed that lower neuroticism and higher conscientiousness were associated with decreased risk of conversion from SCD to objective cognitive impairment. Conclusion: Among individuals with SCD, those with a resilient personality may have more cognitive and psychological reserve to maintain cognitive functioning and delay conversion to objective cognitive impairment. The findings further contribute to a better understanding of personality along the cognitive continuum: The observed effect sizes were smaller than those reported in cognitively normal individuals but larger than in individuals with mild cognitive impairment. Personality could provide useful information to identify individuals with SCD who may develop objective cognitive impairment—namely those who hold a vulnerable personality (higher neuroticism, lower conscientiousness). Show more

Keywords: Conscientiousness, neuroticism, progression to cognitive impairment, resilient personality, subjective cognitive decline

DOI: 10.3233/JAD-220319

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 87-105, 2022

Authors: Man, Viet Hoang | Lin, Da | He, Xibing | Gao, Jie | Wang, Junmei

Article Type: Research Article

Abstract: Background: Tau assembly produces soluble oligomers and insoluble neurofibrillary tangles, which are neurotoxic to the brain and associated with Alzheimer’s and Parkinson’s diseases. Therefore, preventing tau aggregation is a promising therapy for those neurodegenerative disorders. Objective: The aim of this study was to develop a joint computational/cell-based oligomerization protocol for screening inhibitors of tau assembly. Methods: Virtual oligomerization inhibition (VOI) experiment using molecular dynamics simulation was performed to screen potential oligomerization inhibitors of PHF6 hexapeptide. Tau seeding assay, which is directly related to the outcome of therapeutic intervention, was carried out to confirm a ligand’s ability …in inhibiting tau assembly formation. Results: Our protocol was tested on two known compounds, EGCG and Blarcamesine. EGCG inhibited both the aggregation of PHF6 peptide in VOI and tau assembly in tau seeding assay, while Blarcamesine was not a good inhibitor at the two tasks. We also pointed out that good binding affinity to tau aggregates is needed, but not sufficient for a ligand to become a good inhibitor of tau oligomerization. Conclusion: VOI goes beyond traditional computational inhibitor screening of amyloid aggregation by directly examining the inhibitory ability of a ligand to tau oligomerization. Comparing with the traditional biochemical assays, tau seeding activities in cells is a better indicator for the outcome of a therapeutic intervention. Our hybrid protocol has been successfully validated. It can effectively and efficiently identify the inhibitors of amyloid oligomerization/aggregation processes, thus, facilitate to the drug development of tau-related neurodegenerative diseases. Show more

Keywords: Aggregation, EGCG, MD simulation, oligomerization, PHF6, tau protein

DOI: 10.3233/JAD-220450

Citation: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 107-119, 2022