Journal of Alzheimer's Disease - Volume 79, issue 4

Authors: de la Torre, Jack C.

Article Type: Review Article

Abstract: This review examines new biomolecular findings that lend support to the hemodynamic role played by chronic brain hypoperfusion (CBH) in driving a pathway to Alzheimer’s disease (AD). CBH is a common clinical feature of AD and the current topic of intense investigation in AD models. CBH is also the basis for the vascular hypothesis of AD which we originally proposed in 1993. New biomolecular findings reveal the interplay of CBH in increasing tau phosphorylation (p-Tau) in the hippocampus and cortex of AD mice, damaging fast axonal transport, increasing signaling of mammalian target of rapamycin (mTOR), impairing learning-memory function, and promoting …the formation of neurofibrillary tangles, a neuropathologic hallmark of AD. These pathologic elements have been singularly linked with neurodegeneration and AD but their abnormal, collective participation during brain aging have not been fully examined. The format for this review will provide a consolidated analysis of each pathologic phase contributing to cognitive decline and AD onset, summarized in nine chronological steps. These steps galvanize each factor’s active participation and contribution in constructing a biomolecular pathway to AD onset generated by CBH. Show more

Keywords: Axonal transport, brain hypoperfusion, cognition, mammalian target of rapamycin, neurofibrillary tangles, tau, vascular hypothesis of Alzheimer’s

DOI: 10.3233/JAD-201165

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1381-1396, 2021

Authors: Magnin, Eloi

Article Type: Review Article

Abstract: Neurodevelopmental and neurodegenerative disorders are both growing major public health topics with similarities and frequent complex interactions with each other. Taking these aspects into account can provide a new point of view on lifelong neurocognitive trajectories. Assessing both neurodevelopmental and neurodegenerative dimensions during cognitive and behavioral clinical assessments is challenging but might improve diagnostic accuracy and physiopathological understanding. It is therefore necessary to understand the lifelong specific neurocognitive trajectory of each patient in order to develop personalized precision cognitive medicine.

Keywords: Atypical dementia, neurodegenerative disorders, neurodevelopmental disorders

DOI: 10.3233/JAD-201207

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1397-1407, 2021

Authors: Huang, Lei | Zhang, Yang | Wang, Yongwei | Lan, Yajia

Article Type: Review Article

Abstract: Degenerative dementia, of which Alzheimer’s disease is the most common form, is characterized by the gradual deterioration of cognitive function. The events that trigger and promote degenerative dementia are not clear, and treatment options are limited. Experimental and epidemiological studies have revealed chronic noise exposure (CNE) as a potential risk factor for cognitive impairment and degenerative dementia. Experimental studies have indicated that long-term exposure to noise might accelerate cognitive dysfunction, amyloid-β deposition, and tau hyperphosphorylation in different brain regions such as the hippocampus and cortex. Epidemiological studies are increasingly examining the possible association between external noise exposure and dementia. In …this review, we sought to construct a comprehensive summary of the relationship between CNE, cognitive dysfunction, and degenerative dementia. We also present the limitations of existing evidence as a guide regarding important prospects for future research. Show more

Keywords: Alzheimer’s disease, amyloid-β, cognition, dementia, neuropathology, noise, tau

DOI: 10.3233/JAD-201037

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1409-1427, 2021

Authors: Lao, Kejing | Zhang, Ruisan | Luan, Jing | Zhang, Yuelin | Gou, Xingchun

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a chronic neurodegenerative disease that has been recognized as one of the most intractable medical problems with heavy social and economic costs. Amyloid-β (Aβ) has been identified as a major factor that participates in AD progression through its neurotoxic effects. The major mechanism of Aβ-induced neurotoxicity is by interacting with membrane receptors and subsequent triggering of aberrant cellular signaling. Besides, Aβ transporters also plays an important role by affecting Aβ homeostasis. Thus, these Aβ receptors and transporters are potential targets for the development of AD therapies. Here, we summarize the reported therapeutic strategies targeting Aβ receptors …and transporters to provide a molecular basis for future rational design of anti-AD agents. Show more

Keywords: Aβ receptor, Aβ transporter, EphB2, LilrB2, LRP-1, NgR, p75NTR, PrPc, RAGE

DOI: 10.3233/JAD-200851

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1429-1442, 2021

Authors: Delic, Vedad | Ratliff, Whitney A. | Citron, Bruce A.

Article Type: Review Article

Abstract: An estimated 5 million Americans are living with Alzheimer's disease (AD), and there is also a significant impact on caregivers, with an additional 16 million Americans providing unpaid care for individuals with AD and other dementias. These numbers are projected to increase in the coming years. While AD is still without a cure, continued research efforts have led to better understanding of pathology and potential risk factors that could be exploited to slow disease progression. A bidirectional relationship between sleep deprivation and AD has been suggested and is well supported by both human and animal studies. Even brief episodes of …inadequate sleep have been shown to cause an increase in amyloidβ and tau proteins, both well-established contributors toAD pathology. Sleep deprivation is also the most common consequence of post-traumatic stress disorder (PTSD). Patients with PTSD frequently present with sleep disturbances and also develop dementia at twice the rate of the general population accounting for a disproportionate representation of AD among U.S. Veterans. The goal of this review is to highlight the relationship triad between sleep deprivation, AD, and PTSD as well as their impact on molecular mechanisms driving AD pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β, post-traumatic stress disorder, sleep deprivation, tau

DOI: 10.3233/JAD-201378

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1443-1449, 2021

Authors: Baril, Andrée-Ann | Beiser, Alexa S. | Redline, Susan | McGrath, Emer R. | Gottlieb, Daniel J. | Aparicio, Hugo | Seshadri, Sudha | Himali, Jayandra J. | Pase, Matthew P.

Article Type: Short Communication

Abstract: Because of their roles as potential risk factors, we evaluated whether obstructive sleep apnea (OSA) severity interacts with interleukin-6 (IL-6) in predicting incident dementia of the Alzheimer’s type (DAT). In 269 dementia-free participants, IL-6 and the apnea-hypopnea index (AHI) were measured at baseline and incident DAT was surveilled for up to 22.8 years. Cox models revealed a significant interaction: In the lowest IL-6 quartile only, a higher AHI was associated with an elevated risk of DAT. The association between OSA severity and incident DAT might be especially apparent in the absence of inflammation or absence of potential benefits from IL-6.

Keywords: Alzheimer’s disease, dementia, inflammation, interleukin-6, sleep apnea, sleep-disordered breathing, sleep disorders

DOI: 10.3233/JAD-200545

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1451-1457, 2021

Authors: Kristensen, Rachel Underlien | Jensen-Dahm, Christina | Gasse, Christiane | Waldemar, Gunhild

Article Type: Research Article

Abstract: Background: Studies have shown declining use of potentially inappropriate medication (PIM), medication where risks associated with use outweigh potential benefits in older people. However, the trend in people with dementia remains unknown. Objective: To test the hypothesis that the use of PIM has decreased in people with dementia in line with the declining use in the general older population. Methods: Repeated cross-sectional register-based study of the entire Danish population aged ≥65 years (2000: N = 802,106; 2015: N = 1,056,476). PIM was identified using the Danish “Red-yellow-green list”. Changes in the use of PIM were examined by calculating the annual …prevalence of filling prescriptions for at least one PIM in older people with and without dementia. Characteristics of the study population were examined annually including comorbidity. Results: From 2000 to 2015, the prevalence of PIM use decreased from 54.7%to 43.5%in people with dementia and from 39.5%to 28.8%in people without dementia; the decrease was significant across all age groups and remained so in a sensitivity analysis where antipsychotics were removed. During the same period, comorbidity scores increased in people with and without dementia. Conclusion: The declining use of PIM in people with dementia from 2000 to 2015 parallels the trend in the general older population. The use of PIM decreased despite increasing levels of comorbidity and was not solely attributable to the decreasing use of antipsychotics in people with dementia. However, PIM use remained more widespread in people with dementia who may be more vulnerable to the risks associated with PIM. Show more

Keywords: Dementia, inappropriate prescribing, pharmacoepidemiology, potentially inappropriate medication, time trend

DOI: 10.3233/JAD-200627

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1459-1470, 2021

Authors: Lee, Yang Hyun | Jeon, Seun | Yoo, Han Soo | Chung, Seok Jong | Jung, Jin Ho | Baik, Kyoungwon | Sohn, Young H. | Lee, Phil Hyu | Yun, Mijin | Evans, Alan C. | Ye, Byoung Seok

Article Type: Research Article

Abstract: Background: The relationship among amyloid-β (Aβ) deposition on amyloid positron emission tomography (PET), cortical metabolism on 18 F-fluoro-2-deoxy-D-glucose (FDG)-PET, and clinical diagnosis has not been elucidated for both Alzheimer’s disease (AD) and Lewy body disease (LBD). Objective: We investigated the patterns of cerebral metabolism according to the presence of AD and LBD. Methods: A total of 178 subjects were enrolled including 42 pure AD, 32 pure LBD, 34 Lewy body variant AD (LBVAD), 15 LBD with amyloid, 26 AD with dementia with Lewy bodies (DLB), and 29 control subjects. Pure AD, LBVAD, and AD with DLB …groups had biomarker-supported diagnoses of typical AD, while pure LBD, LBD with amyloid, and AD with DLB groups had biomarker-supported diagnoses of typical LBD. Typical AD and LBD with amyloid showed amyloid-positivity on 18 F-florbetaben (FBB) PET, while typical LBD and LBVAD had abnormalities on dopamine transporter PET. We measured regional patterns of glucose metabolism using FDG-PET and evaluated their relationship with AD and LBD. Results: Compared with control group, typical AD and typical LBD commonly exhibited hypometabolism in the bilateral temporo-parietal junction, precuneus, and posterior cingulate cortex. Typical AD showed an additional hypometabolism in the entorhinal cortex, while patients with dopamine transporter abnormality-supported diagnosis of LBD showed diffuse hypometabolism that spared the sensory-motor cortex. Although the diffuse hypometabolism in LBD also involved the occipital cortex, prominent occipital hypometabolism was only seen in LBD with amyloid group. Conclusion: Combining clinical and metabolic evaluations may enhance the diagnostic accuracy of AD, LBD, and mixed disease cases. Show more

Keywords: Alzheimer’s disease, amyloid, glucose metabolism, lewy body disease

DOI: 10.3233/JAD-201094

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1471-1487, 2021

Authors: Ilango, Sindana D. | Gonzalez, Kevin | Gallo, Linda | Allison, Matthew A. | Cai, Jianwen | Isasi, Carmen R. | Hosgood, Dean H. | Vasquez, Priscilla M. | Zeng, Donglin | Mortamais, Marion | Gonzalez, Hector | Benmarhnia, Tarik

Article Type: Research Article

Abstract: Background: Hispanics/Latinos in the United States are more likely to live in neighborhoods with greater exposure to air pollution and are projected to have the largest increase in dementia among race/ethnic minority groups. Objective: We examined the associations of air pollution with performance on cognitive function tests in Hispanic/Latino adults. Methods: We used data from the San Diego site of the Hispanic Community Health Study/Study of Latinos, an ongoing cohort of Hispanics/Latinos. This analysis focused on individuals ≥45 years of age who completed a neurocognitive battery examining overall mental status, verbal learning, memory, verbal fluency, and …executive function (n  = 2,089). Air pollution (PM2.5 and O3 ) before study baseline was assigned to participants’ zip code. Logistic and linear regression were used to estimate the associations of air pollution on overall mental status and domain-specific standardized test scores. Models accounted for complex survey design, demographic, and socioeconomic characteristics. Results: We found that for every 10μg/m3 increase in PM2.5 , verbal fluency worsened (β: –0.21 [95%CI: –0.68, 0.25]). For every 10 ppb increase in O3 , verbal fluency and executive function worsened (β: –0.19 [95%CI: –0.34, –0.03]; β: –0.01 [95%CI: –0.01, 0.09], respectively). We did not identify any detrimental effect of pollutants on other domains. Conclusion: Although we found suggestions that air pollution may impact verbal fluency and executive function, we observed no consistent or precise evidence to suggest an adverse impact of air pollution on cognitive level among this cohort of Hispanic/Latino adults. Show more

Keywords: Air pollution, cognitive dysfunction, cohort study, dementia, hispanics, latinos, particulate matter, ozone

DOI: 10.3233/JAD-200766

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1489-1496, 2021

Authors: Jobin, Benoît | Zahal, Rayane | Bussières, Eve-Line | Frasnelli, Johannes | Boller, Benjamin

Article Type: Research Article

Abstract: Background: Recently, subjective cognitive decline (SCD) has been considered to be one of the first signs of Alzheimer’s disease (AD). Since this potential early marker is sensitive but not specific to AD, combining it with other markers could ensure higher accuracy when predicting which persons with SCD will convert to AD. Since olfactory dysfunction is observable in both AD and mild cognitive impairment (MCI), it is a promising marker that could help improve the early diagnosis of AD. Objective: The aim of this meta-analysis was to verify whether the presence of SCD is associated with a decrease in …olfactory identification ability. Methods: We collected articles from the following databases: PsychNet, PubMed, Ebsco, and ProQuest using the keywords: “SCD”, “subjective cognitive decline”, “subjective cognitive impairment”, “subjective memory impairment”, “subjective memory decline”, “cognitive complaints”, “memory complaints”, “cognitive concerns”, “memory concerns”, “olfac*” and “smell”. We included articles according to the following criteria: 1) participants aged 50 and over; 2) presence of an SCD group or a conceptual equivalent; 3) presence of a healthy control group with the same age range; and 4) assessment of olfactory identification ability. Results: Five studies met the inclusion criteria. Small and homogeneous effects were observed for olfactory identification alteration in individuals with SCD relative to controls (g  = –0.16, 95% CI [–0.46, 0.14]). Conclusion: Despite the low number of studies included, the findings suggest that odor identification is slightly altered in SCD compared to healthy older adults. This alteration in individuals with SCD could be an early marker of AD. Show more

Keywords: Alzheimer’s disease, biomarker, meta-analysis, olfaction, olfactory identification, smell, subjective cognitive decline

DOI: 10.3233/JAD-201022

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1497-1507, 2021

Authors: Castagna, Alberto | Fabbo, Andrea | Manzo, Ciro | Lacava, Roberto | Ruberto, Carmen | Ruotolo, Giovanni

Article Type: Research Article

Abstract: Background: Background: Citicoline has been proven to have beneficial effects in patients with cognitive impairment. In previous studies, combined treatment with memantine and acetylcholinesterase inhibitors (AChEIs) maintained cognitive function in patients with Alzheimer’s disease (AD) better than memantine or AChEIs alone. Objective: To evaluate the effectiveness and safety of a combination therapy of oral citicoline, memantine, and an AChEI in AD when compared with memantine and an AChEI without citicoline. Methods: This was a retrospective multi-centric case-control study, conducted in Italian Centers for Cognitive Impairment and Dementia. Overall, 170 patients were recruited (34.11%of men, mean …age 76,81±4.93 years): 48.8%treated with memantine and donepezil; 48.2%with memantine and rivastigmine; 2.9%with memantine and galantamine. 89 patients (control-group) were treated with memantine and an AChEI, whereas 81 patients (case-group) were treated with oral citicoline 1000 mg/day added to memantine and an AChEI given orally. Cognitive functions, activities of daily living, instrumental activities of daily living, comorbidities, mood and behavioral disturbances were assessed at baseline, month 6, and month 12. Results: In the case group, MMSE score had a statistically significant increasing trend between T0 and T2 (14.88±2.95 versus 15.09±3.00; p  = 0.040), whereas in the control group, MMSE score showed a statistically significant decrease trend (14.37±2.63 versus 14.03±2.92 p  = 0.024). Conclusion: In older patients with AD, a triple therapy with citicoline, memantine, and AChEI was more effective than memantine and AChEI without citicoline in maintaining the MMSE total score after 12 months. Show more

Keywords: Acetylcholinesterase inhibitors, Alzheimer’s disease, citicoline, combined treatment, memantine

DOI: 10.3233/JAD-201211

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1509-1515, 2021

Authors: Martínez-Maldonado, Alejandra | Ontiveros-Torres, Miguel Ángel | Harrington, Charles R. | Montiel-Sosa, José Francisco | Prandiz, Raúl García-Tapia | Bocanegra-López, Patricia | Sorsby-Vargas, Andrew Michael | Bravo-Muñoz, Marely | Florán-Garduño, Benjamín | Villanueva-Fierro, Ignacio | Perry, George | Garcés-Ramírez, Linda | de la Cruz, Fidel | Martínez-Robles, Sandra | Pacheco-Herrero, Mar | Luna-Muñoz, José

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and progressive supranuclear palsy (PSP) are examples of neurodegenerative diseases, characterized by abnormal tau inclusions, that are called tauopathies. AD is characterized by highly insoluble paired helical filaments (PHFs) composed of tau with abnormal post-translational modifications. PSP is a neurodegenerative disease with pathological and clinical heterogeneity. There are six tau isoforms expressed in the adult human brain, with repeated microtubule-binding domains of three (3R) or four (4R) repeats. In AD, the 4R:3R ratio is 1:1. In PSP, the 4R isoform predominates. The lesions in PSP brains contain phosphorylated tau aggregates in both neurons and glial cells. …Objective: Our objective was to evaluate and compare the processing of pathological tau in PSP and AD. Methods: Double and triple immunofluorescent labeling with antibodies to specific post-translational tau modifications (phosphorylation, truncation, and conformational changes) and thiazin red (TR) staining were carried out and analyzed by confocal microscopy. Results: Our results showed that PSP was characterized by phosphorylated tau in neurofibrillary tangles (NFTs) and glial cells. Tau truncated at either Glu391 or Asp421 was not observed. Extracellular NFTs (eNFTs) and glial cells in PSP exhibited a strong affinity for TR in the absence of intact or phosphorylated tau. Conclusion: Phosphorylated tau was as abundant in PSP as in AD. The development of eNFTs from both glial cells and neuronal bodies suggests that truncated tau species, different from those observed in AD, could be present in PSP. Additional studies on truncated tau within PSP lesions could improve our understanding of the pathological processing of tau and help identify a discriminatory biomarker for AD and PSP. Show more

Keywords: Alzheimer’s disease, neurofibrillary tangle, progressive supranuclear palsy, tau protein, truncation

DOI: 10.3233/JAD-201139

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1517-1531, 2021

Authors: Prakash, Mithilesh | Abdelaziz, Mahmoud | Zhang, Linda | Strange, Bryan A. | Tohka, Jussi | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Quantitatively predicting the progression of Alzheimer’s disease (AD) in an individual on a continuous scale, such as the Alzheimer’s Disease Assessment Scale-cognitive (ADAS-cog) scores, is informative for a personalized approach as opposed to qualitatively classifying the individual into a broad disease category. Objective: To evaluate the hypothesis that the multi-modal data and predictive learning models can be employed for future predicting ADAS-cog scores. Methods: Unimodal and multi-modal regression models were trained on baseline data comprised of demographics, neuroimaging, and cerebrospinal fluid based markers, and genetic factors to predict future ADAS-cog scores for 12, 24, and …36 months. We subjected the prediction models to repeated cross-validation and assessed the resulting mean absolute error (MAE) and cross-validated correlation (ρ) of the model. Results: Prediction models trained on multi-modal data outperformed the models trained on single modal data in predicting future ADAS-cog scores (MAE12, 24 & 36 months = 4.1, 4.5, and 5.0, ρ12, 24 & 36 months = 0.88, 0.82, and 0.75). Including baseline ADAS-cog scores to prediction models improved predictive performance (MAE12, 24 & 36 months = 3.5, 3.7, and 4.6, ρ12, 24 & 36 months = 0.89, 0.87, and 0.80). Conclusion: Future ADAS-cog scores were predicted which could aid clinicians in identifying those at greater risk of decline and apply interventions at an earlier disease stage and inform likely future disease progression in individuals enrolled in AD clinical trials. Show more

Keywords: Alzheimer’s disease, machine learning, magnetic resonance imaging, multi-modal imaging, neuropsychology

DOI: 10.3233/JAD-200906

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1533-1546, 2021

Authors: Mehder, Rasha H. | Bennett, Brian M. | Andrew, R. David

Article Type: Research Article

Abstract: Background: Neuronal damage resulting from increased oxidative stress is important in the development of late onset/age-related Alzheimer’s disease (LOAD). We have developed an oxidative stress–related mouse model of LOAD based on gene deletion of aldehyde dehydrogenase 2 (ALDH2), an enzyme important for the detoxification of endogenous aldehydes arising from lipid peroxidation. Compared to wildtype (WT) mice, the knockout (KO) mice exhibit AD-like pathologies and a progressive decline in recognition and spatial memory. This progression presumably has a morphological basis induced by oxidative damage. Objective: We performed morphometric analyses in the dorsal hippocampal CA1 region (dCA1) to determine if …altered neuronal structure can help account for the progressive cognitive impairment in 3- to 12-month-old KO mice. Methods: Dendritic morphology was quantitatively analyzed by branched structured analysis and Sholl analysis following Golgi-Cox staining in WT mice (148 neurons) versus KO mice (180 neurons). Results: The morphology and complexity of dCA1 pyramidal neurons were similar at age 3 months in WTs and KOs. However, by 6 months there were significant reductions in apical and basal dendritic length, dendrite complexity, and spine density in KO versus WT mice that were maintained through ages 9 and 12 months. Immunostaining for protein adducts of the lipid peroxidation product 4-hydroxynonenal revealed significant increases in staining in dCA1 (but not ventral CA1) by 3 months, increasing through 12 months. Conclusion: This specific and progressive increase in dCA1 oxidative damage preceded detectable synaptic trimming in KO mice, in keeping with studies showing that lesions to dorsal hippocampus primarily impair cognitive memory. Show more

Keywords: CA1, dendrite, hippocampus, morphometry, oxidative stress, pyramidal neurons, spatial memory, spines

DOI: 10.3233/JAD-201024

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1547-1561, 2021

Authors: Lim, Yen Ying | Pase, Matthew P. | Buckley, Rachel F. | Yassi, Nawaf | Bransby, Lisa | Fowler, Christopher | Laws, Simon M. | Masters, Colin L. | Maruff, Paul

Article Type: Research Article

Abstract: Background: The apolipoprotein E (APOE ) ɛ 4 allele is associated with dose-response effects on cognitive dysfunction and dementia risk in older adults. However, its effects on cognition in middle-aged adults remains unclear. Objective: We examined effects of ɛ 4 heterozygosity and homozygosity on objective and subjective cognition in middle-aged adults enrolled in the Healthy Brain Project (HBP) and in older adults from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. Methods: HBP participants (1,000 non-carriers; 450 ɛ 4 heterozygotes; 50 ɛ 4 homozygotes) completed unsupervised assessments of the Cogstate Brief Battery (CBB), ratings of subjective …cognitive function and provided a saliva sample. AIBL cognitively normal participants (650 non-carriers; 204 ɛ 4 heterozygotes; 31 ɛ 4 homozygotes) completed in-person assessments of the CBB, ratings of subjective cognitive function and provided a blood sample. Results: Greater memory impairment was observed in middle-aged ɛ 4 homozygotes compared with ɛ 4 heterozygotes and non-carriers. When data from middle-aged (HBP) and older (AIBL) adults were pooled, the effect of ɛ 4 homozygosity and memory impairment increased with age. In both middle-aged and older adults, ɛ 4 heterozygotes did not differ from non-carriers on any measure of objective or subjective cognition. Conclusion: Memory impairment in ɛ 4 homozygotes is evident in adults aged 50-60 years, and this can be detected through unsupervised cognitive assessments. The effect of ɛ 4 homozygosity increases with older age. APOE ɛ 4 homozygosity has a negative impact on memory as early as midlife, but due to the subtle magnitude of effect, our findings support the necessity of online platforms in large cohorts to assess these complex relationships. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, early detection, memory

DOI: 10.3233/JAD-201281

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1563-1573, 2021

Authors: Peng, Zhouyuan | Nishimoto, Hiroyuki | Kinoshita, Ayae

Article Type: Research Article

Abstract: Background: With the rapid aging of the population, the issue of driving by dementia patients has been causing increasing concern worldwide. Objective: To investigate the driving difficulties faced by senior drivers with cognitive impairment and identify the specific neuropsychological tests that can reflect specific domains of driving maneuvers. Methods: Senior drivers with cognitive impairment were investigated. Neuropsychological tests and a questionnaire on demographic and driving characteristics were administered. Driving simulator tests were used to quantify participants’ driving errors in various domains of driving. Results: Of the 47 participants, 23 current drivers, though they had …better cognitive functions than 24 retired drivers, were found to have impaired driving performance in the domains of Reaction, Starting and stopping, Signaling, and Overall (wayfinding and accidents). The parameters of Reaction were significantly related to the diagnosis, and the scores of MMSE, TMT-A, and TMT-B. As regards details of the driving errors, “Sudden braking” was associated with the scores of MMSE (ρ = –0.707, p  < 0.01), BDT (ρ = –0.560, p  < 0.05), and ADAS (ρ = 0.758, p  < 0.01), “Forgetting to use turn signals” with the TMT-B score (ρ = 0.608, p  < 0.05), “Centerline crossings” with the scores of MMSE (ρ = –0.582, p  < 0.05) and ADAS (ρ = 0.538, p  < 0.05), and “Going the wrong way” was correlated with the score of CDT (ρ = –0.624, p  < 0.01). Conclusion: Different neuropsychological factors serve as predictors of different specific driving maneuvers segmented from driving performance. Show more

Keywords: Automobile driving, cognitive impairment, computer simulation, dementia, neuropsychological tests

DOI: 10.3233/JAD-201323

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1575-1587, 2021

Authors: Rodriguez, Francisca S. | Pabst, Alexander | Heser, Kathrin | Kleineidam, Luca | Hajek, Andre | Eisele, Marion | Röhr, Susanne | Löbner, Margrit | Wiese, Birgitt | Angermeyer, Matthias C. | Maier, Wolfgang | Scherer, Martin | Wagner, Michael | König, Hans-Helmut | Riedel-Heller, Steffi G.

Article Type: Research Article

Abstract: Background: Only little evidence is available on disorientation, one of the most challenging symptoms of Alzheimer’s disease and related dementias. Objectives: The aim of this study was to investigate the prevalence of disorientation in older age in association with the level of cognitive status, personal characteristics, and life events. Methods: Three longitudinal population-based cohort studies on cognitive health of elderly adults were harmonized (LEILA 75 + , AgeCoDe/AgeQualiDe, AgeMooDe). Participants who completed a baseline and at least one follow-up assessment of cognitive functioning and who did not have stroke, Parkinson’s disease, atherosclerosis, kidney disease, and/or alcoholism were included …in the analysis (n  = 2135, 72.6% female, mean age 80.2 years). Data was collected in standardized interviews and questionnaires with the participant, a proxy informant, and the participant’s general practitioner. Results: Making three errors in the MMSE other than in the questions on orientation (MMSEwo ) came with a probability of 7.8% for disorientation, making ten errors with a probability of 88.9%. A lower MMSEwo score (HR 0.75, CI 95 0.71–0.79, p  < 0.001), older age (HR 1.11, CI 95 1.08–1.14, p  < 0.001), and living in a nursing home (HR 1.64, CI 95 1.02–2.64, p  = 0.042) were associated with incident disorientation. Impairments in walking (OR 2.41, CI 95 1.16–4.99, p  = 0.018) were associated with a greater probability for prevalent disorientation. None of the life events were significant. Conclusion: Our findings suggest that disorientation is primarily associated with cognitive status. Regular walking activities might possibly reduce the risk for disorientation but further research is necessary. Show more

Keywords: Cognitive functioning, cognitive status, dementia, longitudinal cohort, orientation, symptoms

DOI: 10.3233/JAD-201008

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1589-1599, 2021

Authors: Arendt, Johan Frederik Håkonsen | Horváth-Puhó, Erzsébet | Sørensen, Henrik Toft | Nexø, Ebba | Pedersen, Lars | Ording, Anne Gulbech | Henderson, Victor W.

Article Type: Research Article

Abstract: Background: It is controversial whether B12 deficiency causes dementia or B12 treatment can prevent dementia. Objective: To assess associations between low plasma (P-)B12 levels, B12 treatment, and risk of Alzheimer’s disease (AD; primary outcome) and all-cause or vascular dementia (secondary outcomes). Methods: We conducted a population-based cohort study using Danish registry data to assess associations between low P-B12 levels, high-dose injection or oral B12 treatment, and risk of dementia (study period 2000–2013). The primary P-B12 cohort included patients with a first-time P-B12 measurement whose subsequent B12 treatment was recorded. The secondary B12 treatment cohort included patients …with a first-time B12 prescription and P-B12 measurement within one year before this prescription. For both cohorts, patients with low P-B12 levels (<200 pmol/L) were propensity score-matched 1:1 with patients with normal levels (200–600 pmol/L). We used multivariable Cox regression to compute 0–15-year hazard ratios for dementia. Results: For low P-B12 and normal P-B12 level groups, we included 53,089 patients in the primary P-B12 cohort and 13,656 patients in the secondary B12 treatment cohort. In the P-B12 cohort, hazard ratios for AD centered around one, regardless of follow-up period or treatment during follow-up. In the B12 treatment cohort, risk of AD was unaffected by low pre-treatment P-B12 levels, follow-up period and type of B12 treatment. Findings were similar for all-cause and vascular dementia. Conclusion: We found no associatio1n between low P-B12 levels and dementia. Associations were unaffected by B12 treatment. Results do not support routine screening for B12 deficiency in patients with suspected dementia. Show more

Keywords: Alzheimer’s disease, cobalamin, cohort studies, clinical nutrition, registries

DOI: 10.3233/JAD-201096

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1601-1612, 2021

Authors: Li, Sen | Yi, Yushan | Cui, Ke | Zhang, Yanqiu | Chen, Yange | Han, Dou | Sun, Ling | Zhang, Xiaohui | Chen, Fei | Zhang, Yixin | Yang, Yufeng

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a common cause of dementia among elderly people. Hyperphosphorylation and aggregation of tau correlates with the clinical progression of AD; therefore, therapies targeting the aggregation of tau may have potential applications for anti-AD drug development. Several inhibitors of tau aggregation, including small molecules and antibodies, have been found to decrease the aggregation of tau and the corresponding pathology. Objective: To screen one kind of single-chain variable fragment (scFv) antibody which could inhibit the aggregation of tau and ameliorate its cytotoxicity. Methods/Results: Using phosphorylated tau (pTau) as an antigen, we obtained a …scFv antibody via the screening of a high-capacity phage antibody library. Biochemical analysis revealed that this scFv antibody (scFv T1) had a strong ability to inhibit pTau aggregation both in dilute solutions and under conditions of macromolecular crowding. ScFv T1 could also depolymerize preformed pTau aggregates in vitro . Furthermore, scFv T1 was found to be able to inhibit the cytotoxicity of extracellular pTau aggregates and ameliorate tau-mediated toxicity when coexpressed with a hTauR406W mutant in the eye of transgenic Drosophila flies. Conclusion: This scFv T1 antibody may be a potential new therapeutic agent against AD. Our methods can be used to develop novel strategies against protein aggregation for the treatment of neurodegenerative diseases. Show more

Keywords: Aggregation, Alzheimer’s disease, Drosophila , single-chain variable fragment antibody, tau, tauopathy, toxicity

DOI: 10.3233/JAD-191266

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1613-1629, 2021

Authors: Park, Jin-Hyuck | Lee, Sang Ah

Article Type: Research Article

Abstract: Background: Although episodic memory impairment is one of the hallmarks of Alzheimer’s disease (AD), the relative decline in the components of episodic memory (What, Where , and When ) and the effects of cognitive training on each of them are still unknown. Objective: We aimed to independently assess the impairment in each component of episodic memory in early to moderate AD and address whether it can be enhanced through active, spatiotemporal episodic training. Methods: A non-verbal scene-based episodic memory task was developed to assess the ability to remember What, Where, and When information. Experiment …1 tested whether this task can differentiate AD subjects (N = 16) from healthy controls (N = 16). In Experiment 2, 13 AD subjects underwent 16 training sessions, followed by a re-administration of the scene-based memory task. Experiment 3 tested 42 healthy older adults and 51 younger adults on the same task to investigate the effects of normal aging. Results: Of the three components, When memory had the highest predictive power in distinguishing AD from normal aging. Following training of AD subjects, only Where memory improved. Only What memory revealed a significant decline in healthy subjects from 65–85 years of age. Conclusion: These findings shed new light on the importance of the temporal component of episodic memory as a behavioral marker of AD. The selective improvement of spatial but not temporal memory through training further demonstrates the fragility of temporal memory even in early AD. Neuroscientific research is needed to distinguish whether the Where component was enhanced by improvements in hippocampal spatial representation or by other compensatory mechanisms. Show more

Keywords: Alzheimer’s disease, cognitive training, episodic memory, temporal order memory, visual scene memory, What-Where-When memory

DOI: 10.3233/JAD-200892

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1631-1646, 2021

Authors: Wu, Ruozhen | Gu, Jianlan | Zhou, Dingwei | Tung, Yunn Chyn | Jin, Nana | Chu, Dandan | Hu, Wen | Wegiel, Jerzy | Gong, Cheng-Xin | Iqbal, Khalid | Liu, Fei

Article Type: Research Article

Abstract: Background: Neurofibrillary pathology of abnormally hyperphosphorylated tau spreads along neuroanatomical connections, underlying the progression of Alzheimer’s disease (AD). The propagation of tau pathology to axonally connected brain regions inevitably involves trafficking of seeding-competent tau within the axonal compartment of the neuron. Objective: To determine the seeding activity of tau in cerebral gray and white matters of AD. Methods: Levels of total tau, hyperphosphorylation of tau, and SDS- and β-mercaptoethanol–resistant high molecular weight tau (HMW-tau) in crude extracts from gray and white matters of AD frontal lobes were analyzed by immuno-blots. Tau seeding activity …was quantitatively assessed by measuring RIPA buffer–insoluble tau in HEK-293FT/tau151-391 cells treated with brain extracts. Results: We found a comparable level of soluble tau in gray matter versus white matter of control brains, but a higher level of soluble tau in gray matter than white matter of AD brains. In AD brains, tau is hyperphosphorylated in both gray and white matters, with a higher level in the former. The extracts of both gray and white matters of AD brains seeded tau aggregation in HEK-293FT/tau151–391 cells but the white matter showed less potency. Seeding activity of tau in brain extracts was positively correlated with the levels of tau hyperphosphorylation and HMW-tau. RIPA-insoluble tau, but not RIPA-soluble tau, was hyperphosphorylated tau at multiple sites. Conclusion: Both gray and white matters of AD brain contain seeding-competent tau that can template aggregation of hyperphosphorylated tau, but the seeding potency is markedly higher in gray matter than in white matter. Show more

Keywords: Alzheimer’s disease, gray matter, propagation of tau pathology, seeding-competent tau, white matter

DOI: 10.3233/JAD-201290

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1647-1659, 2021

Authors: Costa, Ana Sofia | Pinho, João | Kučikienė, Domantė | Reich, Arno | Schulz, Jörg B. | Reetz, Kathrin

Article Type: Research Article

Abstract: Background: The overlap between cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD) is frequent and relevant for patients with cognitive impairment. Objective: To assess the role of the diagnosis of CAA on the phenotype of amyloid-β (Aβ) positive patients from a university-hospital memory clinic. Methods: Consecutive patients referred for suspected cognitive impairment, screened for Aβ pathological changes in cerebrospinal fluid (CSF), with available MRI and neuropsychological results were included. We determined the association between probable CAA and clinical, neuropsychological (at presentation and after a mean follow-up of 17 months in a sub-sample) and MRI (atrophy, white …matter hyperintensities, perivascular spaces) characteristics. Results: Of 218 amyloid-positive patients, 8.3% fulfilled criteria for probable CAA. A multivariable logistic regression showed an independent association of probable CAA with lower Aβ1–42 (adjusted odds ratio [aOR] = 0.94, 95% confidence interval [95% CI] = 0.90–0.98, p  = 0.003), and Aβ1–40 (aOR = 0.98, 95% CI=0.97–0.99 p  = 0.017) levels in CSF, and presence of severe burden of enlarged perivascular spaces (EPVS) in the centrum semiovale (aOR = 3.67, 95% CI = 1.21–11.15, p  = 0.022). Linear mixed-model analysis showed that both groups significantly deteriorated in global clinical severity, executive function and memory. Nevertheless, the presence of probable CAA did not differently affect the rate of cognitive decline. Conclusion: The presence of probable CAA in Aβ positive patients was associated with lower Aβ1–42 and Aβ1–40 CSF levels and increased centrum semiovale EPVS burden, but did not independently influence clinical phenotype nor the rate of cognitive decline within our follow-up time window. Show more

Keywords: Alzheimer’s disease, brain perivascular spaces, cerebral amyloid angiopathy, cerebral small vessel disease, cognitive decline, longitudinal studies

DOI: 10.3233/JAD-201218

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1661-1672, 2021

Authors: Hassanin, Hany I. | Tawfik, Heba M. | Zygouris, Stelios | Tsatali, Marianna | Sweed, Hala S. | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: With greying of nations, dementia becomes a public health priority. The rising dementia prevalence escalates both health care expenses and burden, placing the entire healthcare system and caregivers under huge stress. Cognition-oriented interventions have been shown to enhance the overall cognitive performance among healthy and cognitively impaired older adults. Objective: This article is assumed to be a steppingstone for the introduction and establishment of cognition- oriented interventions in Egypt. In addition, it aims to offer provisional guidance for health care providers in Arab speaking countries in a stepwise approach in order to establish cognition-oriented intervention services and …help them to evaluate and monitor their efficacy. Methods: Aconsortium of Egyptian and Greek specialists developed a protocol for the operations of the Ain Shams Cognitive Training Lab and the provision of cognition-oriented interventions. This protocol is based on a previous successful protocol that has been implemented in Greece for more than 10 years and is co-designed to fit the needs of older adults in Arabic speaking countries. Results: The types of services offered, their objectives, recruitment of participants, delivery of interventions, measurement of outcomes and privacy policy are all outlined in the policy. Conclusion: Establishing the appropriate framework in which cognitive training strategies can be adapted and implemented in Arabic population, constitutes an inevitable achievement in healthy ageing and can be also assumed as a dementia prevention strategy. Moreover, setting up the first cognitive laboratory in Egypt older adults, can be a model of good practice across the Arabic countries. Show more

Keywords: Aging, Alzheimer’s disease, cognitive remediation, computers, dementia, memory disorders, mild cognitive impairment, psychosocial support systems, web-based intervention

DOI: 10.3233/JAD-201278

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1673-1682, 2021

Authors: Bohlken, Jens | Riedel-Heller, Steffi | Steininger, Gilles | Kostev, Karel | Michalowsky, Bernhard

Article Type: Research Article

Abstract: Background: The number of patients with dementia is forecast to grow continuously. However, there are indications that the incidence and prevalence is falling in high-income countries. Objective: To examine whether any effects of declining incidence and prevalence rates of dementia and mild cognitive impairment (MCI) were evident in Germany between 2015 and 2019. Methods: The analysis was based on 797 general and 132 specialists (neurological/psychiatric) practices and included 10.1 million patients aged 18 years and older who visited between January 2014 and December 2019 one of the practitioners. The prevalence and incidence of dementia and MCI …were demonstrated descriptively. Results: Between 2015 and 2019, the prevalence (incidence) of dementia decreased from 2.18%(0.44%) in 2015 to 2.07%(0.35%) in 2019. A relatively large decrease in the prevalence (incidence) of dementia was observed in patients aged 80 and older, at –1.47%(–0.62%), compared to younger patients, at –0.40%(–0.18%). By contrast, the prevalence and incidence of MCI have remained constant over the years (0.19%to 0.22%and 0.06%, respectively). Overall, the number of patients diagnosed with dementia decreased slightly by 1%while the number of patients diagnosed with MCI increased by 17%. Conclusion: Our results confirmed the reduction in the prevalence and incidence of dementia and revealed a decrease in the number of patients with dementia despite continued demographic changes. Future studies are warranted to determine whether the results are caused by changing risk and lifestyle factors or changes in medical diagnosis and treatment behavior of the practitioners. Show more

Keywords: Alzheimer’s disease, dementia, diagnosis, incidence, mild cognitive impairment, prevalence

DOI: 10.3233/JAD-201385

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1683-1690, 2021

Authors: Zhang, Fan | Petersen, Melissa | Johnson, Leigh | Hall, James | O’Bryant, Sid E.

Article Type: Research Article

Abstract: Background: There is a need for more reliable diagnostic tools for the early detection of Alzheimer’s disease (AD). This can be a challenge due to a number of factors and logistics making machine learning a viable option. Objective: In this paper, we present on a Support Vector Machine Leave-One-Out Recursive Feature Elimination and Cross Validation (SVM-RFE-LOO) algorithm for use in the early detection of AD and show how the SVM-RFE-LOO method can be used for both classification and prediction of AD. Methods: Data were analyzed on n  = 300 participants (n  = 150 AD; n  = 150 cognitively normal …controls). Serum samples were assayed via a multi-plex biomarker assay platform using electrochemiluminescence (ECL). Results: The SVM-RFE-LOO method reduced the number of features in the model from 21 to 16 biomarkers and achieved an area under the curve (AUC) of 0.980 with a sensitivity of 94.0% and a specificity of 93.3%. When the classification and prediction performance of SVM-RFE-LOO was compared to that of SVM and SVM-RFE, we found similar performance across the models; however, the SVM-RFE-LOO method utilized fewer markers. Conclusion: We found that 1) the SVM-RFE-LOO is suitable for analyzing noisy high-throughput proteomic data, 2) it outperforms SVM-RFE in the robustness to noise and in the ability to recover informative features, and 3) it can improve the prediction performance. Our recursive feature elimination model can serve as a general model for biomarker discovery in other diseases. Show more

Keywords: Alzheimer’s disease, blood biomarkers, machine learning, recursive feature elimination, support vector machine

DOI: 10.3233/JAD-201254

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1691-1700, 2021

Authors: Hayashi, Tetsuo | Shimonaka, Shotaro | Elahi, Montasir | Matsumoto, Shin-Ei | Ishiguro, Koichi | Takanashi, Masashi | Hattori, Nobutaka | Motoi, Yumiko

Article Type: Research Article

Abstract: Background: Human tauopathy brain injections into the mouse brain induce the development of tau aggregates, which spread to functionally connected brain regions; however, the features of this neurotoxicity remain unclear. One reason may be short observational periods because previous studies mostly used mutated-tau transgenic mice and needed to complete the study before these mice developed neurofibrillary tangles. Objective: To examine whether long-term incubation of Alzheimer’s disease (AD) brain in the mouse brain cause functional decline. Methods: We herein used Tg601 mice, which overexpress wild-type human tau, and non-transgenic littermates (NTg) and injected an insoluble fraction of …the AD brain into the unilateral hippocampus. Results: After a long-term (17–19 months) post-injection, mice exhibited learning deficits detected by the Barnes maze test. Aggregated tau pathology in the bilateral hippocampus was more prominent in Tg601 mice than in NTg mice. No significant changes were observed in the number of Neu-N positive cells or astrocytes in the hippocampus, whereas that of Iba-I-positive microglia increased after the AD brain injection. Conclusion: These results potentially implicate tau propagation in functional decline and indicate that long-term changes in non-mutated tau mice may reflect human pathological conditions. Show more

Keywords: Microglia, neurodegeneration, propagation, tau protein, tauopathies

DOI: 10.3233/JAD-201002

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1701-1711, 2021

Authors: Borda, Miguel Germán | Ayala Copete, Ana María | Tovar-Rios, Diego Alejandro | Jaramillo-Jimenez, Alberto | Giil, Lasse Melvær | Soennesyn, Hogne | Gómez-Arteaga, Camilo | Venegas-Sanabria, Luis Carlos | Kristiansen, Ida | Chavarro-Carvajal, Diego Andrés | Caicedo, Sandra | Cano-Gutierrez, Carlos Alberto | Vik-Mo, Audun | Aarsland, Dag

Article Type: Research Article

Abstract: Background: In dementia, functional status depends on multiple factors in addition to cognition. Nutritional status is a potentially modifiable factor related to homeostasis and proper functioning of body systems and may contribute to cognitive and functional decline. Objective: This paper aims to analyze the association of malnutrition with the course of cognitive and functional decline in people living with dementia. Methods: This is an analysis of a longitudinal cohort study, the Dementia Study of Western Norway. Data of 202 patients diagnosed with mild dementia were analyzed; Alzheimer’s disease (AD) (n  = 103), Lewy body dementia (LBD) (n … = 74), and other dementias (OD) (n  = 25). Cognition was assessed with the Mini-Mental State Examination and functional decline through the activities of daily living included in the Rapid Disability Rating Scale. The Global Leadership Initiative on Malnutrition Index was used to determine nutritional status. Associations of nutritional status with cognitive and functional decline were evaluated through adjusted linear mixed models. Results: At baseline, the prevalence of general malnutrition was 28.7%; 17.3% were classified as moderate malnutrition and 11.38% as severe malnutrition (there were no significant differences between AD and LBD). Malnutrition at diagnosis and over follow-up was a significant predictor of functional-decline, but not of cognitive decline. Conclusion: According to our results malnutrition was associated with faster functional loss but, not cognitive decline in older adults with dementia. A more comprehensive dementia approach including nutritional assessments could improve prognosis. Show more

Keywords: Activities of daily living, Alzheimer’s disease, dementia, Lewy body dementia, malnutrition

DOI: 10.3233/JAD-200961

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1713-1722, 2021

Authors: Sragovich, Shlomo | Gershovits, Michael | Lam, Jacqueline C.K. | Li, Victor O.K. | Gozes, Illana

Article Type: Research Article

Abstract: Background: We recently discovered autism/intellectual disability somatic mutations in postmortem brains, presenting higher frequency in Alzheimer’s disease subjects, compared with the controls. We further revealed high impact cytoskeletal gene mutations, coupled with potential cytoskeleton-targeted repair mechanisms. Objective: The current study was aimed at further discerning if somatic mutations in brain diseases are presented only in the most affected tissue (the brain), or if blood samples phenocopy the brain, toward potential diagnostics. Methods: Variant calling analyses on an RNA-seq database including peripheral blood samples from 85 soldiers (58 controls and 27 with symptoms of post-traumatic stress disorder, …PTSD) was performed. Results: High (e.g., protein truncating) as well as moderate impact (e.g., single amino acid change) germline and putative somatic mutations in thousands of genes were found. Further crossing the mutated genes with autism, intellectual disability, cytoskeleton, inflammation, and DNA repair databases, identified the highest number of cytoskeletal-mutated genes (187 high and 442 moderate impact). Most of the mutated genes were shared and only when crossed with the inflammation database, more putative high impact mutated genes specific to the PTSD-symptom cohorts versus the controls (14 versus 13) were revealed, highlighting tumor necrosis factor specifically in the PTSD-symptom cohorts. Conclusion: With microtubules and neuro-immune interactions playing essential roles in brain neuroprotection and Alzheimer-related neurodegeneration, the current mutation discoveries contribute to mechanistic understanding of PTSD and brain protection, as well as provide future diagnostics toward personalized military deployment strategies and drug design. Show more

Keywords: Alzheimer’s disease, autism, blood biomarkers, cognition, post-traumatic stress disorder

DOI: 10.3233/JAD-201158

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1723-1734, 2021

Authors: Lehingue, Elsa | Gueniat, Julien | Jourdaa, Sandra | Hardouin, Jean BenoÎt | Pallardy, Amandine | Courtemanche, Hélène | Rocher, Laëtitia | Etcharry-Bouyx, Frédérique | Auriacombe, Sophie | Mollion, Hélène | Formaglio, Maité | Rouaud, Olivier | Bretonnière, Cédric | Thomas-Antérion, Catherine | Boutoleau-Bretonnière, Claire

Article Type: Research Article

Abstract: Background: The frontal variant of Alzheimer’s disease (fAD) is poorly understood and poorly defined. The diagnosis remains challenging. The main differential diagnosis is the behavioral variant of frontotemporal degeneration (bvFTD). For fAD, there is some dissociation between the clinical frontal presentation and imaging and neuropathological studies, which do not always find a specific involvement of the frontal lobes. DAPHNE is a behavioral scale, which demonstrated excellent performance to distinguish between bvFTD and AD. Objective: The aim of the present study was to assess the reliability of this new tool to improve the clinical diagnosis of fAD. …Methods: Twenty fAD patients and their caregivers were prospectively included and were compared with 36 bvFTD and 22 AD patients. Results: The three main behavioral disorders in the fAD patients were apathy, loss of empathy, and disinhibition. Three disorders were discriminant because they were less frequent and less severe in the fAD patients than in the bvFTD patients, namely hyperorality, neglect, and perseverations. This specific pattern of behavioral disorders was corroborated by SPECT or 18 FDG PET-CT scan that showed that patients with fAD could have a medial frontal hypoperfusion, whereas in bvFTD patients the orbitofrontal cortex was the main involved region, with more diffuse hypoperfusion. Conclusion: We demonstrated that DAPHNE had good sensitivity and good specificity to discriminate between the three groups and in particular between fAD and bvFTD patients. DAPHNE is a quick tool that could help clinicians in memory clinics not only to differentiate bvFTD from typical AD but also from fAD. Show more

Keywords: Alzheimer’s disease, behavioral disorders, frontotemporal dementia, scale

DOI: 10.3233/JAD-201088

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1735-1745, 2021

Authors: Iliadou, Paraskevi | Paliokas, Ioannis | Zygouris, Stelios | Lazarou, Eftychia | Votis, Konstantinos | Tzovaras, Dimitrios | Tsolaki, Magdalini

Article Type: Research Article

Abstract: Background: Electroencephalography (EEG) has been used to assess brain activity while users are playing an immersive serious game. Objective: To assess differences in brain activation as measured with a non-intrusive wearable EEG device, differences in game performance and correlations between EEG power, game performance and global cognition, between cognitively impaired and non-impaired older adults, during the administration of a novel self-administered serious game-based test, the Virtual Supermarket Test (VST). Methods: 43 older adults with subjective cognitive decline (SCD) and 33 older adults with mild cognitive impairment (MCI) were recruited from day centers for cognitive disorders. Global …cognition was assessed with the Montreal Cognitive Assessment (MoCA). Brain activity was measured with a non-intrusive wearable EEG device in a resting state condition and while they were administered the VST. Results: During resting state condition, the MCI group showed increased alpha, beta, delta, and theta band power compared to the SCD group. During the administration of the VST, the MCI group showed increased beta and theta band power compared to the SCD group. Regarding game performance, alpha, beta, delta, and theta rhythms were positively correlated with average duration, while delta rhythm was positively correlated with mean errors. MoCA correlated with alpha, beta, delta, and theta rhythms and with average game duration and mean game errors indicating that elevated EEG rhythms in MCI may be associated with an overall cognitive decline. Conclusion: VST performance can be used as a digital biomarker. Cheap commercially available wearable EEG devices can be used for obtaining brain activity biomarkers. Show more

Keywords: Age-related memory disorders, cognitive assessment screening instrument, computer games, dementia, EEG, mild cognitive impairment, neurocognitive tests, screening, self-evaluation

DOI: 10.3233/JAD-201300

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1747-1759, 2021

Authors: Shaffer, Rachel M. | Li, Ge | Adar, Sara D. | Dirk Keene, C. | Latimer, Caitlin S. | Crane, Paul K. | Larson, Eric B. | Kaufman, Joel D. | Carone, Marco | Sheppard, Lianne

Article Type: Research Article

Abstract: Background: Evidence links fine particulate matter (PM2.5 ) to Alzheimer’s disease (AD), but no community-based prospective cohort studies in older adults have evaluated the association between long-term exposure to PM2.5 and markers of AD neuropathology at autopsy. Objective: Using a well-established autopsy cohort and new spatiotemporal predictions of air pollution, we evaluated associations of 10-year PM2.5 exposure prior to death with Braak stage, Consortium to Establish a Registry for AD (CERAD) score, and combined AD neuropathologic change (ABC score). Methods: We used autopsy specimens (N = 832) from the Adult Changes in Thought (ACT) study, with …enrollment ongoing since 1994. We assigned long-term exposure at residential address based on two-week average concentrations from a newly developed spatiotemporal model. To account for potential selection bias, we conducted inverse probability weighting. Adjusting for covariates with tiered models, we performed ordinal regression for Braak and CERAD and logistic regression for dichotomized ABC score. Results: 10-year average (SD) PM2.5 from death across the autopsy cohort was 8.2 (1.9) μg/m3 . Average age (SD) at death was 89 (7) years. Each 1μg/m3 increase in 10-year average PM2.5 prior to death was associated with a suggestive increase in the odds of worse neuropathology as indicated by CERAD score (OR: 1.35 (0.90, 1.90)) but a suggestive decreased odds of neuropathology as defined by the ABC score (OR: 0.79 (0.49, 1.19)). There was no association with Braak stage (OR: 0.99 (0.64, 1.47)). Conclusion: We report inconclusive associations between PM2.5 and AD neuropathology at autopsy among a cohort where 94% of individuals experienced 10-year exposures below the current EPA standard. Prior studies of AD risk factors and AD neuropathology are similarly inconclusive, suggesting alternative mechanistic pathways for disease or residual confounding. Show more

Keywords: Air pollution, Alzheimer’s disease, autopsy, dementia, neuropathology, particulate matter

DOI: 10.3233/JAD-201005

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1761-1773, 2021

Authors: Lu, Yifei | Pike, James R. | Selvin, Elizabeth | Mosley, Thomas | Palta, Priya | Sharrett, A. Richey | Thomas, Alvin | Loehr, Laura | Sidney Barritt, A. | Hoogeveen, Ron C. | Heiss, Gerardo

Article Type: Research Article

Abstract: Background: Low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the low physiologic range, surrogate markers for reduced liver metabolic function, are associated with cerebral hypometabolism, impairment in neurotransmitter production and synaptic maintenance, and a higher prevalence of dementia. It is unknown whether a prospective association exists between low liver enzyme levels and incident dementia. Objective: To determine whether low levels of ALT and AST are associated with higher risk of incident dementia. Methods: Plasma ALT and AST were measured on 10,100 study participants (mean age 63.2 years, 55% female, 22% black) in 1996–1998. …Dementia was ascertained from comprehensive neuropsychological assessments, annual contact, and medical record surveillance. Cox proportional hazards regression was used to estimate the association. Results: During a median follow-up of 18.3 years (maximum 21.9 years), 1,857 individuals developed dementia. Adjusted for demographic factors, incidence rates of dementia were higher at the lower levels of ALT and AST. Compared to the second quintile, ALT values <10th percentile were associated with a higher risk of dementia (hazard ratio [HR] 1.34, 95% CI 1.08–1.65). The corresponding HR was 1.22 (0.99–1.51) for AST. Conclusion: Plasma aminotransferases <10th percentile of the physiologic range at mid-life, particularly ALT, were associated with greater long-term risk of dementia, advocating for attention to the putative role of hepatic function in the pathogenesis of dementia. Show more

Keywords: ALT, Alzheimer’s disease, AST, dementia, liver hypometabolism

DOI: 10.3233/JAD-201241

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1775-1784, 2021

Authors: Qian, Xueshen | Zhang, Shuang | Duan, Lian | Yang, Fengchun | Zhang, Kun | Yan, Fuhua | Ge, Song

Article Type: Research Article

Abstract: Background: Although periodontitis is reportedly associated with increased cognitive decline in Alzheimer’s disease, the mechanisms underlying this process remain unknown. Porphyromonas gingivalis lipopolysaccharide (P.g-LPS) is an endotoxin associated with periodontal disease. Objective: We investigated the effect of periodontitis on learning capacity and memory of amyloid-β protein precursor (AβPP)/presenilin (PS1) transgenic mice along with the mechanisms underlying these effects. Methods: Mice were randomly assigned to three groups, namely AβPP/PS1 (control), P.g-LPS Injection, and P.g-LPS Injection + Ligation. Mice from the P.g-LPS Injection group were injected with P.g-LPS in the periodontal tissue three times per week for …8 weeks, while mice from the P.g-LPS Injection + Ligation group were injected with P.g-LPS and subjected to ligation of the gingival sulcus of the maxillary second molar. Results: Expression of gingival proinflammatory cytokines as well as alveolar bone resorption in P.g-LPS-injected and ligatured mice was increased compared to that in control mice. Mice in the P.g-LPS Injection + Ligation group exhibited cognitive impairment and a significant reduction in the number of neurons. Glial cell activation in the experimental groups with significantly increased amyloid-β (Aβ) levels was more pronounced relative to the control group. Induction of periodontitis was concurrent with an increase in cyclooxygenase-2, inducible nitric oxide synthase, AβPP, and beta-secretase 1 expression and a decrease in A disintegrin and metalloproteinase domain-containing protein 10 expression. Conclusion: These findings indicated that periodontitis exacerbated learning and memory impairment in AβPP/PS1 mice and augmented Aβ and neuroinflammatory responses. Our study provides a theoretical basis for risk prediction and early intervention of Alzheimer’s disease and periodontitis. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, lipopolysaccharide, periodontitis, Porphyromonas gingivalis

DOI: 10.3233/JAD-201007

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1785-1800, 2021

Authors: Ly, Maria | Raji, Cyrus A. | Yu, Gary Z. | Wang, Qing | Wang, Yong | Schindler, Suzanne E. | An, Hongyu | Samara, Amjad | Eisenstein, Sarah A. | Hershey, Tamara | Smith, Gordon | Klein, Samuel | Liu, Jingxia | Xiong, Chengjie | Ances, Beau M. | Morris, John C. | Benzinger, Tammie L.S.

Article Type: Research Article

Abstract: Background: Obesity is related to quantitative neuroimaging abnormalities including reduced gray matter volumes and impaired white matter microstructural integrity, although the underlying mechanisms are not well understood. Objective: We assessed influence of obesity on neuroinflammation imaging that may mediate brain morphometric changes. Establishing the role of neuroinflammation in obesity will enhance understanding of this modifiable disorder as a risk factor for Alzheimer’s disease (AD) dementia. Methods: We analyzed brain MRIs from 104 cognitively normal participants (CDR = 0) and biomarker negativity for CSF amyloid or tau. We classified body mass index (BMI) as normal (BMI <25, N = 62) or …overweight and obese (BMI ≥25, N = 42). Blood pressure was measured. BMI and blood pressure classifications were related to neuroinflammation imaging (NII) derived edema fraction in 17 white matter tracts. This metric was also correlated to hippocampal volumes and CSF biomarkers of inflammation and neurodegeneration: YKL-40, SNAP25, VILIP, tau, and NFL. Results: Participants with BMI <25 had lower NII-derived edema fraction, with protective effects of normal blood pressure. Statistically significant white matter tracts included the internal capsule, external capsule, and corona radiata, FDR correc-ted for multiple comparisons to alpha = 0.05. Higher NII-derived edema fractions in the internal capsule, corpus callosum, gyrus, and superior fronto-occipital fasciculus were related with smaller hippocampal volumes only in individuals with BMI ≥25. There were no statistically significant correlations between NII-derived edema fraction and CSF biomarkers. Conclusion: We demonstrate statistically significant relationships between neuroinflammation, elevated BMI, and hippocampal volume, raising implications for neuroinflammation mechanisms of obesity-related brain dysfunction in cognitively normal elderly. Show more

Keywords: Alzheimer’s disease, neuroinflammation imaging, obesity

DOI: 10.3233/JAD-201242

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1801-1811, 2021

Authors: Gnanaprakash, Madhumathi | Staniszewski, Agnieszka | Zhang, Hong | Pitstick, Rose | Kavanaugh, Michael P. | Arancio, Ottavio | Nicholls, Russell E.

Article Type: Research Article

Abstract: Background: The serine/threonine protein phosphatase, PP2A, is thought to play a central role in the molecular pathogenesis of Alzheimer’s disease (AD), and the activity and substrate specificity of PP2A is regulated, in part, through methylation and demethylation of its catalytic subunit. Previously, we found that transgenic overexpression of the PP2A methyltransferase, LCMT-1, or the PP2A methylesterase, PME-1, altered the sensitivity of mice to impairments caused by acute exposure to synthetic oligomeric amyloid-β (Aβ). Objective: Here we sought to test the possibility that these molecules also controlled sensitivity to impairments caused by chronically elevated levels of Aβ produced in …vivo . Methods: To do this, we examined the effects of transgenic LCMT-1, or PME-1 overexpression on cognitive and electrophysiological impairments caused by chronic overexpression of mutant human APP in Tg2576 mice. Results: We found that LCMT-1 overexpression prevented impairments in short-term spatial memory and synaptic plasticity in Tg2576 mice, without altering APP expression or soluble Aβ levels. While the magnitude of the effects of PME-1 overexpression in Tg2576 mice was small and potentially confounded by the emergence of non-cognitive impairments, Tg2576 mice that overexpressed PME-1 showed a trend toward earlier onset and/or increased severity of cognitive and electrophysiological impairments. Conclusion: These data suggest that the PP2A methyltransferase, LCMT-1, and the PP2A methylesterase, PME-1, may participate in the molecular pathogenesis of AD by regulating sensitivity to the pathogenic effects of chronically elevated levels of Aβ. Show more

Keywords: Alzheimer’s disease, amyloid-β, cognitive impairment, leucine carboxyl methyltransferase, long-term potentiation, MAPT protein, protein phosphatase 2A, protein phosphatase methylesterase

DOI: 10.3233/JAD-200462

Citation: Journal of Alzheimer's Disease, vol. 79, no. 4, pp. 1813-1829, 2021