Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Farugia, Taya L. | Cuni-Lopez, Carla | White, Anthony R.

Article Type: Research Article

Abstract: Australia often experiences natural disasters and extreme weather conditions such as: flooding, sandstorms, heatwaves, and bushfires (also known as wildfires or forest fires). The proportion of the Australian population aged 65 years and over is increasing, alongside the severity and frequency of extreme weather conditions and natural disasters. Extreme heat can affect the entire population but particularly at the extremes of life, and patients with morbidities. Frequently identified as a vulnerable demographic in natural disasters, there is limited research on older adults and their capacity to deal with extreme heat and bushfires. There is a considerable amount of literature that …suggests a significant association between mental disorders such as dementia, and increased vulnerability to extreme heat. The prevalence rate for dementia is estimated at 30% #x0025;by age 85 years, but there has been limited research on the effects extreme heat and bushfires have on individuals living with dementia. This review explores the differential diagnosis of dementia, the Australian climate, and the potential impact Australia’s extreme heat and bushfires have on individuals from vulnerable communities including low socioeconomic status Indigenous and Non-Indigenous populations living with dementia, in both metropolitan and rural communities. Furthermore, we investigate possible prevention strategies and provide suggestions for future research on the topic of Australian bushfires and heatwaves and their impact on people living with dementia. This paper includes recommendations to ensure rural communities have access to appropriate support services, medical treatment, awareness, and information surrounding dementia. Show more

Keywords: Bushfire, climate change, dementia, extreme heat, wildfire

DOI: 10.3233/JAD-201388

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

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

Article Type: Research 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 mericans 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. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Mai, Yingren | Yu, Qun | Zhu, Feiqi | Luo, Yishan | Liao, Wang | Zhao, Lei | Xu, Chunyan | Fang, Wenli | Ruan, Yuting | Cao, Zhiyu | Lei, Ming | Au, Lisa | Mok, Vincent C.T. | Shi, Lin | Liu, Jun

Article Type: Research Article

Abstract: Background: Magnetic resonance imaging (MRI) provides objective information about brain structural atrophy in patients with Alzheimer’s disease (AD). This multi-structural atrophic information, when integrated as a single differential index, has the potential to further elevate the accuracy of AD identification from normal control (NC) compared to the conventional structure volumetric index. Objective: We herein investigated the performance of such an MRI-derived AD index, AD-Resemblance Atrophy Index (AD-RAI), as a neuroimaging biomarker in clinical scenario. Method: Fifty AD patients (19 with the Amyloid, Tau, Neurodegeneration (ATN) results assessed in cerebrospinal fluid) and 50 age- and gender-matched NC …(19 with ATN results assessed using positron emission tomography) were recruited in this study. MRI-based imaging biomarkers, i.e., AD-RAI, were quantified using AccuBrain® . The accuracy, sensitivity, specificity, and area under the ROC curve (AUC) of these MRI-based imaging biomarkers were evaluated with the diagnosis result according to clinical criteria for all subjects and ATN biological markers for the subgroup. Results: In the whole groups of AD and NC subjects, the accuracy of AD-RAI was 91%, sensitivity and specificity were 88% and 96%, respectively, and the AUC was 92%. In the subgroup of 19 AD and 19 NC with ATN results, AD-RAI results matched completely with ATN classification. AD-RAI outperforms the volume of any single brain structure measured. Conclusion: The finding supports the hypothesis that MRI-derived composite AD-RAI is a more accurate imaging biomarker than individual brain structure volumetry in the identification of AD from NC in the clinical scenario. Show more

Keywords: AD-Resemblance atrophy index, Alzheimer’s disease, ATN biological markers, automated brain volumetry, magnetic resonance imaging

DOI: 10.3233/JAD-201033

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Underlien Kristensen, Rachel | 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. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: de la Torre, Jack C.

Article Type: Research 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. Pre-press, no. Pre-press, pp. 1-16, 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. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Clark, Ian Albert | Vissel, Bryce

Article Type: Review Article

Abstract: Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post- traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia …chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer’s disease and Parkinson’s disease sufferers. In contrast, Alzheimer’s disease and Parkinson’s disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this. Show more

Keywords: Alzheimer’s disease, cardiac arrest survival, locus coeruleus, neurological COVID-19, norepinephrine, parkinson’s disease, stroke, traumatic brain injury, tumor necrosis factor

DOI: 10.3233/JAD-201186

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2020

Authors: Schonfeld, Ethan | Schonfeld, Elan | Aman, Casey | Gill, Navroop | Kim, Dami | Rabin, Sydney | Shamshuddin, Bushraa | Sealey, Lloyd | Senno, Ricardo Gabriel

Article Type: Research Article

Abstract: Background: There exist functional deficits in motor, sensory, and olfactory abilities in dementias. Measures of these deficits have been discussed as potential clinical markers. Objective: We measured the deficit of motor, sensory, and olfactory functions on both the left and right body side, to study potential body lateralizations. Methods: This IRB-approved study (N = 84) performed left/right clinical tests of gross motor (dynamometer test), sensory (Von Frey test), and olfactory (peppermint oil test) ability. The Mini-Mental Status Exam was administered to determine level of dementia; medical and laboratory data were collected. Results: Sensory and olfactory deficits …lateralized to the left side of the body, while motor deficits lateralized to the right side. We found clinical correlates of motor lateralization: female, depression, MMSE <15, and diabetes. While clinical correlates of sensory lateralization: use of psychotherapeutic agent, age ≥85, MMSE <15, and male. Lastly, clinical correlates of olfactory lateralization: age <85, number of medications >10, and male. Conclusion: These lateralized deficits in body function can act as early clinical markers for improved diagnosis and treatment. Future research should identify correlates and corresponding therapies to strengthen at-risk areas. Show more

Keywords: Alzheimer’s disease, clinical markers, functional laterality, motor skills, olfactory perception, sensory thresholds, therapeutics

DOI: 10.3233/JAD-201216

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

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. Pre-press, no. Pre-press, pp. 1-7, 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%, which is caused by continued demographic changes. 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: Cognitive dysfunction, dementia, diagnosis, incidence, prevalence

DOI: 10.3233/JAD-201385

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 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 test 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. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Darst, Burcu F. | Huo, Zhiguang | Jonaitis, Erin M. | Koscik, Rebecca L. | Clark, Lindsay R. | Lu, Qiongshi | Kremen, William S. | Franz, Carol E. | Rana, Brinda | Lyons, Michael J. | Hogan, Kirk J. | Zhao, Jinying | Johnson, Sterling C. | Engelman, Corinne D.

Article Type: Research Article

Keywords: Alzheimer’s disease, amino acids, cognition, executive function, fatty acids, longitudinal analysis, metabolomics

DOI: 10.3233/JAD-200176

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Russ, Tom C. | Cherrie, Mark P.C. | Dibben, Chris | Tomlinson, Sam | Reis, Stefan | Dragosits, Ulrike | Vieno, Massimo | Beck, Rachel | Carnell, Ed | Shortt, Niamh K. | Muniz-Terrera, Graciela | Redmond, Paul | Taylor, Adele M. | Clemens, Tom | van Tongeren, Martie | Agius, Raymond M. | Starr, John M. | Deary, Ian J. | Pearce, Jamie R.

Article Type: Research Article

Keywords: Aging, air pollution, Alzheimer’s disease, atmosphere, cognition, dementia, epidemiologic methods

DOI: 10.3233/JAD-200910

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

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

Article Type: Research Article

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. Pre-press, no. Pre-press, pp. 1-11, 2021

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

Article Type: Research 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. Pre-press, no. Pre-press, pp. 1-19, 2021

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

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. Pre-press, no. Pre-press, pp. 1-16, 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. Pre-press, no. Pre-press, pp. 1-10, 2021

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

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. Pre-press, no. Pre-press, pp. 1-17, 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. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Magnin, Eloi

Article Type: Research 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. Pre-press, no. Pre-press, pp. 1-11, 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. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Erkoyun, Hulya Ulugut | van der Lee, Sven J. | Nijmeijer, Bas | Spaendonk, Rosalina van | Nelissen, Anne | Scarioni, Marta | Dijkstra, Anke | Samancı, Bedia | Gürvit, Hakan | Yıldırım, Zerrin | Tepgeç, Fatih | Bilgic, Basar | Barkhof, Frederik | Rozemuller, Annemieke | van der Flier, Wiesje M. | Scheltens, Philip | Cohn-Hokke, Petra | Pijnenburg, Yolande

Article Type: Research Article

Abstract: Background: Right temporal variant frontotemporal dementia (rtvFTD) has been generally considered as a right sided variant of semantic variant primary progressive aphasia (svPPA), which is a genetically sporadic disorder. Recently, we have shown that rtvFTD has a unique clinical syndrome compared to svPPA and behavioral variant frontotemporal dementia. Objective: We challenge the assumption that rtvFTD is a sporadic, non-familial variant of FTD by identifying potential autosomal dominant inheritance and related genes in rtvFTD. Methods: We collected all subjects with a diagnosis of FTD or primary progressive aphasia who had undergone genetic screening (n  = 284) and subsequently …who had a genetic variant (n  = 48) with a diagnosis of rtvFTD (n  = 6) in 2 specialized memory clinics. Results: Genetic variants in FTD related genes were found in 33% of genetically screened rtvFTD cases; including MAPT (n  = 4), GRN (n  = 1), and TARDBP (n  = 1) genes, whereas only one svPPA case had a genetic variant in our combined cohorts. Additionally, 4 out of 6 rtvFTD subjects had a strong family history for dementia. Conclusion: Our results demonstrate that rtvFTD, unlike svPPA, is not a pure sporadic, but a heterogeneous potential genetic variant of FTD, and screening for genetic causes for FTD should be performed in patients with rtvFTD. Show more

Keywords: Dementia, frontotemporal dementia, frontotemporal lobar degeneration, genetic, GRN, MAPT, right temporallobe, TARDBP

DOI: 10.3233/JAD-201191

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2021

Authors: Innis, Ashley D. | Tolea, Magdalena I. | Galvin, James E.

Article Type: Research Article

Abstract: Background: Mindfulness is the practice of awareness and living in the present moment without judgment. Mindfulness-based interventions may improve dementia-related outcomes. Before initiating interventions, it would be beneficial to measure baseline mindfulness to understand targets for therapy and its influence on dementia outcomes. Objective: This cross-sectional study examined patient and caregiver mindfulness with patient and caregiver rating scales and patient cognitive performance and determined whether dyadic pairing of mindfulness influences patient outcomes. Methods: Individuals (N = 291) underwent comprehensive evaluations, with baseline mindfulness assessed using the 15-item Applied Mindfulness Process Scale (AMPS). Correlation, regression, and …mediation models tested relationships between patient and caregiver mindfulness and outcomes. Results: Patients had a mean AMPS score of 38.0±11.9 and caregivers had a mean AMPS score of 38.9±11.5. Patient mindfulness correlated with activities of daily living, behavior and mood, health-related quality of life, subjective cognitive complaints, and performance on episodic memory and attention tasks. Caregiver mindfulness correlated with preparedness, care confidence, depression, and better patient cognitive performance. Patients in dyads with higher mindfulness had better cognitive performance, less subjective complaints, and higher health-related quality of life (all p -values<0.001). Mindfulness effects on cognition were mediated by physical activity, social engagement, frailty, and vascular risk factors. Conclusion: Higher baseline mindfulness was associated with better patient and caregiver outcomes, particularly when both patients and caregivers had high baseline mindfulness. Understanding the baseline influence of mindfulness on the completion of rating scales and neuropsychological test performance can help develop targeted interventions to improve well-being in patients and their caregivers. Show more

Keywords: Alzheimer’s disease, dementia, inflammation, mild cognitive impairment, mindfulness

DOI: 10.3233/JAD-201292

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-23, 2021

Authors: Khan, Mostafa J. | Desaire, Heather | Lopez, Oscar L. | Kamboh, M. Ilyas | Robinson, Renã A.S.

Article Type: Research Article

Abstract: Background: African American/Black adults have a disproportionate incidence of Alzheimer’s disease (AD) and are underrepresented in biomarker discovery efforts. Objective: This study aimed to identify potential diagnostic biomarkers for AD using a combination of proteomics and machine learning approaches in a cohort that included African American/Black adults. Methods: We conducted a discovery-based plasma proteomics study on plasma samples (N  = 113) obtained from clinically diagnosed AD and cognitively normal adults that were self-reported African American/Black or non-Hispanic White. Sets of differentially-expressed proteins were then classified using a support vector machine (SVM) to identify biomarker candidates. …Results: In total, 740 proteins were identified of which, 25 differentially-expressed proteins in AD came from comparisons within a single racial and ethnic background group. Six proteins were differentially-expressed in AD regardless of racial and ethnic background. Supervised classification by SVM yielded an area under the curve (AUC) of 0.91 and accuracy of 86%for differentiating AD in samples from non-Hispanic White adults when trained with differentially-expressed proteins unique to that group. However, the same model yielded an AUC of 0.49 and accuracy of 47%for differentiating AD in samples from African American/Black adults. Other covariates such as age, APOE4 status, sex, and years of education were found to improve the model mostly in the samples from non-Hispanic White adults for classifying AD. Conclusion: These results demonstrate the importance of study designs in AD biomarker discovery, which must include diverse racial and ethnic groups such as African American/Black adults to develop effective biomarkers. Show more

Keywords: African American, Alzheimer’s disease, biomarker, black, discovery, disparities, machine learning, plasma, proteomics, race

DOI: 10.3233/JAD-201318

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2021

Authors: Hilal, Saima | Mutsaerts, Henri J.M.M | Ferro, Doeschka A. | Petr, Jan | Kuijf, Hugo J. | Biessels, Geert Jan | Chen, Christopher

Article Type: Research Article

Abstract: Background: Intracranial stenosis (ICS) may contribute to cognitive dysfunction by decreased cerebral blood flow (CBF) which can be measured quantitatively by arterial spin labelling (ASL). Interpretation of CBF measurements with ASL, however, becomes difficult in patients with vascular disease due to prolonged arterial transit time (ATT). Recently, spatial coefficient of variation (sCoV) of ASL signal has been proposed that approximates ATT and utilized as a proxy marker for assessment of hemodynamic status of cerebral circulation. Objective: We investigate the association of ICS with CBF and sCoV parameters and its eventual effects on cognition in a memory clinic population. …Methods: We included 381 patients (mean age = 72.3±7.9 years, women = 53.7%) who underwent 3T MRI and detailed neuropsychological assessment. ICS was defined as≥50% stenosis in any intracranial vessel on 3D Time-of-Flight MR Angiography. Gray matter sCoV and CBF were obtained from 2D EPI pseudo-continuous ASL images. Results: ICS was present in 58 (15.2%) patients. Patients with ICS had higher gray matter sCoV and lower CBF. The association with sCoV remained statistically significant after correction for cardiovascular risk factors. Moreover, ICS was associated with worse performance on visuoconstruction, which attenuated with higher sCoV. Mediation analysis showed that there was an indirect effect of ICS on visuoconstruction via sCoV. Conclusion: These findings suggest that compromised CBF as detected by higher sCoV is related to cognitive impairment among individuals diagnosed with ICS. We also showed that sCoV partially mediates the link between ICS and cognition. Therefore, sCoV may provide valuable hemodynamic information in patients with vascular disease. Show more

Keywords: Arterial spin labeling, cerebral perfusion, coefficient of variation, cognition, intracranial stenosis

DOI: 10.3233/JAD-201131

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Ahmed, Mehnaz | Herrmann, Nathan | Chen, Jinghan Jenny | Saleem, Mahwesh | Oh, Paul I. | Andreazza, Ana C. | Kiss, Alexander | Lanctôt, Krista L.

Article Type: Research Article

Abstract: Background: Coronary artery disease (CAD) increases risk for vascular cognitive impairment-no dementia (VCIND), a precursor to dementia, potentially through persistent oxidative stress. Objective: This study assessed peripheral glutathione peroxidase activity (GPX), which is protective against oxidative stress, in VCIND versus cognitively normal CAD controls (CN). GPX activity was also evaluated as a biomarker of cognition, particularly verbal memory. Methods: 120 CAD patients with VCIND (1SD below norms on executive function or verbal memory (VM)) or without (CN) participated in exercise rehabilitation for 24 weeks. Neurocognitive and cardiopulmonary fitness (VO2 peak ) assessments and plasma were …collected at baseline and 24-weeks. Results: GPX was higher in VCIND compared to CN (F1,119  = 3.996, p  = 0.048). Higher GPX was associated with poorer baseline VM (β= –0.182, p  = 0.048), and longitudinally with VM decline controlling for sex, body mass index, VO2 peak , and education (b[SE] = –0.02[0.01], p  = 0.004). Only CN participants showed improved VM performance with increased fitness (b[SE] = 1.30[0.15], p  <  0.005). Conclusion: GPX was elevated in VCIND consistent with a compensatory response to persistent oxidative stress. Increased GPX predicted poorer cognitive outcomes (verbal memory) in VCIND patients despite improved fitness. Show more

Keywords: Alzheimer’s disease, coronary artery disease, dementia, glutathione peroxidase, cognition, vascular cognitive impairment

DOI: 10.3233/JAD-200754

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Yan, Yibing | Wu, Xingqi | Wang, Xiaojing | Geng, Zhi | Wang, Lu | Xiao, Guixian | Wu, Yue | Zhou, Shanshan | Wei, Ling | Tian, Yanghua | Wang, Kai

Article Type: Research Article

Abstract: Background: There is increasing evidence that Alzheimer’s disease (AD) patients may present decreased cerebral blood perfusion before pathological brain changes. Using the retina as a window to the brain, we can study disorders of the central nervous system through the eyes. Objective: This study aimed to investigate differences in retinal structure and vessel density (VD) between patients with mild AD and healthy controls (HCs). Furthermore, we explored the relationship between retinal VD and cognitive function. Methods: We enrolled 37 patients with AD and 29 age-matched HCs who underwent standard ophthalmic optical coherence tomography angiography (OCTA) for …evaluation of the retinal layer thickness and VD parameters. Cognitive function was evaluated using a battery of neuropsychological assessments. Finally, the correlations among retinal layer thickness, VD parameters, and cognitive function were evaluated. Results: The retinal fiber layer thickness and retinal VD of patients with AD were significantly reduced compared with HCs. The retinal VD was significantly correlated with overall cognition, memory, executive, and visual-spatial perception functions. However, there was no significant between-group difference in the macular thickness. Conclusion: Our findings indicate a positive correlation between retinal VD and some, but not all, cognitive function domains. Most importantly, we demonstrated the role of OCTA in detecting early capillary changes, which could be a noninvasive biomarker for early AD. Show more

Keywords: Alzheimer’s disease, biomarker, cognitive function, optical coherence tomography angiography, vessel density

DOI: 10.3233/JAD-200971

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Jing, Jiaojiao | Zhang, Feng | Zhao, Li | Xie, Jinghui | Chen, Jianwen | Zhong, Rujia | Zhang, Yanjun | Dong, Chunbo

Article Type: Research Article

Abstract: Background: Florbetapir (AV45) and fluorodeoxyglucose (FDG) PET imaging are valuable techniques to detect the amyloid-β (Aβ) load and brain glucose metabolism in patients with Alzheimer’s disease (AD). Objective: The purpose of this study is to access the characteristics of Aβ load and FDG metabolism in brain for further investigating their relationships with cognitive impairment in AD patients. Methods: Twenty-seven patients with AD (average 70.6 years old, N = 13 male, N = 14 female) were enrolled in this study. These AD patients underwent the standard clinical assessment and received detailed imaging examinations of the nervous system by using Mini-Mental State …Examination (MMSE), Montreal Cognitive Assessment (MOCA), 18 F-AV45, and 18 F-FDG PET scans. Results: Of 27 AD patients, 22 patients (81.5%) showed significantly increases in Aβ load and 26 patients (96.3%) had significantly reductions in FDG metabolism. The moderate AD patients had more brain areas of reduced FDG metabolism and more severe reductions in some regions compared to mild AD patients, with no differences in Aβ load observed. Moreover, the range and degree of reduced FDG metabolism in several regions were positively correlated with the total score of MMSE or MOCA, whereas the range of Aβ load did not. No correlation was found between the range of Aβ load and the range of reduced FDG metabolism in this study. Conclusion: The reduction in FDG metabolisms captured by 18 F-FDG imaging can be used as a potential biomarker for AD diagnosis in the future. 18 F-AV45 imaging did not present valuable evidence for evaluating AD patient in this study. Show more

Keywords: Alzheimer’s disease, amyloid-β load, AV45, glucose metabolism, PET

DOI: 10.3233/JAD-201335

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Sharma, Manu J. | Callahan, Brandy L.

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is considered by some to be a prodromal phase of a progressive disease (i.e., neurodegeneration) resulting in dementia; however, a substantial portion of individuals (ranging from 5–30%) remain cognitively stable over the long term (sMCI). The etiology of sMCI is unclear but may be linked to cerebrovascular disease (CVD), as evidence from longitudinal studies suggest a significant proportion of individuals with vasculopathy remain stable over time. Objective: To quantify the presence of neurodegenerative and vascular pathologies in individuals with long-term (>5-year) sMCI, in a preliminary test of the hypothesis that CVD may be …a contributor to non-degenerative cognitive impairment. We expect frequent vasculopathy at autopsy in sMCI relative to neurodegenerative disease, and relative to individuals who convert to dementia. Methods: In this retrospective study, using data from the National Alzheimer’s Coordinating Center, individuals with sMCI (n  = 28) were compared to those with MCI who declined over a 5 to 9-year period (dMCI; n  = 139) on measures of neurodegenerative pathology (i.e., Aβ plaques, neurofibrillary tangles, TDP-43, and cerebral amyloid angiopathy) and CVD (infarcts, lacunes, microinfarcts, hemorrhages, and microbleeds). Results: Alzheimer’s disease pathology (Aβ plaques, neurofibrillary tangles, and cerebral amyloid angiopathy) was significantly higher in the dMCI group than the sMCI group. Microinfarcts were the only vasculopathy associated with group membership; these were more frequent in sMCI. Conclusion: The most frequent neuropathology in this sample of long-term sMCI was microinfarcts, tentatively suggesting that silent small vessel disease may characterize non-worsening cognitive impairment. Show more

Keywords: Autopsy, cerebrovascular, cognition, dementia, longitudinal, neuropathology

DOI: 10.3233/JAD-200829

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2021

Authors: Driscoll, Ira | Ma, Yue | Gallagher, Catherine L. | Johnson, Sterling C. | Asthana, Sanjay | Hermann, Bruce P. | Sager, Mark A. | Blennow, Kaj | Zetterberg, Henrik | Carlsson, Cynthia M. | Engelman, Corinne D. | Dubal, Dena B. | Okonkwo, Ozioma C.

Article Type: Research Article

Abstract: Background: Identification of new genetic variants that modify Alzheimer’s disease (AD) risk will elucidate novel targets for curbing the disease progression or delaying symptom onset. Objective: To examine whether the functionally advantageous KLOTHO gene KL-VS variant attenuates age-related alteration in cerebrospinal fluid (CSF) biomarkers or cognitive function in middle-aged and older adults enriched for AD risk. Methods: Sample included non-demented adults (N = 225, mean age = 63±8, 68% women) from the Wisconsin Registry for Alzheimer’s Prevention and the Wisconsin Alzheimer’s Disease Research Center who were genotyped for KL-VS, underwent CSF sampling and had neuropsychological testing data available proximal …to CSF draw. Covariate-adjusted multivariate regression examined relationships between age group (Younger versus Older; mean split at 63 years), AD biomarkers, and neuropsychological performance tapping memory and executive function, and whether these relationships differed between KL-VS non-carriers (KL-VSNC ) and heterozygote (KL-VSHET ). Results: In the pooled analyses, older age was associated with higher levels of total tau (tTau), phosphorylated tau (pTau), and their respective ratios to amyloid-β (Aβ)42 (ps ≤ 0.002), and with poorer performance on neuropsychological tests (ps ≤ 0.001). In the stratified analyses, KL-VSNC exhibited this age-related pattern of associations with CSF biomarkers (all ps ≤ 0.001), and memory and executive function (ps ≤ 0.003), which were attenuated in KL-VSHET (ps ≥0.14). Conclusion: Worse memory and executive function, and higher tau burden with age were attenuated in carriers of a functionally advantageous KLOTHO variant. KL-VS heterozygosity seems to be protective against age-related cognitive and biomolecular alterations that confer risk for AD. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, executive function, memory

DOI: 10.3233/JAD-200944

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Atkins, Janice L. | Pilling, Luke C. | Heales, Christine J. | Savage, Sharon | Kuo, Chia-Ling | Kuchel, George A. | Steffens, David C. | Melzer, David

Article Type: Research Article

Abstract: Background: Brain iron deposition occurs in dementia. In European ancestry populations, the HFE p.C282Y variant can cause iron overload and hemochromatosis, mostly in homozygous males. Objective: To estimated p.C282Y associations with brain MRI features plus incident dementia diagnoses during follow-up in a large community cohort. Methods: UK Biobank participants with follow-up hospitalization records (mean 10.5 years). MRI in 206 p.C282Y homozygotes versus 23,349 without variants, including T2 * measures (lower values indicating more iron). Results: European ancestry participants included 2,890 p.C282Y homozygotes. Male p.C282Y homozygotes had lower T2 * measures in areas including …the putamen, thalamus, and hippocampus, compared to no HFE mutations. Incident dementia was more common in p.C282Y homozygous men (Hazard Ratio HR = 1.83; 95% CI 1.23 to 2.72, p  = 0.003), as was delirium. There were no associations in homozygote women or in heterozygotes. Conclusion: Studies are needed of whether early iron reduction prevents or slows related brain pathologies in male HFE p.C282Y homozygotes. Show more

Keywords: Cohort, dementia, delirium, gene, hemochromatosis, iron, mutation

DOI: 10.3233/JAD-201080

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2021

Authors: Sohrabi, Mona | Pecoraro, Heidi L. | Combs, Colin K.

Article Type: Research Article

Abstract: Background: Although it is known that the brain communicates with the gastrointestinal (GI) tract via the well-established gut-brain axis, the influence exerted by chronic intestinal inflammation on brain changes in Alzheimer’s disease (AD) is not fully understood. We hypothesized that increased gut inflammation would alter brain pathology of a mouse model of AD. Objective: Determine whether colitis exacerbates AD-related brain changes. Methods: To test this idea, 2% dextran sulfate sodium (DSS) was dissolved in the drinking water and fed ad libitum to male C57BL/6 wild type and App NL  - G  - F …mice at 6–10 months of age for two cycles of three days each. DSS is a negatively charged sulfated polysaccharide which results in bloody diarrhea and weight loss, changes similar to human inflammatory bowel disease (IBD). Results: Both wild type and App NL  - G  - F mice developed an IBD-like condition. Brain histologic and biochemical assessments demonstrated increased insoluble Aβ 1–40/42 levels along with the decreased microglial CD68 immunoreactivity in DSS treated App NL  - G  - F mice compared to vehicle treated App NL  - G  - F mice. Conclusion: These data demonstrate that intestinal dysfunction is capable of altering plaque deposition and glial immunoreactivity in the brain. This study increases our knowledge of the impact of peripheral inflammation on Aβ deposition via an IBD-like model system. Show more

Keywords: Alzheimer’s disease, Aβ deposition, dextran sulfate sodium, inflammatory bowel disease, neuroinflammation

DOI: 10.3233/JAD-201099

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2021

Authors: GjØra, Linda | Heine Strand, BjØrn | Bergh, Sverre | Borza, Tom | Brækhus, Anne | Engedal, Knut | Johannessen, Aud | Kvello-Alme, Marte | Krokstad, Steinar | Livingston, Gill | Matthews, Fiona E. | Myrstad, Christian | Skjellegrind, Håvard | Thingstad, Pernille | Aakhus, Eivind | Aam, Stina | Selbæk, Geir

Article Type: Research Article

Abstract: Background: Having accurate, up-to-date information on the epidemiology of mild cognitive impairment (MCI) and dementia is imperative. Objective: To determine the prevalence of MCI and dementia in Norway using data from a large population-based study. Methods: All people 70 + years of age, n  = 19,403, in the fourth wave of the Trøndelag Health Study (HUNT4) were invited to participate in the study HUNT4 70 + . Trained health personnel assessed participants using cognitive tests at a field station, at homes, or at their nursing home. Interviewers also completed a structured carer questionnaire in regard to participants suspected of having dementia. …Clinical experts made diagnoses according to DSM-5 criteria. We calculated prevalence weighing the data to ensure population representativeness. Results: A total of 9,930 (51.1%) of the possible 19,403 people participated, and 9,663 of these had sufficient information for analysis. Standardized prevalence of dementia and MCI was 14.6% (95% confidence interval (CI) 13.9–15.4) and 35.3% (95% CI 34.3–36.4), respectively. Dementia was more prevalent in women and MCI more prevalent in men. The most prevalent dementia subtype was Alzheimer’s disease (57%). By adding data collected from a study of persons ≤70 years in the same region, we estimate that there are 101,118 persons with dementia in Norway in 2020, and this is projected to increase to 236,789 and 380,134 in 2050 and 2100, respectively. Conclusion: We found a higher prevalence of dementia and MCI than most previous studies. The present prevalence and future projections are vital for preparing for future challenges to the healthcare system and the entire society. Show more

Keywords: Alzheimer’s disease, dementia, epidemiology, population study, prevalence

DOI: 10.3233/JAD-201275

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Themistocleous, Charalambos | Ficek, Bronte | Webster, Kimberly | den Ouden, Dirk-Bart | Hillis, Argye E. | Tsapkini, Kyrana

Article Type: Research Article

Abstract: Background: The classification of patients with primary progressive aphasia (PPA) into variants is time-consuming, costly, and requires combined expertise by clinical neurologists, neuropsychologists, speech pathologists, and radiologists. Objective: The aim of the present study is to determine whether acoustic and linguistic variables provide accurate classification of PPA patients into one of three variants: nonfluent PPA, semantic PPA, and logopenic PPA. Methods: In this paper, we present a machine learning model based on deep neural networks (DNN) for the subtyping of patients with PPA into three main variants, using combined acoustic and linguistic information elicited automatically via …acoustic and linguistic analysis. The performance of the DNN was compared to the classification accuracy of Random Forests, Support Vector Machines, and Decision Trees, as well as to expert clinicians’ classifications. Results: The DNN model outperformed the other machine learning models as well as expert clinicians’ classifications with 80% classification accuracy. Importantly, 90% of patients with nfvPPA and 95% of patients with lvPPA was identified correctly, providing reliable subtyping of these patients into their corresponding PPA variants. Conclusion: We show that the combined speech and language markers from connected speech productions can inform variant subtyping in patients with PPA. The end-to-end automated machine learning approach we present can enable clinicians and researchers to provide an easy, quick, and inexpensive classification of patients with PPA. Show more

Keywords: Classification, machine learning, natural language processing, primary progressive aphasia

DOI: 10.3233/JAD-201101

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Fernández-Matarrubia, Marta | Goni, Leticia | Rognoni, Teresa | Razquin, Cristina | Fernández-Lázaro, César Ignacio | Bes-Rastrollo, Maira | Martínez-González, Miguel Ángel | Toledo, Estefanía

Article Type: Research Article

Abstract: Background: Available evidence on the association of physical activity (PA) or sedentary behavior with cognitive decline is inconclusive. Objective: To assess the association between an active lifestyle score and leisure-time physical activity (LTPA) and changes in cognitive function in the Seguimiento Universidad de Navarra (SUN) prospective cohort. Methods: Cognitive function was evaluated in a subsample of 806 participants of the SUN cohort study using the validated Telephone Interview for Cognitive Status-modified (STICS-m) questionnaire at baseline and after 6 years. LTPA was evaluated with a previously validated 17-item self-administered questionnaire and with information on sedentary lifestyles. We …also calculated a multidimensional 8-item PA score. Multivariable linear regression analysis evaluated the association between PA and changes in cognitive function and its interaction by APOE genotype. Results: Mean age of participants was 66 (SD 5.3) years and 69.7% were male. When stratifying by APOE variants, no significant associations between the active lifestyle score or LTPA and changes in cognitive performance over time were found among APOE ɛ4 carriers. However, we observed that a higher adherence to an active lifestyle (high versus low PA score β= 0.76 95% CI 0.15,1.36; p trend = 0.011) and a high LTPA (Q4 versus Q1 β= 0.63; 95% CI –0.01,1.26; p trend = 0.030) were associated with more favorable changes in cognitive function over time among APOE ɛ4 non-carriers with statistically significant interactions in both cases (p for interaction = 0.042 for PA score, and p  = 0.039 for LTPA). Conclusion: The results of the present study suggest that an active lifestyle is associated with a better status of cognitive function over time only among APOE ɛ4 non-carriers. Show more

Keywords: APOE , cognition, cognitive function, exercise, physical activity, prospective study, sedentarism

DOI: 10.3233/JAD-201090

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Soldevila-Domenech, Natalia | Forcano, Laura | Boronat, Anna | Lorenzo, Thais | Piera, Iris | Puig-Pijoan, Albert | Mateus, Julian | González de Echevarri Gómez, José María | Knezevic, Iva | Soteras, Anna | Fauria, Karine | Pizarro, Nieves | Molinuevo, Jose Luis | de la Torre, Rafael | PENSA Study Group. From IMIM: | From BBRC:

Collaborators: de la Torre, Rafael | Forcano, Laura | Pizarro, Neus | Puig-Pijoan, Albert | Soldevila-Domenech, Natalia | Boronat, Anna | Lorenzo, Thais | Cuenca, Aida | Mateus, Julian | Piera, Iris | Aldea, Ana | Diaz-Pellicer, Patricia | Dierssen, Mara | Gomis, Maria | Molinuevo, Jose Luis | Knezevic, Iva | Menezes-Cabral, Sofia | Soteras, Anna | González-de-Echávarri, José Maria | Sánchez-Benavides, Gonzalo | Gispert, Juan Domingo | Fauria, Karine | Minguillón, Carolina

Article Type: Short Communication

Abstract: We explored the impact of the Spanish COVID-19 strict home confinement on mental health and cognition in non-infected subjects (N = 16, 60–80 years) diagnosed with subjective cognitive decline and APOE ɛ 3/ɛ 4 carriers. Mental health was monitored for 2 months on a daily, weekly, or monthly basis, and compared to pre-confinement values. Emotional distress, anxiety, and depression scores increased to pathological threshold values during and after confinement. Those with lower mood during confinement experienced a decline in their mood after confinement. Cognition did not change. These preliminary results suggest that mental health consequences of corona measures in preclinical stages …of Alzheimer’s disease should be further evaluated. Show more

Keywords: Alzheimer’s disease, confinement, COVID-19, mental health, subjective cognitive decline

DOI: 10.3233/JAD-201408

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Zhu, Lihong | Yuan, Qiongru | Zeng, Zhaohao | Zhou, Ruiyi | Luo, Rixin | Zhang, Jiawei | Tsang, Chi Kwan | Bi, Wei

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) deposition. The metabolism of Aβ is critically affected by autophagy. Although rifampicin is known to mediate neuroinflammation, the underlying mechanism by which rifampicin regulates the cognitive sequelae remains unknown. Objective: Based on our previous findings that rifampicin possesses neuroprotective effects on improving cognitive function after neuroinflammation, we aimed to examine in this study whether rifampicin can inhibit Aβ accumulation by enhancing autophagy in a mouse model of lipopolysaccharide (LPS)-induced cognitive impairment. Methods: Adult C57BL/6 mice were intraperitoneally injected with rifampicin, chloroquine, and/or LPS every day for 7 …days. Pathological and biochemical assays and behavioral tests were performed to determine the therapeutic effect and mechanism of rifampicin on the hippocampus of LPS-induced mice. Results: We found that rifampicin ameliorated cognitive impairments in the LPS-induced mice. In addition, rifampicin attenuated the inhibition of autophagosome formation, suppressed the accumulation of Aβ1–42 , and protected the hippocampal neurons against LPS-induced damage. Our results further demonstrated that rifampicin improved the neurological function by promoting autophagy through the inhibition of Akt/mTOR/p70S6K signaling pathway in the hippocampus of LPS-induced mice. Conclusion: Rifampicin ameliorates cognitive impairment by suppression of Aβ1–42 accumulation through inhibition of Akt/mTOR/p70S6K signaling and enhancement of autophagy in the hippocampus of LPS-induced mice. Show more

Keywords: Alzheimer’s disease, amyloid-β, autophagy, cognitive impairment, neuroinflammation, rifampicin

DOI: 10.3233/JAD-200690

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Fu, Zhenrong | Zhao, Mingyan | Wang, Xuetong | He, Yirong | Tian, Yuan | Yang, Yujing | Han, Ying | Li, Shuyu

Article Type: Research Article

Keywords: Brainprint, brain asymmetry, early diagnosis, subjective cognitive decline

DOI: 10.3233/JAD-201116

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Benítez, María J. | Cuadros, Raquel | Jiménez, Juan S.

Article Type: Research Article

Abstract: Background: Tau is a microtubule associated protein that regulates the stability of microtubules and the microtubule-dependent axonal transport. Its hyperphosphorylated form is one of the hallmarks of Alzheimer’s disease and other tauopathies and the major component of the paired helical filaments that form the abnormal proteinaceous tangles found in these neurodegenerative diseases. It is generally accepted that the phosphorylation extent of tau is the result of an equilibrium in the activity of protein kinases and phosphatases. Disruption of the balance between both types of enzyme activities has been assumed to be at the origin of tau hyperphosphorylation and the subsequent …toxicity and progress of the disease. Objective: We explore the possibility that, beside the phosphatase action on phosphorylated tau, the catalytic subunit of PKA catalyzes both tau phosphorylation and also tau dephosphorylation, depending on the ATP/ADP ratio. Methods: We use the shift in the relative electrophoretic mobility suffered by different phosphorylated forms of tau, as a sensor of the catalytic action of the enzyme. Results: The results are in agreement with the long-known thermodynamic reversibility of the phosphorylation reaction (ATP + Protein = ADP+Phospho-Protein) catalyzed by PKA and many other protein kinases. Conclusion: The results contribute to put the compartmentalized energy state of the neuron and the mitochondrial-functions disruption upstream of tau-related pathologies. Show more

Keywords: Dephosphorylation, electrophoretic mobility, phosphorylation, PKA, tau protein, thermodynamic reversibility

DOI: 10.3233/JAD-201077

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Gonzalez, Christopher | Tommasi, Nicole S. | Briggs, Danielle | Properzi, Michael J. | Amariglio, Rebecca E. | Marshall, Gad A. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Financial capacity is often one of the first instrumental activities of daily living to be affected in cognitively normal (CN) older adults who later progress to amnestic mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. Objective: The objective of this study was to investigate the association between financial capacity and regional cerebral tau. Methods: Cross-sectional financial capacity was assessed using the Financial Capacity Instrument –Short Form (FCI-SF) in 410 CN, 199 MCI, and 61 AD dementia participants who underwent flortaucipir tau positron emission tomography from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Linear regression models …with backward elimination were used with FCI-SF total score as the dependent variable and regional tau and tau-amyloid interaction as predictors of interest in separate analyses. Education, age sex, Rey Auditory Verbal Learning Test Total Learning, and Trail Making Test B were used as covariates. Results: Significant associations were found between FCI-SF and tau regions (entorhinal: p  <  0.001; inferior temporal: p  <  0.001; dorsolateral prefrontal: p  = 0.01; posterior cingulate: p  = 0.03; precuneus: p  <  0.001; and supramarginal gyrus: p  = 0.005) across all participants. For the tau-amyloid interaction, significant associations were found in four regions (amyloid and dorsolateral prefrontal tau interaction: p  = 0.005; amyloid and posterior cingulate tau interaction: p  = 0.005; amyloid and precuneus tau interaction: p  <  0.001; and amyloid and supramarginal tau interaction: p  = 0.002). Conclusion: Greater regional tau burden was modestly associated with financial capacity impairment in early-stage AD. Extending this work with longitudinal analyses will further illustrate the utility of such assessments in detecting clinically meaningful decline, which may aid clinical trials of early-stage AD. Show more

Keywords: Alzheimer’s disease, amyloid, financial capacity, instrumental activities of daily living, mild cognitive impairment, positron emission tomography, tau

DOI: 10.3233/JAD-201122

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Gruters, Angélique A. | Ramakers, Inez H.G.B. | Stiekema, Annemarie P.M. | Verhey, Frans R.J. | Kessels, Roy P.C. | de Vugt, Marjolein E.

Article Type: Research Article

Abstract: Background: Neuropsychological feedback is an important part of the neuropsychological assessment process. However, patients have difficulties remembering this information. Objective: The aim of this study was to develop a web-based visual tool to improve the understanding of neuropsychological results, information retention, and psychologist-patient communication. Methods: The visual tool was developed and optimized using an iterative three-phase stepwise approach to determine its usability, technology acceptance, and feasibility in a memory clinic population. Feedback from different user perspectives (patients, family members, and psychologists) was obtained in each phase using a multimethod approach (e.g., a multidisciplinary brainstorm session, think-aloud …sessions, focus groups). The prototype was subsequently tested in a pilot study. Results: The first phases offered insights that led to optimization of the prototype. On a scale ranging from 0 to 100, psychologists evaluated the usability as high [88.1±7.6,70–87]. During the pilot study, both patients and significant others gave positive feedback, but information retention in patients remained low. All participants thought the benefits of the visual tool included seeing cognitive strengths and weaknesses with a translation to daily life all at one glance and receiving feedback on paper to take home. Important barriers were mentioned by psychologists, such as a limited set of tests included and no integration with hospital systems. Conclusion: Overall, patients, family members, and psychologists reported that a visual display of the cognitive profile with insights into daily life had added value to clinical practice. Feedback from the pilot study was adopted in the tool for future implementation purposes. Show more

Keywords: Communication, dementia, neuropsychological tests, neuropsychology, visual aids

DOI: 10.3233/JAD-201128

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Nozaki, Shoko | Sawada, Norie | Matsuoka, Yutaka J. | Shikimoto, Ryo | Mimura, Masaru | Tsugane, Shoichiro

Article Type: Research Article

Abstract: Background: The relationship between midlife dietary habits and risk of dementia remains unclear. Objective: To investigate the association between dietary fish and n-3 polyunsaturated fatty acid (PUFA) consumption in midlife and risk of dementia in later life. Methods: This population-based cohort study assessed food frequency (average intake in 1995 and 2000) and cognition (2014-2015) in 1,127 participants (aged 45–64 in 1995). We used logistic regression analyses to calculate odds ratios (ORs) for dementia and mild cognitive impairment (MCI) diagnoses for consumption quartiles of fish, PUFA-rich fish, total n-3 PUFAs, total n-6 PUFAs, types of PUFAs, and …n-3/n-6 PUFA ratio. Estimated ORs were adjusted for age; sex; education; smoking status; alcohol consumption frequency; physical activity; histories of cancer, myocardial infarction, and diabetes mellitus; and depression. Results: Significantly reduced risks of dementia over non-dementia (MCI plus cognitively normal) were observed in the second (OR = 0.43 (95%CI = 0.20–0.93)), third (OR = 0.22 (95%CI = 0.09–0.54)), and highest quartiles (OR = 0.39 (95%CI = 0.18–0.86)) for fish; the third (OR = 0.39(95%CI = 0.16–0.92)) and highest quartiles (OR = 0.44(95%CI = 0.19–0.98)) for eicosapentaenoic acid (EPA); the second (OR = 0.39(95%CI = 0.18–0.84)), third (OR = 0.30(95%CI = 0.13–0.70)), and highest quartiles (OR = 0.28(95%CI = 0.12–0.66)) for docosahexaenoic acid (DHA); and the third (OR = 0.36 (95%CI = 0.16–0.85)) and highest quartiles (OR = 0.42 (95%CI = 0.19–0.95)) for docosapentaenoic acid (DPA). Conclusion: High intake of fish in midlife might aid in preventing dementia. Show more

Keywords: Cognitive dysfunction, dementia, diet, epidemiology, habits, longitudinal studies, observational study, risk factors, unsaturated fatty acids

DOI: 10.3233/JAD-191313

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Ryan, Margaret | Tan, Valerie T.Y. | Thompson, Nasya | Guévremont, Diane | Mockett, Bruce G. | Tate, Warren P. | Abraham, Wickliffe C. | Hughes, Stephanie M. | Williams, Joanna

Article Type: Research Article

Abstract: Background: Secreted amyloid precursor protein-alpha (sAPPα) can enhance memory and is neurotrophic and neuroprotective across a range of disease-associated insults, including amyloid-β toxicity. In a significant step toward validating sAPPα as a therapeutic for Alzheimer’s disease (AD), we demonstrated that long-term overexpression of human sAPPα (for 8 months) in a mouse model of amyloidosis (APP/PS1) could prevent the behavioral and electrophysiological deficits that develop in these mice. Objective: To explore the underlying molecular mechanisms responsible for the significant physiological and behavioral improvements observed in sAPPα-treated APP/PS1 mice. Methods: We assessed the long-term effects on the hippocampal …transcriptome following continuous lentiviral delivery of sAPPα or empty-vector to male APP/PS1 mice and wild-type controls using Affymetrix Mouse Transcriptome Assays. Data analysis was carried out within the Affymetrix Transcriptome Analysis Console and an integrated analysis of the resulting transcriptomic data was performed with Ingenuity Pathway analysis (IPA). Results: Mouse transcriptome assays revealed expected AD-associated gene expression changes in empty-vector APP/PS1 mice, providing validation of the assays used for the analysis. By contrast, there were specific sAPPα-associated gene expression profiles which included increases in key neuroprotective genes such as Decorin, betaine-GABA transporter, and protocadherin beta-5, subsequently validated by qRT-PCR. An integrated biological pathways analysis highlighted regulation of GABA receptor signaling, cell survival, and inflammatory responses. Furthermore, upstream gene regulatory analysis implicated sAPPα activation of Interleukin-4, which can counteract inflammatory changes in AD. Conclusion: This study identified key molecular processes that likely underpin the long-term neuroprotective and therapeutic effects of increasing sAPPα levels in vivo Show more

Keywords: Alzheimer’s disease, drug development, oligonucleotide array, real-time polymerase chain reaction, transcriptome, transgenic mouse

DOI: 10.3233/JAD-200757

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Barthelson, Karissa | Pederson, Stephen Martin | Newman, Morgan | Lardelli, Michael

Article Type: Research Article

Abstract: Background: The early cellular stresses leading to Alzheimer’s disease (AD) remain poorly understood because we cannot access living, asymptomatic human AD brains for detailed molecular analyses. Sortilin-related receptor 1 (SORL1 ) encodes a multi-domain receptor protein genetically associated with both rare, early-onset familial AD (EOfAD) and common, sporadic, late-onset AD (LOAD). SORL1 protein has been shown to act in the trafficking of the amyloid β A4 precursor protein (AβPP) that is proteolysed to form one of the pathological hallmarks of AD, amyloid-β (Aβ) peptide. However, other functions of SORL1 in AD are less well understood. Objective: To investigate …the effects of heterozygosity for an EOfAD-like mutation in SORL1 on the brain transcriptome of young-adult mutation carriers using zebrafish as a model organism. Methods: We performed targeted mutagenesis to generate an EOfAD-like mutation in the zebrafish orthologue of SORL1 and performed RNA-sequencing on mRNA isolated from the young adult brains of siblings in a family of fish either wild type (non-mutant) or heterozygous for the EOfAD-like mutation. Results: We identified subtle differences in gene expression indicating changes in mitochondrial and ribosomal function in the mutant fish. These changes appear to be independent of changes in mitochondrial content or the expression of AβPP-related proteins in zebrafish. Conclusion: These findings provided evidence supporting that EOfAD mutations in SORL1 affect mitochondrial and ribosomal function and provide the basis for future investigation elucidating the nature of these effects. Show more

Keywords: Alzheimer’s disease, mitochondria, ribosome, RNA-seq, sorl1, zebrafish

DOI: 10.3233/JAD-201383

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Kumon, Hiroshi | Yoshino, Yuta | Funahashi, Yu | Mori, Hiroaki | Ueno, Mariko | Ozaki, Yuki | Yamazaki, Kiyohiro | Ochi, Shinichiro | Mori, Takaaki | Iga, Jun-ichi | Nagai, Masahiro | Nomoto, Masahiro | Ueno, Shu-ichi

Article Type: Research Article

Abstract: Background: Phosphatidylinositol-binding clathrin assembly protein (PICALM) is a validated genetic risk factor for late-onset Alzheimer’s disease (AD) and is associated with other neurodegenerative diseases. However, PICALM expression in the blood of neurodegenerative diseases remains elusive. Objective: This study aimed to assess the usefulness of PICALM expression levels in the blood of patients with AD, Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and geriatric major depressive disorder (MDD) as a diagnostic biomarker. Methods: In total, 45, 20, 21, and 19 patients with AD, PD, DLB, and geriatric MDD, respectively, and 54 healthy controls (HCs) were …enrolled in the study. Expression data from Gene Expression Omnibus database (GSE97760), (GSE133347) and (GSE98793), (GSE48350), and (GSE144459) were used to validate the ability of biomarkers in the blood of patients with AD, PD, geriatric MDD, and a postmortem human AD brain and animal model of AD (3xTg-AD mouse), respectively. Results: PICALM mRNA expression in human blood was significantly increased in patients with AD compared with that in HCs. PICALM mRNA expression and age were negatively correlated only in patients with AD. PICALM mRNA expression in human blood was significantly lower in patients with PD than in HCs. No changes in PICALM mRNA expression were found in patients with DLB and geriatric MDD. Conclusion: PICALM mRNA expression in blood was higher in patients with AD, but lower in patients with PD, which suggests that PICALM mRNA expression in human blood may be a useful biomarker for differentiating neurodegenerative diseases and geriatric MDD. Show more

Keywords: Alzheimer’s disease, blood, gene expression, major depressive disorder, phosphatidylinositol-binding clathrin assembly protein

DOI: 10.3233/JAD-201046

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Trumbore, Conrad N.

Article Type: Other

Abstract: Amyloid-β (Aβ) and tau oligomers have been identified as neurotoxic agents responsible for causing Alzheimer’s disease (AD). Clinical trials using Aβ and tau as targets have failed, giving rise to calls for new research approaches to combat AD. This paper provides such an approach. Most basic AD research has involved quiescent Aβ and tau solutions. However, studies involving laminar and extensional flow of proteins have demonstrated that mechanical agitation of proteins induces or accelerates protein aggregation. Recent MRI brain studies have revealed high energy, chaotic motion of cerebrospinal fluid (CSF) in lower brain and brainstem regions. These and studies showing …CSF flow within the brain have shown that there are two energetic hot spots. These are within the third and fourth brain ventricles and in the neighborhood of the circle of Willis blood vessel region. These two regions are also the same locations as those of the earliest Aβ and tau AD pathology. In this paper, it is proposed that cardiac systolic pulse waves that emanate from the major brain arteries in the lower brain and brainstem regions and whose pulse waves drive CSF flows within the brain are responsible for initiating AD and possibly other amyloid diseases. It is further proposed that the triggering of these diseases comes about because of the strengthening of systolic pulses due to major artery hardening that generates intense CSF extensional flow stress. Such stress provides the activation energy needed to induce conformational changes of both Aβ and tau within the lower brain and brainstem region, producing unique neurotoxic oligomer molecule conformations that induce AD. Show more

Keywords: Amyloid-β, arteries, atherosclerosis, cerebrospinal fluid, extensional flow, fluid flow stress, heart failure, oligomer, shear, strain, systolic pulse, tau, ventricles

DOI: 10.3233/JAD-201025

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-24, 2020

Authors: Chatterjee, Pratishtha | Fagan, Anne M. | Xiong, Chengjie | McKay, Matthew | Bhatnagar, Atul | Wu, Yunqi | Singh, Abhay K. | Taddei, Kevin | Martins, Ian | Gardener, Samantha L. | Molloy, Mark P. | Multhaup, Gerhard | Masters, Colin L. | Schofield, Peter R. | Benzinger, Tammie L.S. | Morris, John C. | Bateman, Randall J. | Greenberg, Steven M. | Wermer, Marieke J.H. | van Buchem, Mark A. | Sohrabi, Hamid R. | Martins, Ralph N. | Dominantly Inherited Alzheimer Network

Article Type: Research Article

Abstract: Background: Cerebral amyloid angiopathy (CAA) is one of the major causes of intracerebral hemorrhage and vascular dementia in older adults. Early diagnosis will provide clinicians with an opportunity to intervene early with suitable strategies, highlighting the importance of pre-symptomatic CAA biomarkers. Objective: Investigation of pre-symptomatic CAA related blood metabolite alterations in Dutch-type hereditary CAA mutation carriers (D-CAA MCs). Methods: Plasma metabolites were measured using mass-spectrometry (AbsoluteIDQ® p400 HR kit) and were compared between pre-symptomatic D-CAA MCs (n = 9) and non-carriers (D-CAA NCs, n = 8) from the same pedigree. Metabolites that survived correction for multiple …comparisons were further compared between D-CAA MCs and additional control groups (cognitively unimpaired adults). Results: 275 metabolites were measured in the plasma, 22 of which were observed to be significantly lower in theD-CAAMCs compared to D-CAA NCs, following adjustment for potential confounding factors age, sex, and APOE ε4 (p < 00.05). After adjusting for multiple comparisons, only spermidine remained significantly lower in theD-CAAMCscompared to theD-CAA NCs (p  < 0.00018). Plasma spermidine was also significantly lower in D-CAA MCs compared to the cognitively unimpaired young adult and older adult groups (p < 0.01). Spermidinewas also observed to correlate with CSF Aβ40 (rs = 0.621, p = 0.024), CSF Aβ42 (rs = 0.714, p = 0.006), and brain Aβ load (rs = –0.527, p = 0.030). Conclusion: The current study provides pilot data on D-CAA linked metabolite signals, that also associated with Aβ neuropathology and are involved in several biological pathways that have previously been linked to neurodegeneration and dementia. Show more

Keywords: Blood biomarkers, cerebral amyloid angiopathy, early diagnosis, hereditary cerebral hemorrhage with amyloidosis - dutch type, intracerebral hemorrhage, metabolomics, vascular dementia

DOI: 10.3233/JAD-201267

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Bao, Yi-Wen | Chau, Anson C.M. | Chiu, Patrick Ka-Chun | Shea, Yat Fung | Kwan, Joseph S.K. | Chan, Felix Hon Wai | Mak, Henry Ka-Fung

Article Type: Research Article

Abstract: Background: With the more widespread use of 18F-radioligand-based amyloid-β (Aβ) PET-CT imaging, we evaluated Aβ binding and the utility of neocortical 18 F-Flutemetamol standardized uptake value ratio (SUVR) as a biomarker. Objective: 18 F-Flutemetamol SUVR was used to differentiate 1) mild cognitive impairment (MCI) from Alzheimer’s disease (AD), and 2) MCI from other non-AD dementias (OD). Methods: 109 patients consecutively recruited from a University memory clinic underwent clinical evaluation, neuropsychological test, MRI and 18 F-Flutemetamol PET-CT. The diagnosis was made by consensus of a panel consisting of 1 neuroradiologist and 2 geriatricians. The final cohort included …13 subjective cognitive decline (SCD), 22 AD, 39 MCI, and 35 OD. Quantitative analysis of 16 region-of-interests made by Cortex ID software (GE Healthcare). Results: The global mean 18 F-Flutemetamol SUVR in SCD, MCI, AD, and OD were 0.50 (SD-0.08), 0.53 (SD-0.16), 0.76 (SD-0.10), and 0.56 (SD-0.16), respectively, with SUVR in SCD and MCI and OD being significantly lower than AD. Aβ binding in SCD, MCI, and OD was heterogeneous, being 23%, 38.5%, and 42.9% respectively, as compared to 100% amyloid positivity in AD. Using global SUVR, ROC analysis showed AUC of 0.868 and 0.588 in differentiating MCI from AD and MCI from OD respectively. Conclusion: 18 F-Flutemetamol SUVR differentiated MCI from AD with high efficacy (high negative predictive value), but much lower efficacy from OD. The major benefit of the test was to differentiate cognitively impaired patients (either SCD, MCI, or OD) without AD-related-amyloid-pathology from AD in the clinical setting, which was under-emphasized in the current guidelines proposed by Amyloid Imaging Task Force. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, early-onset Alzheimer’s disease, 18F-Flutemetamol, mild cognitive impairment, positron emission tomography

DOI: 10.3233/JAD-200890

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Streit, Wolfgang J. | Khoshbouei, Habibeh | Bechmann, Ingo

Article Type: Review Article

Abstract: Microglia constitute the brain’s immune system and their involvement in Alzheimer’s disease has been discussed. Commonly, and in line with the amyloid/neuroinflammation cascade hypothesis, microglia have been portrayed as potentially dangerous immune effector cells thought to be overactivated by amyloid and producing neurotoxic inflammatory mediators that lead to neurofibrillary degeneration. We disagree with this theory and offer as an alternative the microglial dysfunction theory stating that microglia become impaired in their normally neuroprotective roles because of aging, i.e., they become senescent and aging neurons degenerate because they lack the needed microglial support for their survival. Thus, while the amyloid cascade …theory relies primarily on genetic data, the dysfunction theory incorporates aging as a critical etiological factor. Aging is the greatest risk factor for the sporadic (late-onset) and most common form of Alzheimer’s disease, where fully penetrant genetic mutations are absent. In this review, we lay out and discuss the human evidence that supports senescent microglial dysfunction and conflicts with the amyloid/neuroinflammation idea. Show more

Keywords: Aging, dystrophy, late-onset Alzheimer’s disease, neurodegeneration, neuroinflammation, senescence

DOI: 10.3233/JAD-201248

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Futamura, Akinori | Hieda, Sotaro | Mori, Yukiko | Sugimoto, Azusa | Kasai, Hideyo | Kuroda, Takeshi | Yano, Satoshi | Kasuga, Kensaku | Murakami, Hidetomo | Ikeuchi, Takeshi | Ono, Kenjiro

Article Type: Short Communication

Abstract: We compared ‘CIScore’ determined by quantitative single photon emission computed tomography studies of the cingulate island sign to cerebrospinal fluid (CSF) biomarkers in Lewy body disease (LBD) and Alzheimer’s disease (AD) to assess its usefulness and pathological background. Among the 16 each age-matched LBD and AD patients, the CIScore differed significantly but was not correlated with CSF biomarkers. In LBD, hippocampal atrophy significantly correlated with Clinical Dementia Rating and CSF p-tau and t-tau levels. Our results showed CIS was not related to CSF biomarkers in LBD and high CSF tau levels were related to clinical disease severity and hippocampal atrophy.

Keywords: Alzheimer’s disease, amyloid β-protein 42, cingulate island sign, Lewy body disease, medial temporal atrophy, phosphorylated tau protein

DOI: 10.3233/JAD-201145

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2020