Journal of Alzheimer's Disease - Volume 69, issue 3

Authors: Cai, Hong-Bin | Fan, Zhen-Zhen | Tian, Ting | Zhao, Chon-Chon | Ge, Zhao-Ming

Article Type: Research Article

Abstract:  Cyclin-dependent kinase-5 (CDK5) is activated by p35 and then binds to both p35 and its truncated form p25 to promote hyperphosphorylation of tau protein, thereby facilitating the pathological progression of Alzheimer’s disease (AD). However, it is unknown whether a patient’s diabetic status promotes the later onset of AD in a CDK5-dependent manner. Here, we induced pro-diabetic insulin resistance and glucose intolerance in rats using a combined high fat and high glucose diet. Compared to normal diet-fed rats, these pro-diabetic rats exhibited poorer behavioral performance in the Morris water maze test and the novel object recognition test. Increased phosphorylation of tau …protein was detected in the hippocampal CA1 region of the rat brain, suggesting neurodegeneration. Moreover, CDK5 transcriptional activity was significantly increased in the HFGD-rat brain, likely resulting from an increase in acetylation and a decrease in methylation of the CDK5 promoter. Together, these data suggest that epigenetic control of the CDK5 promoter by acetylation and methylation may regulate the diabetes-associated development of AD. Show more

Keywords: Alzheimer’s disease, cyclin-dependent kinase-5, diabetes, methylation, promoter acetylation, tau

DOI: 10.3233/JAD-190227

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 743-750, 2019

Authors: Haddad, Mohamed | Perrotte, Morgane | Landri, Sarra | Lepage, Aurelie | Fülöp, Tamàs | Ramassamy, Charles

Article Type: Research Article

Abstract: Background: Both advanced glycation end products (AGEs) N-(1-carboxymethyl)-L-lysine (CML) and pentosidine were found in the brain from Alzheimer’s disease (AD) patients and were associated with the neuropathological hallmarks of AD. In AD patients, the circulating level of both AGEs remains unknown. Moreover, their levels in peripheral extracellular vesicles (EVs) and their association with AD remain to be determined. Finally, it is not known if neuronal cells can release AGEs via EVs and propagate AGEs. Objective: To determine the levels of circulating CML and pentosidine during the progression of AD. Moreover, their levels in circulating EVs were determined and …their association with the clinical cognitive scores were analyzed. Finally, we have studied the possibility that neuronal cells eliminate and transfer these AGEs through EVs. Methods: CML and pentosidine levels were measured in serum and in circulating EVs. Released-EVs from SK-N-SH neuronal cells were isolated and CML levels were also determined. Results: The levels of CML in albumin-free serum proteins were higher in the early stage of AD while the levels of pentosidine remained unchanged. In contrast, the levels of CML in the EVs were lower in the moderate stage of AD. Interestingly, the levels of CML in serum were negatively correlated with the clinical cognitive scores MMSE and MoCA. For the first time, we were able to demonstrate that CML was present in EVs released from neuronal cells in culture. Conclusion: Peripheral and circulating EVs levels of CML can differentiate early to moderate AD. In the brain, neuronal CML can propagate from cells-to-cells via EVs. Show more

Keywords: Alzheimer’s disease, carboxymethyl lysine (CML), extracellular vesicles, Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), pentosidine

DOI: 10.3233/JAD-181272

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 751-762, 2019

Authors: Figueira, João | Adolfsson, Rolf | Nordin Adolfsson, Annelie | Nyberg, Lars | Öhman, Anders

Article Type: Research Article

Abstract: There is a great need for diagnostic biomarkers of impending dementia. Metabolite markers in blood have been investigated in several studies, but inconclusive findings encourage further investigation, particularly in the pre-diagnostic phase. In the present study, the serum metabolomes of 110 dementia or pre-diagnostic dementia individuals and 201 healthy individuals matched for age, gender, and education were analyzed by nuclear magnetic resonance spectroscopy in combination with multivariate data analysis. 58 metabolites were quantified in each of the 311 samples. Individuals with dementia were discriminated from controls using a panel of seven metabolites, while the pre-diagnostic dementia subjects were distinguished from …controls using a separate set of seven metabolites, where threonine was a common significant metabolite in both panels. Metabolite and pathway alterations specific for dementia and pre-diagnostic dementia were identified, in particular a disturbed threonine catabolism at the pre-diagnostic stage that extends to several threonine-linked pathways at the dementia stage. Show more

Keywords: Alzheimer’s disease, biomarker, dementia, metabolomics/metabonomics, NMR, serum, vascular dementia

DOI: 10.3233/JAD-181189

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 763-774, 2019

Authors: Luukkainen, Laura | Helisalmi, Seppo | Kytövuori, Laura | Ahmasalo, Riitta | Solje, Eino | Haapasalo, Annakaisa | Hiltunen, Mikko | Remes, Anne M. | Krüger, Johanna

Article Type: Research Article

Abstract: A lot of effort has been done to unravel the genetics underlying early-onset Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). However, many familial early-onset dementia (EOD) cases still show an unclear genetic background. The aim of this study was to evaluate the role of the known causative mutations and possible pathogenic variants associated with AD and FTLD in a Finnish EOD cohort. The cohort consisted of 39 patients (mean age at onset 54.8 years, range 39–65) with a positive family history of dementia or an atypical or rapidly progressive course of the disease. None of the patients carried the …C9orf72 hexanucleotide repeat expansion. Mutations and variants in APP, PSEN1, PSEN2, MAPT, GRN, VCP, CHMP2B, FUS, TARDBP, TREM2, TMEM106B, UBQLN2, SOD1, PRNP, UBQLN1 , and BIN1 were screened by using a targeted next generation sequencing panel. Two previously reported pathogenic mutations (PSEN1 p.His163Arg and MAPT p.Arg406Trp) were identified in the cohort. Both patients had familial dementia with an atypical early onset phenotype. In addition, a heterozygous p.Arg71Trp mutation in PSEN2 with an uncertain pathogenic nature was identified in a patient with neuropathologically confirmed AD. In conclusion, targeted investigation of the known dementia-linked genes is worthwhile in patients with onset age under 55 and a positive family history, as well as in patients with atypical features. Show more

Keywords: Alzheimer’s disease, early onset, frontotemporal dementia, frontotemporal lobar degeneration, genetics, human, microtubule-associated protein tau, missense, mutation, presenilin-1

DOI: 10.3233/JAD-181256

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 775-782, 2019

Authors: Toledo, Jon B. | Habes, Mohamad | Sotiras, Aristeidis | Bjerke, Maria | Fan, Yong | Weiner, Michael W. | Shaw, Leslie M. | Davatzikos, Christos | Trojanowski, John Q. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: There are conflicting results regarding how APOE genotype, the strongest genetic risk factor for Alzheimer’s disease (AD), influences spatial and longitudinal amyloid-β (Aβ) deposition and its impact on the selection of biomarker cut-points. In our study, we sought to determine the impact of APOE genotype on cross-sectional and longitudinal florbetapir positron emission tomography (PET) amyloid measures and its impact in classification of patients and interpretation of clinical cohort results. We included 1,019 and 1,072 Alzheimer’s Disease Neuroimaging Initiative participants with cerebrospinal fluid Aβ1 - 42 and florbetapir PET values, respectively. 623 of these subjects had a second florbetapir PET …scans two years after the baseline visit. We evaluated the effect of APOE genotype on Aβ distribution pattern, pathological biomarker cut-points, cross-sectional clinical associations with Aβ load, and longitudinal Aβ deposition rate measured using florbetapir PET scans. 1) APOE ɛ 4 genotype influences brain amyloid deposition pattern; 2) APOE ɛ 4 genotype does not modify Aβ biomarker cut-points estimated using unsupervised mixture modeling methods if white matter and brainstem references are used (but not when cerebellum is used as a reference); 3) findings of large differences in Aβ biomarker value differences based on APOE genotype are due to increased probability of having AD neuropathology and are most significant in mild cognitive impairment subjects; and 4) APOE genotype and age (but not gender) were associated with increased Aβ deposition rate. APOE ɛ 4 carrier status affects rate and location of brain Aβ deposition but does not affect choice of biomarker cut-points if adequate references are selected for florbetapir PET processing. Show more

Keywords: Alzheimer’s disease, amyloid-β, cerebrospinal fluid, diagnosis, mild cognitive impairment, positron emission tomography

DOI: 10.3233/JAD-181282

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 783-793, 2019

Authors: Yan, Xin | Li, Fangyu | Chen, Shuoqi | Jia, Jianping

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) exerts a heavy burden on China. Substantial factors are found associated with high expenditure of AD in high-income countries. To date, few studies have been conducted in China. Objective: This study aimed to analyze the associated factors of the total annual costs of AD in China. Methods: Data were drawn from a multi-center, cross-sectional, socioeconomic study on the costs of AD conducted in China from October 2015 to March 2016. Generalized linear model (GLM) using gamma distribution with a log-link function was employed to examine the associated factors of the total cost. …Results: Univariate analysis showed that the demographic and clinical characteristics of AD patients and their caregivers had a substantial impact on the total cost. In GLM analysis, age, monthly household income, AD severity, number of comorbidities, and treatment with memantine were associated with higher expenditure, while the use of a nursing home/care facility was associated with lower expenditure. The mean annual costs for patients with severe dementia were almost twice as high as those for patients with mild dementia (US$ 25,601 versus US$ 13,387, p  < 0.001). The mean total cost of AD patients with at least five comorbidities (US$ 38,348) was almost three times than those with no comorbidities (US$ 13,744). Conclusion: In China, AD severity and comorbidities were the most critical factors impacting the total cost. Optimizing care patterns, delaying disease progression, and managing comorbidities comprehensively could decrease the heavy burden of AD. Show more

Keywords: Alzheimer’s disease, caregiver, cost of illness, comorbidity, dementia severity

DOI: 10.3233/JAD-190166

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 795-806, 2019

Authors: Hamina, Aleksi | Taipale, Heidi | Karttunen, Niina | Tanskanen, Antti | Tiihonen, Jari | Tolppanen, Anna-Maija | Hartikainen, Sirpa

Article Type: Research Article

Abstract: Background: Pneumonia is a common cause for hospitalization and excess mortality among persons with Alzheimer’s disease (AD), but little research exists evaluating drug use as its risk factor. Objective: We investigated the association between opioid use and hospital-treated pneumonia among community dwellers with AD. Methods: This study was part of the Medication use and Alzheimer’s Disease (MEDALZ) cohort. We included all community dwellers newly diagnosed with AD during 2010–2011 in Finland with incident prescription opioid use (n  = 5,623) and age-, sex-, and time since AD diagnosis-matched nonusers (n  = 5,623). Opioid use data, modelled from pharmacy dispensing …data, and hospital-treated pneumonia were retrieved from nationwide registers. Patients with active cancer treatment were excluded. Hazard models compared opioid users to nonusers, adjusting for comorbidities, socioeconomic position. and other drug use. Results: Incident opioid use was associated with an increased risk of hospital-treated pneumonia compared to nonuse (adjusted HR, aHR 1.34, 95% CI 1.14–1.57). Highest risk was observed during the first two months of use (aHR 2.58, 95% CI 1.87–3.55). Compared to weak opioids, buprenorphine was not associated with a higher risk of pneumonia (aHR 1.20, 95% CI 0.83–1.76), but strong opioids were (aHR 1.84, 95% CI 1.15–2.97). The risk was higher for those using ≥50 morphine milligram equivalents (MME)/day (aHR 2.03, 95% CI 1.24–3.31), compared to using <50 MME/day. Conclusions: Opioid use was associated with a risk of hospital-treated pneumonia in a dose-dependent manner among persons with AD. Risk-minimization strategies should be considered if opioid therapy is needed. Show more

Keywords: Aged, Alzheimer’s disease, dementia, opioids, pharmacoepidemiology, pneumonia

DOI: 10.3233/JAD-181295

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 807-816, 2019

Authors: Thirunavu, Vineeth | McCullough, Austin | Su, Yi | Flores, Shaney | Dincer, Aylin | Morris, John C. | Cruchaga, Carlos | Benzinger, Tammie L.S. | Gordon, Brian A.

Article Type: Research Article

Abstract: Background: Both low and high body mass index (BMI) have been associated with an increased risk of dementia, including that caused by Alzheimer’s disease (AD). Specifically, high middle-age BMI or a low late-age BMI has been considered a predictor for the development of AD dementia. Less studied is the relationship between BMI and AD pathology. Objective: We explored the association between BMI and cortical amyloid-β (Aβ) burden in cognitively normal participants that were either in mid-life (45–60 years) or late-life (>60). Methods: We analyzed cross-sectional baseline data from the Knight Alzheimer Disease Research Center (ADRC) at …Washington University. Aβ pathology was measured in 373 individuals with Aβ PET imaging and was quantified using Centiloid units. We split the cohort into mid- and late-life groups for analyses (n  = 96 and n  = 277, respectively). We ran general linear regression models to predict Aβ levels from BMI while controlling for age, sex, years of education, and APOE4 status. Analyses were also conducted to test the interaction between BMI and APOE4 genotype and between BMI and sex. Results: Higher BMI was associated with lower cortical Aβ burden in late-life (β= –0.81, p  = 0.0066), but no relationship was found in mid-life (β= 0.04, p  > 0.5). The BMI×APOE4+ and BMI×male interaction terms were not significant in the mid-life (β= 0.28, p  = 0.41; β= 0.64, p  = 0.13) or the late-life (β= 0.17, p  > 0.5; β= 0.50, p  = 0.43) groups. Conclusion: Higher late-life BMI is associated with lower cortical Aβ burden in cognitively normal individuals. Show more

Keywords: Alzheimer disease, amyloid-β, apolipoproteins E, body mass index, obesity, positron emission tomography

DOI: 10.3233/JAD-190154

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 817-827, 2019

Authors: Oliveira, Deborah | Jones, Katy A. | Ogollah, Reuben | Ozupek, Semanur | Hogervorst, Eef | Orrell, Martin

Article Type: Research Article

Abstract: Background: People over 50 are increasing their alcohol intake, potentially increasing their risk of dementia. Objective: This study investigates whether people would be willing to adhere to current United Kingdom (UK, “low-risk”) alcohol guidelines to reduce dementia risk. Methods: A national cross-sectional online survey recruited a non-probabilistic sample of 3,948 individuals aged 50 and over without dementia in the UK. Self-reported willingness to comply with low-risk guidelines was predicted using logistic regression. Other relevant self-reported variables included physical health, lifestyle, and current alcohol intake. Results: Majority of the sample (90%, n  = 3,527) reported drinking …alcohol at least once a month with 23% (n  = 795) exceeding the low-risk guidelines (> 14 units per week). A larger proportion of men, those who were overweight, and people without a partner reported drinking above the recommended level. Most people who consumed alcohol (n  = 2,934; 74.3%) appeared willing to adhere to low-risk guidelines if they were told that their risk of having dementia could be reduced. Increased willingness was found in women (OR 1.81; CI 1.47–2.23), in people who had at least one child (OR 1.36; CI 1.09–1.70), and those who slept well (OR 1.45; CI 1.06–2.00). People who were obese (OR 0.72; CI 0.54–0.95), those who drank alcohol above limits (OR 0.13; CI 0.11–0.16), and those who were smokers (OR 0.56; CI 0.36–0.88) were less willing to adhere to current guidelines. Conclusion: Men and people with more lifestyle risk factors for common chronic diseases (e.g., smoking, obesity, and excess alcohol consumption) are less willing to adhere to current alcohol low-risk guidelines to reduce dementia risk. Show more

Keywords: Alcohol, dementia, disease prevention, older people, risk reduction

DOI: 10.3233/JAD-181224

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 829-837, 2019

Authors: Gallucci, Maurizio | Dell’Acqua, Carola | Boccaletto, Franco | Fenoglio, Chiara | Galimberti, Daniela | Di Battista, Maria Elena

Article Type: Research Article

Abstract: In the present work, we report the case of a patient presenting signs of Lewy body dementia (DLB) and frontotemporal dementia (FTD) throughout different phases of the disease. In January 2017, a 79-year-old right-handed living man was admitted to our Memory Clinic for the presence of behavioral disturbances and progressive cognitive decline. For the previous six years, he was monitored by other Neurological Clinics for the onset of extrapyramidal features. Indeed, through the first phase of the disease (2011–2014), the patient predominantly showed: extrapyramidal features, initial cognitive decline, sleep disturbances, and visual hallucinations, together with a reduced dopamine transporter uptake …in basal ganglia at the DATscan, suggesting a diagnosis of DLB. In a second phase (2015–2017), while his extrapyramidal features remained substantially stable, his cognitive profile deteriorated, with an additional development of severe behavioral and neuropsychiatric disturbances. Again, a subsequent DATscan study was positive and slightly worse than the preceding one; however, the 18 F-FDG PET showed reduced metabolic activity in the frontal and temporal lobes, with the occipital regions left spared. Genetic analysis revealed a hexanucleotide expansion in C9ORF72 (6//38 repeats; ITALSGEN NV <30). In conclusion, we report the case of a patient presenting, firstly, with probable DLB and, in a second phase, with predominant bvFTD features with stable parkinsonism. Even though some clinical and neuropsychological aspects can co-exist in different neurodegenerative diseases, we find such a significant intersection of clinical features to be fairly atypical. Moreover, what is challenging to define is whether the two clinical phenotypes are somehow lying on a continuum, or if they are two individual entities. Show more

Keywords: C9ORF72, dementia with Lewy bodies, diagnosis, frontotemporal dementia, neuroimaging, overlap, Progranulin, TREDEM

DOI: 10.3233/JAD-181298

Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 839-847, 2019