Journal of Alzheimer's Disease - Volume 86, issue 1

Authors: Miron, Justin | Picard, Cynthia | Labonté, Anne | Auld, Daniel | Poirier, Judes | for the PREVENT-AD research group

Article Type: Research Article

Abstract: Background: In mouse models of amyloidosis, macrophage receptor 1 (MSR1) and neprilysin (NEP) have been shown to interact to reduce amyloid burden in the brain. Objective: The purpose of this study is to analyze these two gene products in combination with apolipoproteins and Aβ1-42 in the cerebrospinal fluid (CSF) and plasma of individuals at different stages of Alzheimer’s disease (AD), as well as in autopsied brain samples from ROSMAP (Religious Orders Study and Memory and Aging Project). Methods: CSF/plasma levels of MSR1 and NEP were measured using the sensitive primer extension assay technology. CSF Aβ1-42 …was assessed with ELISA, while CSF ApoE and ApoJ were measured with the Luminex’s multiplex technology. Brain MSR1 , APOE , and CLU (APOJ ) mRNA levels were measured with RNA-Seq and contrasted to amyloid plaques pathology using CERAD staging. Results: While plasma and CSF MSR1 levels are significantly correlated, this correlation was not observed for NEP. In addition to be highly correlated to one another, CSF levels of both MSR1 and NEP are strongly correlated with AD status and CSF Aβ1-42 , ApoE, and ApoJ levels. In the cortical tissues of subjects from ROSMAP, MSR1 mRNA levels are correlated with CLU mRNA levels and the CERAD scores but not with APOE mRNA levels. Conclusion: The discrepancies observed between CSF/plasma levels of MSR1 and NEP with CSF Aβ1-42 and ApoE concentrations can be explained by many factors, such as the disease stage or the involvement of the blood-brain barrier breakdown that leads to the infiltration of peripheral monocytes or macrophages. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, inflammation, MSR1, NEP

DOI: 10.3233/JAD-215410

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 283-296, 2022

Authors: Zhang, Wei | Zhang, Minghui | Wu, Qin | Shi, Jingshan

Article Type: Research Article

Abstract: Background: Dendrobium nobile Lindl. alkaloids (DNLA) are effective in ameliorating cognitive deficit in SAMP8, AβPP/PS1, and LPS-induced AD animal models, and prevented Aβ-induced synaptic degeneration in cultured hippocampal neurons. However, the underlying mechanisms remain unexplored. Objective: This study investigated the protective effects of DNLA on synaptic damage in an Aβ25-35 -induced rat AD model, in primary cortical neuron cultures, and in PC12 cells transfected with human AβPP695, focusing on the Wnt/β-catenin pathway. Methods: Sprague-Dawley rats received a single Aβ25-35 injection (10μ g) into the bilateral hippocampi. DNLA (40 and 80 mg/kg/d) was intragastrically administrated 7 …days prior to Aβ injection and continued for 28 days. The spatial learning and memory, synaptic morphology, synapse-related proteins, and Wnt signaling components GSK3β and β-catenin phosphorylation were evaluated. Rat primary cortical neuron cultures and AβPP695-PC12 cells were used to evaluate axonal mitochondria distribution, reactive oxygen species production, amyloidogenesis, and Wnt pathway in the protection. Results: DNLA ameliorated Aβ-induced cognitive impairment, increased the number of synapses, elevated the postsynaptic density thickness and expression of synapsin and PSD95 in the hippocampus, and suppressed Aβ-mediated GSK3β activity and the β-catenin phosphorylation. In primary neurons and AβPP695-PC12 cells, DNLA restored Aβ25-35 induced mitochondrial dysfunction and inhibited reactive oxygen species production and amyloidogenesis. Furthermore, the Wnt/β-catenin pathway inhibitor Dkk-1 blocked the effect of DNLA on the expression of Aβ1-42 and PSD95. Conclusion: DNLA rescued Aβ-mediated synaptic and mitochondrial injury and inhibited amyloidogenesis in vivo and in vitro , probably through the activation of Wnt/β-catenin signaling pathway to protect synaptic integrity. Show more

Keywords: Aβ-induced synaptic injury, amyloidogenesis, Dendrobium nobile Lindl. alkaloids, mitochondrial dysfunction, spatial learning and memory, Wnt/β-catenin pathways

DOI: 10.3233/JAD-215433

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 297-313, 2022

Authors: Liu, Mingjing | Guo, Shipeng | Huang, Daochao | Hu, Dongjie | Wu, Yili | Zhou, Weihui | Song, Weihong

Article Type: Research Article

Abstract: Background: Chronic alcohol consumption can alter the structure of the central nervous system and disrupt cognitive function. Alcoholics are more likely to develop neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the role of alcohol in promoting neurotoxicity and neurodegeneration remains unclear. Objective: In this study, we aimed at estimating the effects of chronic binge alcohol exposure on brain transcriptome and behavior changes in a chronic “Drinking in the Dark” (DID) mouse model. Methods: The adult C57BL/6J male mice were exposed to alcohol for 4 weeks. RNA-seq was applied to assess the …effects of chronic alcohol exposure on transcriptome in brain. The open field test and novel object recognition test were used to assess the changes of anxiety level, locomotive function, and short-term memory induced by alcohol. RNA-seq analysis revealed that chronic alcohol exposure caused significant change in the brain transcriptome, especially in prefrontal cortex. Results: The gene dysregulation caused by chronic alcohol exposure includes pathways related to mitochondrial energy metabolism (such as oxidative phosphorylation) and multiple neurodegenerative diseases (such as AD and PD). Furthermore, the pathway and network analyses suggest that the genes involved in mitochondrial energy metabolism, ubiquitin-proteasome system, Wnt signaling pathway, and microtubules may attribute to the neurotoxicity and neurodegeneration caused by chronic alcohol consumption. Additionally, locomotive function was also significantly impaired. Conclusion: This work provides gene transcriptional profile data for future research on alcohol-induced neurodegenerative diseases, especially AD and PD. Show more

Keywords: Brain, chronic alcohol consumption, gene expression, neurodegeneration

DOI: 10.3233/JAD-215508

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 315-331, 2022

Authors: Mukaetova-Ladinska, Elizabeta B. | Abdullah, Shahbaz | Critchfield, Mathew | Maltby, John

Article Type: Research Article

Abstract: Background: Memory complaints are frequent among young adults presenting in general practice. Many of them will have reversable, functional cognitive impairment that can easily be mistaken for dementia. Its accurate and timely identification is warranted to prevent further escalation to overt dementia syndrome. Objective: To evaluate the recommended primary care screening cognitive tools for dementia for use in younger people. Methods: 2.5 years clinical data were collected during the course of ongoing patient care for all assessed face-to-face patients in a secondary care memory service for younger adults. Cognitive screening and assessment tests used in primary …[General Practice Assessment of Cognition (GPCOG)] and secondary [Addenbrooke’s Cognitive Examination-III (ACE-III), Rowland Universal Dementia Assessment Scale (RUDAS), Salzburg Dementia Test Prediction (SDTP)] care were analyzed for their accuracy to identify dementia and memory complaints. Area under the curve in receiver operating characteristic curves was used to measure predictive value of tests for a clinical diagnosis of dementia. Results: 348 young adults were assessed for cognitive impairment. Following comprehensive Memory Clinic assessments, 241 (69.25%) were diagnosed with memory complaints in the absence of relevant neuropathology and 107 with dementia. GPCOG, especially the informant part, and RUDAS had low accuracy to identify dementia (AUC = 0.465 and AUC = 0.698, respectively). In contrast, ACE-III and SDTP demonstrated the highest accuracy (AUC = 0.799 and AUC = 0.809/0.817, respectively). Conclusion: Dementia screening in younger people will benefit from SDTP incorporated as part of the screening cognitive toolset. The national guidance on dementia screening tools, diagnostic pathways, and management should also refer to younger adults. Show more

Keywords: Cognitive impairment, cognitive screening, dementia, primary health care, suspected dementia, young adults

DOI: 10.3233/JAD-215514

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 333-341, 2022

Authors: Pritchard, Anna Barlach | Fabian, Zsolt | Lawrence, Clare L. | Morton, Glyn | Crean, StJohn | Alder, Jane E.

Article Type: Research Article

Abstract: Background: The effects of the key pathogens and virulence factors associated with gum disease such as Porphyromonas gingivalis (P. gingivalis ) on the central nervous system is of great interest with respect to development of neuropathologies and hence therapeutics and preventative strategies. Chronic infections and associated inflammation are known to weaken the first line of defense for the brain, the blood-brain barrier (BBB). Objective: The focus of this study is to utilize an established human in vitro BBB model to evaluate the effects of P. gingivalis virulence factors lipopolysaccharide (LPS) and outer membrane vesicles (OMVs) on a …primary-derived human model representing the neurovascular unit of the BBB. Methods: Changes to the integrity of the BBB after application of P. gingivalis LPS and OMVs were investigated and correlated with transport of LPS. Additionally, the effect of P. gingivalis LPS and OMVs on human brain microvascular endothelial cells in monolayer was evaluated using immunofluorescence microscopy. Results: The integrity of the BBB model was weakened by application of P. gingivalis LPS and OMVs, as measured by a decrease in electrical resistance and a recovery deficit was seen in comparison to the controls. Application of P. gingivalis OMVs to a monoculture of human brain microvascular endothelial cells showed disruption of the tight junction zona occludens protein (ZO-1) compared to controls. Conclusion: These findings show that the integrity of tight junctions of the human BBB could be weakened by association with P. gingivalis virulence factors LPS and OMVs containing proteolytic enzymes (gingipains). Show more

Keywords: Alzheimer’s disease, blood-brain barrier, human brain microvascular endothelial cells, in vitro BBB model, microbiome, periodontal disease

DOI: 10.3233/JAD-215054

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 343-364, 2022

Authors: Eastman, Guillermo | Sharlow, Elizabeth R. | Lazo, John S. | Bloom, George S. | Sotelo-Silveira, José R.

Article Type: Research Article

Abstract: Background: Defining cellular mechanisms that drive Alzheimer’s disease (AD) pathogenesis and progression will be aided by studies defining how gene expression patterns change during pre-symptomatic AD and ensuing periods of declining cognition. Previous studies have emphasized changes in transcriptome, but not translatome regulation, leaving the ultimate results of gene expression alterations relatively unexplored in the context of AD. Objective: To identify genes whose expression might be regulated at the transcriptome and translatome levels in AD, we analyzed gene expression in cerebral cortex of two AD model mouse strains, CVN (APPSwDI ;NOS2 -/- ) and Tg2576 (APPSw ), …and their companion wild type (WT) strains at 6 months of age by tandem RNA-Seq and Ribo-Seq (ribosome profiling). Methods: Identical starting pools of bulk RNA were used for RNA-Seq and Ribo-Seq. Differential gene expression analysis was performed at the transcriptome, translatome, and translational efficiency levels. Regulated genes were functionally evaluated by gene ontology tools. Results: Compared to WT mice, AD model mice had similar levels of transcriptome regulation, but differences in translatome regulation. A microglial signature associated with early stages of Aβ accumulation was upregulated at both levels in CVN mice. Although the two mice strains did not share many regulated genes, they showed common regulated pathways related to AβPP metabolism associated with neurotoxicity and neuroprotection. Conclusion: This work represents the first genome-wide study of brain translatome regulation in animal models of AD and provides evidence of a tight and early translatome regulation of gene expression controlling the balance between neuroprotective and neurodegenerative processes in brain. Show more

Keywords: Alzheimer’s disease, amyloid, microglia, RNA-Seq, mRNA translation, transcriptome regulation

DOI: 10.3233/JAD-215357

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 365-386, 2022

Authors: Mesa-Herrera, Fátima | Marín, Raquel | Torrealba, Eduardo | Díaz, Mario

Article Type: Research Article

Abstract: Background: There exists considerable interest in the identification of molecular traits during early stages of Alzheimer’s disease (AD). Mild cognitive impairment (MCI) is considered the closest prodromal stage of AD, and to develop gradually from earlier stages although not always progresses to AD. Classical cerebrospinal fluid (CSF) AD biomarkers, amyloid-β peptides and tau/p-tau proteins, have been measured in prodromal stages yet results are heterogeneous and far from conclusive. Therefore, there exists a pressing need to identify a neurochemical signature for prodromal stages and to predict which cases might progress to AD. Objective: Exploring potential CSF biomarkers related to …brain oxidative and inorganic biochemistry during prodromal stages of the disease. Methods: We have analyzed CSF levels of lipoxidative markers (MDA and 8-isoF2α ), biometals (Cu, Zn, Se, Mn, and Fe), iron-transport protein transferrin (TFER), antioxidant enzymes (SOD and GPx4), detoxifying enzymes (GST and BuChE), as well as classical amyloid-β and total and phosphorylated tau, in cognitively healthy controls, patients with MCI, and subjects exhibiting subjective memory complaints (SMC). Results: Inter-group differences for several variables exhibit differentiable trends along the HC ⟶ SMC ⟶ MCI sequence. More interestingly, the combination of Se, Cu, Zn, SOD, TFER, and GST variables allow differentiable fingerprints for control subjects and each prodromal stage. Further, multivariate scores correlate positively with neurocognitive In-Out test, hence with both episodic memory decline and prediction to dementia. Conclusion: We conclude that changes in the CSF biochemistry related to brain oxidative defense and neurometallomics might provide more powerful and accurate diagnostic tools in preclinical stages of AD. Show more

Keywords: Alzheimer’s disease, butyrylcholinesterase, extracellular superoxide dismutase, glutathione-S-transferase, lipoxidative markers, mild cognitive impairment, neurometalomics, oxidative stress, subjective memory complaints, transferrin

DOI: 10.3233/JAD-215437

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 387-402, 2022

Authors: Teixeira, Antonio L. | Salem, Haitham | Martins, Lais B. | Gonzales, Mitzi M. | Seshadri, Sudha | Suchting, Robert

Article Type: Research Article

Abstract: Background: Apathy is among the most frequent neuropsychiatric syndromes in Alzheimer’s disease (AD). Objective: To determine the prevalence of apathy and the associated clinical and laboratorial parameters (focus on inflammatory biomarkers) in patients with dementia enrolled at the Texas Alzheimer’s Research and Care Consortium (TARCC) study. Methods: This is a cross-sectional analysis of TARCC baseline. Participants were evaluated through different clinical tools, including the Mini-Mental State Examination (MMSE) and the Lawton-Brody Instrumental Activities of Daily Life (IADL)/Physical Self-Maintenance Scale (PSMS). Apathy was defined by a positive response to the respective item in the Neuropsychiatric Inventory–Questionnaire applied …to caregivers. Serum levels of 16 biomarkers were determined by HumanMap multiplex immunoassay. Comparisons between apathy versus non-apathy groups were carried out with non-parametric tests. Logistic regression and the least absolute shrinkage and selection operator (LASSO) were used to separately model apathy as a function of each biomarker, adjusted for the potential confounders. Results: From 1,319 patients with AD (M/F: 579/740, mean age ± SD: 75.3 ± 8.4), 373 (28.3%) exhibited apathy. When categorized according to the presence of apathy, the groups had significant differences in sex, diabetes diagnosis, and tobacco use. The apathy group also had worse cognitive performance and daily functioning than the non-apathy group as assessed, respectively, by MMSE and IADL/PSMS. Higher levels of interleukin-6, interleukin-10, and leptin were associated with higher odds of apathy. Conclusion: Apathy is associated with cognitive and functional status in AD. The association between apathy and peripheral inflammatory mediators deserves further investigation. Show more

Keywords: Alzheimer’s disease, apathy, inflammation, interleukin-6, interleukin-10

DOI: 10.3233/JAD-215314

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 403-411, 2022

Authors: Reed, Marilyn | Freedman, Morris | Mark Fraser, Amy E. | Bromwich, Matthew | Santiago, Anna Theresa | Gallucci, Christina Elizabeth | Frank, Andrew

Article Type: Research Article

Abstract: Background: Hearing loss is the largest potentially modifiable risk factor for dementia and is highly prevalent among older adults, yet it goes largely unreported, unidentified, and untreated, at great cost to health and quality of life. Hearing screening is a proven cost-effective solution to overcome delays in its identification and management yet is not typically recommended by physicians for older adults. Objective: To demonstrate the feasibility and value of hearing screening for older adults at risk for dementia in order to enhance physicians’ awareness of hearing loss and improve access to timely hearing care. Methods: Patients …referred to two academic medical clinics for memory disorders were offered hearing screening as part of clinic protocol. Patients with hearing loss were recruited to the study if they consented to a post-appointment telephone interview and chart review. Memory Clinic physicians were surveyed about the usefulness of the screening information and referral of patients with hearing loss to audiology. Results: Hearing loss was reliably detected in Memory Clinic patients with both in-office and online screening tools. Physicians reported that screening enhanced their awareness of hearing loss and increased the referral rate to audiology. Conclusion: Hearing screening in Memory Clinic patients is a useful component of clinic protocol that facilitates timely access to management and addresses an important risk factor for dementia. Show more

Keywords: Dementia, hearing loss, memory clinic, older adults, screening

DOI: 10.3233/JAD-215377

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 413-424, 2022

Authors: Richter, Nils | David, Lara-Sophia | Grothe, Michel J. | Teipel, Stefan | Dietlein, Markus | Tittgemeyer, Marc | Neumaier, Bernd | Fink, Gereon R. | Onur, Oezguer A. | Kukolja, Juraj

Article Type: Research Article

Abstract: Background: Early and severe neuronal loss in the cholinergic basal forebrain is observed in Alzheimer’s disease (AD). To date, cholinomimetics play a central role in the symptomatic treatment of AD dementia. Although basic research indicates that a cholinergic deficit is present in AD before dementia, the efficacy of cholinomimetics in mild cognitive impairment (MCI) remains controversial. Predictors of cholinergic impairment could guide individualized therapy. Objective: To investigate if the extent of the cholinergic deficit, measured using positron emission tomography (PET) and the tracer 11 C-N-methyl-4-piperidyl acetate (MP4A), could be predicted from the volume of cholinergic basal forebrain nuclei …in non-demented AD patients. Methods: Seventeen patients with a high likelihood of MCI due to AD and 18 age-matched cognitively healthy adults underwent MRI-scanning. Basal forebrain volume was assessed using voxel-based morphometry and a cytoarchitectonic atlas of cholinergic nuclei. Cortical acetylcholinesterase (AChE) activity was measured using MP4A-PET. Results: Cortical AChE activity and nucleus basalis of Meynert (Ch4 area) volume were significantly decreased in MCI. The extent of the cholinergic deficit varied considerably across patients. Greater volumes of anterior basal forebrain nuclei (Ch1/2 area) and younger age (Spearman’s rho (17)   = –0.596, 95% -CI [–0.905, –0.119] and 0.593, 95% -CI [0.092, 0.863])) were associated with a greater cholinergic deficit. Conclusion: Data suggest that less atrophy of the Ch1/2 area and younger age are associated with a more significant cholinergic deficit in MCI due to AD. Further investigations are warranted to determine if the individual response to cholinomimetics can be inferred from these measures. Show more

Keywords: Acetylcholinesterase, aging, MP4A, nucleus basalis of Meynert, positron emission tomography

DOI: 10.3233/JAD-210261

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 425-440, 2022

Authors: Sohn, Bo Kyung | Byun, Min Soo | Yi, Dahyun | Jeon, So Yeon | Lee, Jun Ho | Choe, Young Min | Lee, Dong Woo | Lee, Jun-Young | Kim, Yu Kyeong | Sohn, Chul-Ho | Lee, Dong Young | for the KBASE Research Group

Article Type: Research Article

Abstract: Background: Physical activities (PA) have been suggested to reduce the risk of Alzheimer‘s disease (AD) dementia. However, information on the neuropathological links underlying the relationship is limited. Objective: We investigated the role of midlife and late-life PA with in vivo AD neuropathologies in old adults without dementia. Methods: This study included participants from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s disease (KBASE). The participants underwent comprehensive clinical and neuropsychological assessment, [11 C] Pittsburgh Compound B positron emission tomography (PET), [18 F] fluorodeoxyglucose PET, and magnetic resonance imaging. Using the multi-modal …brain imaging data, in vivo AD pathologies including global amyloid deposition, AD-signature region cerebral glucose metabolism (AD-CM), and AD-signature region cortical thickness (AD-CT) were quantified. Both midlife and late-life PA of participants were measured using the Lifetime Total Physical Activity Questionnaire. Results: This study was performed on 260 participants without dementia (195 with normal cognitive function and 65 with mild cognitive impairment). PA of neither midlife nor late-life showed direct correspondence with any neuroimaging biomarker. However, late-life PA moderated the relationship of brain amyloid-β (Aβ) deposition with AD-CM and AD-CT. Aβ positivity had a significant negative effect on both AD-CM and AD-CT in individuals with lower late-life PA, but those with higher late-life PA did not show such results. Midlife PA did not have such a moderation effect. Conclusion: The findings suggest that physically active lifestyle in late-life, rather than that in midlife, may delay AD-associated cognitive decline by decreasing Aβ-induced neurodegenerative changes in old adults. Show more

Keywords: Amyloid, cortical thickness, neurodegeneration, physical activity

DOI: 10.3233/JAD-215258

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 441-450, 2022

Authors: Pedersen, Frederik Nørregaard | Stokholm, Lonny | Pouwer, Frans | Hass Rubin, Katrine | Peto, Tunde | Frydkjær-Olsen, Ulrik | Thykjær, Anne Suhr | Andersen, Nis | Andresen, Jens | Bek, Toke | La Cour, Morten | Heegaard, Steffen | Højlund, Kurt | Kawasaki, Ryo | Hajari, Javad Nouri | Ohm Kyvik, Kirsten | Laugesen, Caroline Schmidt | Schielke, Katja Christina | Simó, Rafael | Grauslund, Jakob

Article Type: Research Article

Abstract: Background: Retinal neurodegeneration is evident in early diabetic retinopathy (DR) which may be associated with other neurodegenerative diseases like Alzheimer's disease (AD). Objective: To investigate diabetes and DR as a risk marker of present and incident AD. Methods: A register-based cohort study was performed. We included 134,327 persons with diabetes above 60 years of age, who had attended DR screening, and 651,936 age- and gender-matched persons without diabetes. Results: At baseline, the prevalence of AD was 0.7% and 1.3% among patients with and without diabetes, respectively. In a multivariable regression model, patients with diabetes …were less likely to have AD at baseline (adjusted OR 0.63, 95% CI 0.59–0.68). During follow-up, incident AD was registered for 1473 (0.35%) and 6,899 (0.34%) persons with and without diabetes, respectively. Compared to persons without diabetes, persons with diabetes and no DR had a lower risk to develop AD (adjusted HR 0.87, 95% CI 0.81–0.93), while persons with diabetes and DR had higher risk of AD (adjusted HR 1.24, 95% CI 1.08–1.43). When persons with diabetes and no DR were used as references, a higher risk of incident AD was observed in persons with DR (adjusted HR 1.34, 95% CI 1.18–1.53). Conclusion: Individuals with diabetes without DR were less likely to develop AD compared to persons without diabetes. However, individuals with DR had a 34% higher risk of incident AD, which raise the question whether screening for cognitive impairment should be done among individuals with DR. Show more

Keywords: Alzheimer’s disease, cognitive impairment, diabetes mellitus, diabetic retinopathy

DOI: 10.3233/JAD-215313

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 451-460, 2022

Authors: Kuksa, Pavel P. | Liu, Chia-Lun | Fu, Wei | Qu, Liming | Zhao, Yi | Katanic, Zivadin | Clark, Kaylyn | Kuzma, Amanda B. | Ho, Pei-Chuan | Tzeng, Kai-Teh | Valladares, Otto | Chou, Shin-Yi | Naj, Adam C. | Schellenberg, Gerard D. | Wang, Li-San | Leung, Yuk Yee

Article Type: Research Article

Abstract: Background: Recent Alzheimer’s disease (AD) genetics findings from genome-wide association studies (GWAS) span progressively larger and more diverse populations and outcomes. Currently, there is no up-to-date resource providing harmonized and searchable information on all AD genetic associations found by GWAS, nor linking the reported genetic variants and genes with functional and genomic annotations. Objective: Create an integrated/harmonized, and literature-derived collection of population-specific AD genetic associations. Methods: We developed the Alzheimer’s Disease Variant Portal (ADVP), an extensive collection of associations curated from >200 GWAS publications from Alzheimer’s Disease Genetics Consortium and other consortia. Genetic associations were systematically …extracted, harmonized, and annotated from both the genome-wide significant and suggestive loci reported in these publications. To ensure consistent representation of AD genetic findings, all the extracted genetic association information was harmonized across specifically designed publication, variant, and association categories. Results: ADVP V1.0 (February 2021) catalogs 6,990 associations related to disease-risk, expression quantitative traits, endophenotypes, or neuropathology. This extensive harmonization effort led to a catalog containing >900 loci, >1,800 variants, >80 cohorts, and 8 populations. Besides, ADVP provides investigators with a seamless integration of genomic and publicly available functional annotations across multiple databases per harmonized variant and gene records, thus facilitating further understanding and analyses of these genetics findings. Conclusion: ADVP is a valuable resource for investigators to quickly and systematically explore high-confidence AD genetic findings and provides insights into population-specific AD genetic architecture. ADVP is continually maintained and enhanced by NIAGADS and is freely accessible at https://advp.niagads.org . Show more

Keywords: AD GWAS literature curation, Alzheimer’s disease, data curation, database, genome-wide association studies, harmonization

DOI: 10.3233/JAD-215055

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 461-477, 2022

Authors: Levy, Boaz | Priest, Amanda | Delaney, Tyler | Hogan, Jacqueline | Herrawi, Farahdeba

Article Type: Research Article

Abstract: Background: Preventing dementia warrants the pragmatic engagement of primary care. Objective: This study predicted conversion to dementia 12 months before diagnosis with indicators that primary care can utilize within the practical constraints of routine practice. Methods: The study analyzed data from the Alzheimer’s Disease Neuroimaging Initiative (Total sample = 645, converting participants = 54). It predicted the conversion from biological (plasma neurofilament light chain), cognitive (Trails Making Test– B), and functional (Functional Activities Questionnaire) measures, in addition to demographic variables (age and education). Results: A Gradient Booster Trees classifier effectively predicted the conversion, based on a Synthetic Minority …Oversampling Technique (n  = 1,290, F1 Score = 92, AUC = 94, Recall = 87, Precision = 97, Accuracy = 92). Subsequent analysis indicated that the MCI False Positive group (i.e., non-converting participants with cognitive impairment flagged by the model for prospective conversion) scored significantly lower on multiple cognitive tests (Montreal Cognitive Assessment, p  < 0.002; ADAS-13, p  < 0.0004; Rey Auditory Verbal Learning Test, p  < 0.002/0.003) than the MCI True Negative group (i.e., correctly classified non-converting participants with cognitive impairment). These groups also differed in CSF tau levels (p  < 0.04), while consistent effect size differences emerged in the all-pairwise comparisons of hippocampal volume and CSF Aβ1 - 42 . Conclusion: The model effectively predicted 12-month conversion to dementia and further identified non-converting participants with MCI, in the False Positive group, at relatively higher neurocognitive risk. Future studies may seek to extend these results to earlier prodromal phases. Detection of dementia before diagnosis may be feasible and practical in primary care settings, pending replication of these findings in diverse clinical samples. Show more

Keywords: Alzheimer’s disease, dementia, pre-diagnostic detection, prevention, primary care, screening

DOI: 10.3233/JAD-215242

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 479-490, 2022

Authors: Josephs, Kennedy A. | Pham, Nha Trang Thu | Graff-Radford, Jonathan | Machulda, Mary M. | Lowe, Val J. | Whitwell, Jennifer L.

Article Type: Research Article

Abstract: Background: It has been hypothesized that medial temporal sparing may be related to preserved posterior cingulate metabolism and the cingulate island sign (CIS) on [18 F]fluorodeoxyglucose (FDG) PET in posterior cortical atrophy (PCA). Objective: To assess the severity of medial temporal atrophy in PCA and determine whether the presence of a CIS is related to medial temporal sparing. Methods: Fifty-five PCA patients underwent MRI and FDG-PET. The degree and symmetry of medial temporal atrophy on MRI was visually assessed using a five-point scale for both hemispheres. Visual assessments of FDG-PET coded the presence/absence of a CIS …and whether the CIS was symmetric or asymmetric. Hippocampal volumes and a quantitative CIS were also measured. Results: Medial temporal atrophy was most commonly mild or moderate, was symmetric in 55% of patients, and when asymmetric was most commonly worse on the right (76%). Older age and worse memory performance were associated with greater medial temporal atrophy. The CIS was observed in 44% of the PCA patients and was asymmetric in 50% of these. The patients with a CIS showed greater medial temporal asymmetry, but did not show lower medial temporal atrophy scores, compared to those without a CIS. Hippocampal volumes were not associated with quantitative CIS. Conclusion: Mild medial temporal atrophy is a common finding in PCA and is associated with memory impairment. However, medial temporal sparing was not related to the presence of a CIS in PCA. Show more

Keywords: Cingulate island sign, FDG-PET, hippocampus, MRI, visual assessment

DOI: 10.3233/JAD-215263

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 491-498, 2022

Authors: McNerney, M. Windy | Heath, Alesha | Narayanan, Sindhu K. | Yesavage, Jerome

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a debilitating disorder involving the loss of plasticity and cholinergic neurons in the cortex. Pharmaceutical treatments are limited in their efficacy, but brain stimulation is emerging as a treatment for diseases of cognition. More research is needed to determine the biochemical mechanisms and treatment efficacy of this technique. Objective: We aimed to determine if forebrain repetitive transcranial magnetic stimulation can improve cortical BDNF gene expression and cholinergic signaling in the 3xTgAD mouse model of AD. Methods: Both B6 wild type mice and 3xTgAD mice aged 12 months were given daily treatment …sessions for 14 days or twice weekly for 6 weeks. Following treatment, brain tissue was extracted for immunological stains for plaque load, as well as biochemical analysis for BDNF gene expression and cholinergic signaling via acetylcholinesterase and choline acetyltransferase ELISA assays. Results: For the 3xTgAD mice, both 14 days and 6 weeks treatment regimens resulted in an increase in BDNF gene expression relative to sham treatment, with a larger increase in the 6-week group. Acetylcholinesterase activity also increased for both treatments in 3xTgAD mice. The B6 mice only had an increase in BDNF gene expression for the 6-week group. Conclusion: Brain stimulation is a possible non-invasive and nonpharmaceutical treatment option for AD as it improves both plasticity markers and cholinergic signaling in an AD mouse model. Show more

Keywords: Acetylcholinesterase, brain-derived neurotrophic factor, cortex, mouse, transcranial magnetic stimulation

DOI: 10.3233/JAD-215361

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 499-507, 2022

Authors: George, Daniel R. | Whitehouse, Peter J.

Article Type: Book Review

DOI: 10.3233/JAD-220035

Citation: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 509-510, 2022