Journal of Alzheimer's Disease - Volume 85, issue 4

Authors: Suo, William Z.

Article Type: Review Article

Abstract: Prevention of Alzheimer’s disease (AD) is a high priority mission while searching for a disease modifying therapy for AD, a devastating major public health crisis. Clinical observations have identified a prodromal stage of AD for which the patients have mild cognitive impairment (MCI) though do not yet meet AD diagnostic criteria. As an identifiable transitional stage before the onset of AD, MCI should become the high priority target for AD prevention, assuming successful prevention of MCI and/or its conversion to AD also prevents the subsequent AD. By pulling this string, one demonstrated cause of amnestic MCI appears to be the …deficiency of G protein-coupled receptor-5 (GRK5). The most compelling evidence is that GRK5 knockout (GRK5KO) mice naturally develop into aMCI during aging. Moreover, GRK5 deficiency was reported to occur during prodromal stage of AD in CRND8 transgenic mice. When a GRK5KO mouse was crossbred with Tg2576 Swedish amyloid precursor protein transgenic mouse, the resulted double transgenic GAP mice displayed exaggerated behavioral and pathological changes across the spectrum of AD pathogenesis. Therefore, the GRK5 deficiency possesses unique features and advantage to serve as a prophylactic therapeutic target for MCI due to AD. Show more

Keywords: Alzheimer’s disease, amnestic, G protein, kinase, mild cognitive impairment, pathogenesis, receptor

DOI: 10.3233/JAD-215379

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1399-1410, 2022

Authors: Schaefer, Sydney Y. | Malek-Ahmadi, Michael | Hooyman, Andrew | King, Jace B. | Duff, Kevin

Article Type: Short Communication

Abstract: Hippocampal atrophy is a widely used biomarker for Alzheimer’s disease (AD), but the cost, time, and contraindications associated with magnetic resonance imaging (MRI) limit its use. Recent work has shown that a low-cost upper extremity motor task has potential in identifying AD risk. Fifty-four older adults (15 cognitively unimpaired, 24 amnestic mild cognitive impairment, and 15 AD) completed six motor task trials and a structural MRI. Several measures of motor task performance significantly predicted bilateral hippocampal volume, controlling for age, sex, education, and memory. Thus, this motor task may be an affordable, non-invasive screen for AD risk and progression.

Keywords: Alzheimer’s disease, hippocampus, mild cognitive impairment, psychomotor performance

DOI: 10.3233/JAD-210665

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1411-1417, 2022

Authors: Goldsmith, Harry S.

Article Type: Editorial

Abstract: Normally, an adequate cerebral blood flow arrives at individual cerebral neurons in which the blood flow augments activity of intraneuronal mitochondria, which is the source of intraneuronal ATP, the energy source of cerebral neurons. With a decrease in cerebral blood flow that can occur as a function of normal aging phenomena, less blood results in decreased mitochondria, decreased ATP, and a decrease in neuronal activity, which can eventually lead to Alzheimer’s disease. It has been found that placement of the omentum directly on an Alzheimer’s disease brain can lead to improved cognitive function.

Keywords: ATP, cerebral blood flow, mitochondria, omentum

DOI: 10.3233/JAD-215479

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1419-1422, 2022

Authors: Ramos, Claudia | Villalba, Camilo | García, Jenny | Lanata, Serggio | López, Hugo | Aguillón, David | Cordano, Christian | Madrigal, Lucía | Aguirre-Acevedo, Daniel C. | Lopera, Francisco

Article Type: Research Article

Abstract: Background: Cigarette smoking is a known risk factor for Alzheimer’s disease (AD). However, the association between neurodegeneration and other substances has not been fully determined. It is of vital importance to evaluate this relationship in populations at high risk of dementia. Since substance use possibly modifies the progression rate of cognitive decline, we studied this association in a unique and well-phenotyped cohort from the University of Antioquia: carriers of the PSEN1-E280A genetic variant. Objective: To determine the association between substance use and cognitive decline in carriers of the PSEN1-E280A genetic variant. Methods: …A retrospective cohort study was conducted with 94 carriers and 69 noncarriers recruited between January 2019 and April 2020. A psychiatrist interviewed the participants using the Consumption of Alcohol, Cigarettes and other Substances questionnaire. The participants were also submitted to cognitive evaluation. The relationship between cognitive decline and substance use was explored through a mixed effects regression model. Results: There was an association between cigarettes and better performance on tasks related to perceptual organization, verbal fluency, and memory in carriers. Alcohol had a positive or negative effect on memory according to the type of alcoholic beverage. Results on marijuana use were no conclusive. Coffee was associated with progressive improvements in executive function and verbal fluency. Conclusion: Cigarette and alcohol were associated with an improvement of some cognitive assessments, possibly by a survival bias. In addition, coffee was related to improvements in executive function and language; therefore, its short-term neuroprotective potential should be studied. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, disease prevention, substance-related disorders

DOI: 10.3233/JAD-215169

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1423-1439, 2022

Authors: Zhang, Heng | Lyu, Diyang | Jia, Jianping | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Synaptic degeneration has been suggested as an early pathological event that strongly correlates with severity of dementia in Alzheimer’s disease (AD). However, changes in longitudinal cerebrospinal fluid (CSF) growth-associated protein 43 (GAP-43) as a synaptic biomarker in the AD continuum remain unclear. Objective: To assess the trajectory of CSF GAP-43 with AD progression and its association with other AD hallmarks. Methods: CSF GAP-43 was analyzed in 788 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including 246 cognitively normal (CN) individuals, 415 individuals with mild cognitive impairment (MCI), and 127 with AD dementia based on …cognitive assessments. The associations between a multimodal classification scheme with amyloid-β (Aβ), tau, and neurodegeneration, and changes in CSF GAP-43 over time were also analyzed. Results: CSF GAP-43 levels were increased at baseline in MCI and dementia patients, and increased significantly over time in the preclinical (Aβ-positive CN), prodromal (Aβ-positive MCI), and dementia (Aβ-positive dementia) stages of AD. Higher levels of CSF GAP-43 were also associated with higher CSF phosphorylated tau (p-tau) and total tau (t-tau), cerebral amyloid deposition and hypometabolism on positron emission tomography, the hippocampus and middle temporal atrophy, and cognitive performance deterioration at baseline and follow-up. Furthermore, CSF GAP-43 may assist in effectively predicting the probability of dementia onset at 2- or 4-year follow-up. Conclusion: CSF GAP-43 can be used as a potential biomarker associated with synaptic degeneration in subjects with AD; it may also be useful for tracking the disease progression and for monitoring the effects of clinical trials. Show more

Keywords: Alzheimer’s disease, biomarker, growth-associated protein 43, synaptic dysfunction

DOI: 10.3233/JAD-215456

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1441-1452, 2022

Authors: Zhao, Yang | Bao, Jian | Liu, Wei | Gong, Xiaokang | Liang, Zheng | Li, Wenshuang | Wu, Mengjuan | Xiao, Yifan | Sun, Binlian | Wang, Xiaochuan | Wang, Jian-Zhi | Wang, Jun | Shu, Xiji

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD), with cognitive impairment as the main clinical manifestation, is a progressive neurodegenerative disease. The assembly of amyloid-β (Aβ) as senile plaques is one of the most well-known histopathological alterations in AD. Several studies reported that cognitive training reduced Aβ deposition and delayed memory loss. However, the long-term benefits of spatial training and the underlying neurobiological mechanisms have not yet been elucidated. Objective: To explore the long-term effects of spatial training on AD-related pathogenic processes in APP/PS1 mice. Methods: We used Morris water maze (MWM), Open Field, Barnes Maze, western blotting, qPCR, and …immunofluorescence. Results: One-month MWM training in APP/PS1 mice at 2.5 months of age could attenuate Aβ deposition and decrease the expression of β-secretase (BACE1) and amyloid-β protein precursor (AβPP) with long-term effects. Simultaneously, regular spatial training increased the expression of synapse-related proteins in the hippocampus. Moreover, MWM training increased adult hippocampal neurogenesis in AD model mice. Nonetheless, cognitive deficits in APP/PS1 transgenic mice at 7 months of age were not attenuated by MWM training at an early stage. Conclusion: Our study demonstrates that MWM training alleviates amyloid plaque burden and adult hippocampal neurogenesis deficits with long-term effects in AD model mice. Show more

Keywords: Adult hippocampal neurogenesis, Alzheimer’s disease, amyloid-β , AβPP, BACE1, spatial training

DOI: 10.3233/JAD-215016

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1453-1466, 2022

Authors: Jang, Hyemin | Park, Yu-hyun | Choe, Young Sim | Kang, Sung Hoon | Kang, Eun-Sook | Lee, Seunghoon | Seo, Sang Won | Kim, Hee Jin | Na, Duk L.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and normal pressure hydrocephalus (NPH) commonly coexist. Objective: We aimed to characterize an overlapping syndrome of AD and NPH that presents with gait disturbance, ventriculomegaly on magnetic resonance imaging, and significant amyloid deposition on positron emission tomography (PET). Methods: Of 114 patients who underwent cerebrospinal fluid (CSF) drainage for a possible diagnosis of NPH between 2015 and 2020 in Samsung Medical Center, we identified 24 patients (21.1%) with the NPH patients with amyloid deposition on PET, which we referred to as hydrocephalic AD in this study. We compared their clinical and imaging …findings with those of 123 typical AD without hydrocephalic signs/symptoms. We also investigated the frequency and potential predictors of the tap test response in hydrocephalic AD. Results: Evans’ index was 0.36±0.03, and a disproportionately enlarged subarachnoid space was present in 54.2% of the hydrocephalic AD patients. The mean age (75.2±7.3 years) and the APOE4 frequency (68.2%) did not differ from those of AD controls. However, the hydrocephalic AD patients showed better memory and language performance, and a thinner cingulate cortex. About 42% of the hydrocephalic AD patients responded to the tap test, of whom seven underwent shunt surgery. Cognition did not improve, whereas gait improved after shunt surgery in all. Conclusion: Hydrocephalic AD has different neuropsychological and imaging characteristics from typical AD. Future studies are warranted to further investigate the effect of CSF removal on their clinical course and to elucidate the pathophysiological interaction between amyloid and NPH. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, hydrocephalus, MRI, PET

DOI: 10.3233/JAD-215110

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1467-1479, 2022

Authors: Khan, Naazneen | Alimova, Yelena | Clark, Sophie J. | Vekaria, Hemendra J. | Walsh, Adeline E. | Williams, Holden C. | Hawk, Gregory S. | Sullivan, Patrick G. | Johnson, Lance A. | McClintock, Timothy S.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a progressive age-dependent disorder whose risk is affected by genetic factors. Better models for investigating early effects of risk factors such as apolipoprotein E (APOE) genotype are needed. Objective: To determine whether APOE genotype produces neuropathologies in an AD-susceptible neural system, we compared effects of human APOE ɛ3 (E3) and APOE ɛ4 (E4) alleles on the mouse olfactory epithelium. Methods: RNA-Seq using the STAR aligner and DESeq2, immunohistochemistry for activated caspase-3 and phosphorylated histone H3, glucose uptake after oral gavage of 2-[1,2-3 H (N)]-deoxy-D-glucose, and Seahorse Mito …Stress tests on dissociated olfactory mucosal cells. Results: E3 and E4 olfactory mucosae show 121 differentially abundant mRNAs at age 6 months. These do not indicate differences in cell type proportions, but effects on 17 odorant receptor mRNAs suggest small differences in tissue development. Ten oxidoreductases mRNAs important for cellular metabolism and mitochondria are less abundant in E4 olfactory mucosae but this does not translate into differences in cellular respiration. E4 olfactory mucosae show lower glucose uptake, characteristic of AD susceptibility and consistent with greater expression of the glucose-sensitive gene, Asns . Olfactory sensory neuron apoptosis is unaffected at age 6 months but is greater in E4 mice at 10 months. Conclusion: Effects of human APOE alleles on mouse olfactory epithelium phenotype are apparent in early adulthood, and neuronal loss begins to increase by middle age (10 months). The olfactory epithelium is an appropriate model for the ability of human APOE alleles to modulate age-dependent effects associated with the progression of AD. Show more

Keywords: Alzheimer’s disease, apoptosis, glucose metabolic disorder, mitochondria, odorant receptors, olfaction, oxidoreductases

DOI: 10.3233/JAD-215152

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1481-1494, 2022

Authors: Gao, Zhaoyu | Zhang, Rui | Jiang, Lei | Zhou, Huimin | Wang, Qian | Ma, Yingxin | Zhang, Di | Qin, Yushi | Tian, Pei | Zhang, Nan | Shi, Zhongli | Xu, Shunjiang

Article Type: Research Article

Abstract: Background: Mitochondrial dysfunction is an early feature of Alzheimer’s disease (AD) and miR-195 is involved in mitochondrial disorder through targeting MFN-2 protein in hippocampal neurons of AD. Objective: To clarify if administration of miR-195 inhibitor could enhance the memory deficits through improving hippocampal neuron mitochondrial dysfunction in SAMP8 mice. Methods: The expression of miR-195 was detected by RT-qPCR in primary hippocampal neurons and HT-22 cells treated with Aβ1–42 . Morris water maze (MWM) was used to assess the learning and memory function in SAMP8 mice administrated with antagomir-195. Transmission electron microscopy was employed …to determine the morphological changes of synapses and mitochondria of hippocampus in SAMP8 mice. Mitochondrial respiration was measured using a high-resolution oxygraph. Results: The expression of miR-195 were upregulated in the primary hippocampal neurons and HT-22 cells induced by Aβ1–42 . Inhibition of miR-195 ameliorated the mitochondrial dysfunction in HT-22 cells induced by Aβ1–42 , including mitochondrial morphologic damages, mitochondrial membrane potential, respiration function, and ATP production. Administration of antagomir-195 by the third ventricle injection markedly ameliorated the cognitive function, postsynaptic density thickness, length of synaptic active area, mitochondrial aspect ratio, and area in hippocampus of SAMP8 mice. Finally, antagomir-195 was able to promote an increase in the activity of respiratory chain complex CI and II in SAMP8 mice. Conclusion: This study demonstrated that miR-195 inhibitor ameliorated the cognitive impairment of AD mice by improving mitochondrial structure damages and dysfunction in the hippocampal neurons, which provide an experimental basis for further exploring the treatment strategy of AD. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, microRNA-195, mitochondria, synaptic membranes

DOI: 10.3233/JAD-215301

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1495-1509, 2022

Authors: Dong, Liling | Mao, Chenhui | Liu, Caiyan | Li, Jie | Huang, Xinying | Wang, Jie | Lei, Dan | Chu, Shanshan | Sha, Longze | Xu, Qi | Peng, Bin | Cui, Liying | Gao, Jing

Article Type: Research Article

Abstract: Background: The previous studies have identified several genes in relation to Alzheimer’s disease (AD), such as ABCA7 , CR1 , etc. A few studies have explored the association between the common variants, mainly in the non-coding regions of these genes, and cerebrospinal fluid (CSF) biomarkers. Fewer studies target the variants in the coding regions. Objective: To illustrate the association between the common variants within or adjacent to the coding regions of AD susceptible genes and CSF biomarkers in AD patients. Methods: 75 sporadic probable AD patients were extracted from the dementia cohort of Peking Union Medical …College Hospital. They all had history inquiry, physical examination, blood test, cognitive assessment, brain MRI, CSF testing of Aβ42 , 181 p-tau, and t-tau, and next-generation DNA sequencing. Sixty-nine common single nucleotide polymorphisms (SNPs) (minor allele frequency > 0.01) within or near the coding region of 13 AD susceptible genes were included in the analysis. Results: The rs7412-CC (APOE ) genotype showed lower CSF Aβ42 level and higher p-tau/Aβ42 ratio than the rs7412-CT genotype. The rs3752246-C (ABCA7 ) allele correlated with lower CSF Aβ42 level. The alternate alleles of six ABCA7 SNPs were related to lower CSF p-tau, including rs3745842, rs3764648, rs3764652, rs4147930, rs4147934 and rs881768. The rs11609582-TT (A2M ) genotype showed higher CSF p-tau than the rs11609582-TA genotype. The p-tau/Aβ42 ratio was higher in the rs490460-TT (BACE1 ) genotype relative to the rs490460-GT genotype. Conclusion: Some common variants within or near the coding regions of APOE , ABCA7 , A2M , and BACE1 are associated with CSF Aβ42 , p-tau. or p-tau/Aβ42 . Show more

Keywords: ABCA7 , Alzheimer’s disease, amyloid-beta, APOE , cerebrospinal fluid, phosphorylated tau, single nucleotide polymorphism

DOI: 10.3233/JAD-215067

Citation: Journal of Alzheimer's Disease, vol. 85, no. 4, pp. 1511-1518, 2022