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

Authors: Xiao, Shuo | Song, Lin-Lin | Li, Jiang-Tao | Wang, He | Yu, Na | Wang, Zi-Qi | Zhang, Ying | He, Jin-Sheng | Hung, Tao

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common form of dementia, characterized by amyloid-β peptide (Aβ) aggregates, phosphorylated tau protein (p -tau), and progressive neurodegeneration. Amyloid-β peptide 42 (Aβ42 ) is considered an early trigger of AD pathogenesis. We have previously reported that Aβ N-terminus monoclonal antibody (mAb) A8 alleviated cognitive dysfunction and reduced the abundance of soluble Aβ in brain of the senescence-accelerated mouse prone 8 (SAMP8) mouse model. To confirm the efficacy of mAb A8 in the double-transgenic APPswe/PS1Δ E9 (APP/PS1) mice, here we reported the related findings. The Morris water maze (MWM) data showed that the A8 treatment …group had a shorter escape latency than the control groups in the place navigation test and the probe trial (p  < 0.05). Moreover, immunohistochemistry showed decreased levels of both Aβ and p -tau in the brains of APP/PS1 mice. Regarding Aβ levels, western blot results showed that Aβ42 oligomer (p  < 0.01) but not Aβ40 levels were diminished in brains of A8-treated APP/PS1 mice. Western blot results showed that phospho-tau (pSer231 ) (p  < 0.01) but not tau levels were reduced in A8-treated mouse brains. Furthermore, transmission electron microscopy images indicated ultrastructural improvements, including an increased (p  < 0.01) density of synapses and a reduction of abnormally enlarged mitochondria (p  < 0.01), in the brains of A8-treated mice. Taken together, our data showed that mAb A8 is highly efficacious in APP/PS1 mice as a treatment for AD, and the underlying mechanism may target synaptic pathology by inhibiting the amyloid cascade. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, immunotherapy, Morris water maze test, phosphorylated tau protein, synapse

DOI: 10.3233/JAD-190874

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Rogers, Nicole K. | Romero, Cesar | SanMartín, Carol D. | Ponce, Daniela P. | Salech, Felipe | López, Mercedes N. | Gleisner, Alejandra | Tempio, Fabián | Behrens, María I.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the adult population. There is evidence of an inverse epidemiological relationship between AD and cancer, another prevalent age-related disease. This has led to hypothesize that there could be a common biological mechanism, deregulated in opposite directions that might explain the phenomenon of mutual protection. The immunological system and its regulatory checkpoints are good candidates to explain why having survived a cancer could protect from developing AD. During cancerous growth, the neoplastic cells induce immune tolerance to block the host’s immunity system that would prevent tumor growth. This has led to …the development of drugs that block distinct immune checkpoints, such as Programmed Death 1 (PD-1) and its major ligand PD-L1, that have shown great promise in treating diverse types of cancer. We propose that in those individuals who survived a cancer, the immune system is left in a state of diminished tolerance or proinflammatory systemic milieu, after its successful attempt to fight the cancer, that protects them from developing AD. Show more

Keywords: Alzheimer’s disease, cancer, immune checkpoint, inflammation

DOI: 10.3233/JAD-190839

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Wang, Yan-Li | Chen, Wei | Cai, Wen-Jie | Hu, Hao | Xu, Wei | Wang, Zuo-Teng | Cao, Xi-Peng | Tan, Lan | Yu, Jin-Tai | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: White matter hyperintensities (WMHs), mainly caused by cerebrovascular injury, may lead to cognitive impairment. In order to identify whether the volume of WMHs is associated with cognitive decline over years, this longitudinal study involved 818 individuals from the ADNI-2 dataset from August 2010 to May 2017. Cross-sectional and longitudinal associations of WMHs with 8 cognitive domains were explored, using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating Sum of Boxes (CDRSB), Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog13), Rey Auditory Verbal Learning Test (RAVLT), Functional Assessment Questionnaire (FAQ), executive function (ADNI-EF), and memory function (ADNI-Mem). The association analyses were …performed using multiple linear regression models, linear mixed models, Spearman rank correlation, and Kaplan-Meier survival curves. The volumes of WMHs were greater in patients with Alzheimer’s disease (AD) dementia compared with controls (p  < 0.001) and mild cognitive impairment (p  = 0.006) patients at baseline. The bigger volumes of WMHs correlated with worse performances on ADAS-Cog13 and ADNI-EF (p  = 0.029; p  = 0.003) at baseline and MMSE, MoCA, CDRSB, ADAS-Cog13, FAQ, and ADNI-Mem (overall p  < 0.05) longitudinally, after adjusting for age, sex, educational level, apolipoprotein E ɛ 4 genotype, hypertension, hyperlipidemia, diabetes, smoking, infarction, and diagnosis. Additionally, the correlations between the change rate of WMHs and change rates of MMSE, MoCA, CDRSB, FAQ, ADNI-EF, and ADNI-Mem were statistically significant. Furthermore, patients with high WMH volumes showed an increased likelihood of dementia. The results of the study suggest that WMH volume is associated with cognitive decline, and it contributes to the conversion to AD. Show more

Keywords: Alzheimer’s disease, Alzheimer’s Disease Neuroimaging Initiative, cognition, white matter hyperintensities

DOI: 10.3233/JAD-191005

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Wu, Wanqing | Ding, Ding | Zhao, Qianhua | Wang, Ruru | Liang, Xiaoniu | Xiao, Zhenxu | Luo, Jianfeng | Guo, Qihao | Hong, Zhen

Article Type: Research Article

Abstract: Background: There is significant evidence that physical activity has profound effects on the neurochemistry and plasticity of the brain and may prevent cognitive decline. Objective: This study aimed to determine the association between physical activity and incident dementia among older Chinese adults. Methods: In the prospective phase of the Shanghai Aging Study, 1,648 community-dwellers aged 60 years or older were followed for an average of 5 years. Their physical activity was assessed based on questionnaires. The physical activities were further transformed into metabolic equivalent values. A consensus diagnosis of incident dementia was ascertained based on medical, …neurological, and neuropsychological data and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Results: We identified 166 incident dementia cases; the incidence rate was 19.4 per 1000 person-years. A multivariate Cox regression model indicated that compared to low levels of physical activity, medium-to-high levels of physical activity were associated with a reduced risk of dementia (hazard ratio, 95% confidence interval = 0.62, 0.44–0.89) after adjusting for age, sex, years of education, apolipoprotein E ɛ 4, and other confounders. Conclusion: Our findings demonstrate that medium-to-high level of physical activity is protective against dementia in older adults. Show more

Keywords: Chinese, cognition, cohort studies, dementia, incidence, physical activity

DOI: 10.3233/JAD-190937

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Fani, Lana | Hilal, Saima | Sedaghat, Sanaz | Broer, Linda | Licher, Silvan | Arp, Pascal P. | van Meurs, Joyce B.J. | Ikram, M. Kamran | Ikram, M. Arfan

Article Type: Research Article

Abstract: There is a wide interest in biomarkers that capture the burden of detrimental factors as these accumulate with the passage of time, i.e., increasing age. Telomere length has received considerable attention as such a marker, because it is easily quantified and it may aid in disentangling the etiology of dementia or serve as predictive marker. We determined the association of telomere length with risk of Alzheimer’s disease and all-cause dementia in a population-based setting. Within the Rotterdam Study, we performed quantitative PCR to measure mean leukocyte telomere length in blood. We determined the association of telomere length with risk of …Alzheimer’s disease until 2016, using Cox regression models. Of 1,961 participants (mean age 71.4±9.3 years, 57.1% women) with a median follow-up of 8.3 years, 237 individuals were diagnosed with Alzheimer’s disease. We found a U-shaped association between telomere length and risk of Alzheimer’s disease: compared to the middle tertile the adjusted hazard ratio was 1.59 (95% confidence interval (CI), 1.13–2.23) for the lowest tertile and 1.47 (1.03–2.10) for the highest tertile. Results were similarly U-shaped but slightly attenuated for all-cause dementia. In conclusion, shorter and longer telomere length are both associated with an increased risk of Alzheimer’s disease in the general population. Show more

Keywords: Alzheimer’s disease, dementia, population-based, prospective cohort study, telomere

DOI: 10.3233/JAD-190759

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Kumar, Rajnish | Pavlov, Pavel F. | Winblad, Bengt

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) represents a major public health threat and, unfortunately, available therapeutics provide only temporary symptomatic relief. AD is a complex multifactorial disease and failure of single target therapeutics targeting amyloid-β (Aβ) in recent clinical trials suggests that future AD drug development should be focused on simultaneous targeting of several pathological hallmarks of the disease. Recently, we have shown that GMP-1, a 2-(methoxymethyl)pyrimido [1, 2-a ] benzimidazol-4-ol, protects mitochondrial function in drosophila and mice models of AD, and improved memory and behavior indicating neuroprotective effect of GMP-1 treatment. Here, we have found that GMP-1 specifically binds to copper and zinc, …metals that are dysregulated in AD brain. Addition of GMP-1 does not inhibit metal-dependent enzymatic reactions. Also, binding of Zn(II) and Cu(II) by GMP-1 is weaker than the 8-hydroxyquinoline scaffold compound clioquinol previously tested in AD clinical trials. However, GMP-1 affects Cu(II)-dependent Aβ fibrillization as well as oxidative damage and viability of SH-SY5Y cells upon addition of Cu(II) and Aβ. Our data provide new insight on GMP-1 as a Zn(II) and Cu(II) specific metal chelator of moderate affinity that can be responsible for some of its neuroprotective effects observed in AD animal models. Show more

Keywords: Alzheimer’s disease, metal chelation, multi-target-directed ligands, treatment strategies

DOI: 10.3233/JAD-190695

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Fransquet, Peter D. | Ritchie, Karen | Januar, Vania | Saffery, Richard | Ancelin, Marie-Laure | Ryan, Joanne

Article Type: Research Article

Abstract: Brain-derived neurotrophic factor (BDNF) has been implicated in dementia. Preliminary evidence suggests that BDNF DNA methylation may be a diagnostic biomarker of dementia, but the potential pre-clinical utility remains unclear. Participants in the ESPRIT study were assessed for cognitive function and dementia (DSM-IV criteria) over 14 years. BDNF exon 1 promoter methylation was measured in blood at baseline (n  = 769) and buccal samples during follow-up (n  = 1062). Genotyping was carried out for several common BDNF SNPs, including Val66Met (rs6265) and APOE ɛ 4. Multivariable logistic regression analyses determined the association between BDNF methylation and …both prevalent and incident dementia. Adjustment for gender, age, education, APOE ɛ 4 genotype, body mass index, depression, and type 2 diabetes, as well as possible effect modification by gender and genetic variation were also investigated. Weak evidence of an association between lower blood methylation and dementia was observed at one of 11 sites investigated (Δ–0.5%, 95% CI:–0.9,–0.04, p  = 0.03, p  = 0.22 adjusted for multiple comparisons). Buccal methylation at two other sites was associated with 14-year incident dementia cases prior to adjustment for multiple comparisons only, and the effect sizes were small (Δ+0.3%, OR:1.57, SE:0.30, p  = 0.02, p  = 0.14 adjusted and Δ–1.5%, OR:0.85, SE:0.06, p  = 0.03, p  = 0.14 adjusted). Genetic variation in the BDNF gene did not modify these associations, and no gender-specific effects were observed. There was only a weak correlation between blood and buccal BDNF log-methylation at two sites (both r =–0.11). There was no strong evidence that blood or buccal BDNF exon 1 promoter DNA methylation is associated with prevalent or incident dementia, and reported associations would not remain after adjustment for multiple testing. Show more

Keywords: BDNF, biomarkers, blood, dementia, DNA methylation, epigenetics

DOI: 10.3233/JAD-190738

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Zuelsdorff, Megan | Okonkwo, Ozioma C. | Norton, Derek | Barnes, Lisa L. | Graham, Karen L. | Clark, Lindsay R. | Wyman, Mary F. | Benton, Susan F. | Gee, Alexander | Lambrou, Nickolas | Johnson, Sterling C. | Gleason, Carey E.

Article Type: Research Article

Abstract: Background: It is well-documented that African Americans have elevated risk for cognitive impairment and dementia in late life, but reasons for the racial disparities remain unknown. Stress processes have been linked to premature age-related morbidity, including Alzheimer’s and related dementias (ADRD), and plausibly contribute to social disparities in cognitive aging. Objective: We examined the relationship between stressful life events and cognitive decline among African American and White participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP). Methods: Linear mixed models including demographic, literacy, and health-related covariates were used to estimate (1) relationships between a life …event index score and decline in cognitive test performance in two domains of executive function (Speed & Flexibility, Working Memory) and one domain of episodic memory (Verbal Learning & Memory) among 1,241 WRAP enrollees, stratified by race, and (2) contributions of stressful life events to racial differences in cognition within the full sample. Results: African Americans (N = 50) reported more stressful life events than Whites (N = 1,191). Higher stress scores associated with poorer Speed & Flexibility performance in both groups, though not with declines across time, and partially explained racial differentials in this domain. Among African Americans only, stressor exposure also associated with age-related decline in Verbal Learning & Memory. Stressor-cognition relationships were independent of literacy and health-related variables. Conclusions: Greater lifetime stress predicted poorer later-life cognition, and, in a small sample of African Americans, faster declines in a key domain of episodic memory. These preliminary findings suggest that future work in large minority aging cohorts should explore stress as an important source of modifiable, socially-rooted risk for impairment and ADRD in African Americans, who are disproportionately exposed to adverse experiences across the life course. Show more

Keywords: African Americans, Alzheimer’s disease, life course, stress

DOI: 10.3233/JAD-190439

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Fuller-Thomson, Esme | Deng, ZhiDi

Article Type: Research Article

Abstract: Limbic-predominant Age-related TDP-43 Encephalopathy (LATE) is a disease whose clinical presentation mimics that of Alzheimer’s disease. TDP-43 proteinopathy associated with LATE has been identified in more than 20% of autopsies of community-dwelling adults over the age of 80. It is believed to contribute significantly toward tau-negative dementia. Heavy metals such as lead has also been linked to TDP-43 proteinopathy. In particular, lead triggers TDP-43 accumulation and disrupts TDP-43 homeostasis. However, the specific relationship between LATE and lead remains unknown. Before leaded gasoline was phased out during the 1970s and 1980s, average blood lead levels were 15 times what they are …today. Thus, each successive birth cohort entering old age has had less cumulative life exposure to lead. Lifetime exposure can be tracked in the tibia bone, where the half-life of lead is many decades. We hypothesize that lead plays a role in the development of LATE. There are two ways to explore the validity of this hypothesis. Generational differences in lead exposure should result in a steady decline in the prevalence of LATE among older adults. We propose the use of tibia bone lead levels be examined in brain autopsies from different birth cohorts to examine the link between lead exposure and LATE prevalence, holding age constant. Furthermore, individuals with genetic polymorphisms that confer a greater lead absorption phenotype should display a higher degree of TDP-43 accumulation in autopsies. The results of such studies could provide insight into gene by environment interactions relevant to the development of LATE. Show more

Keywords: Alzheimer’s disease, FTLD with TDP-43 pathology, lead poisoning, nervous system, TDP-43 proteinopathies, tetraethyl lead

DOI: 10.3233/JAD-190943

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2019

Authors: Wang, Longcai | Qiao, Yanchun | Zhang, Haihua | Zhang, Yan | Hua, Jiao | Jin, Shuilin | Liu, Guiyou

Article Type: Research Article

Abstract: Observational studies strongly supported the association of low levels of circulating 25-hydroxyvitamin D (25OHD) and cognitive impairment or dementia in aging populations. However, randomized controlled trials have not shown clear evidence that vitamin D supplementation could improve cognitive outcomes. In fact, some studies reported the association between vitamin D and cognitive impairment based on individuals aged 60 years and over. However, it is still unclear that whether vitamin D levels are causally associated with Alzheimer’s disease (AD) risk in individuals aged 60 years and over. Here, we performed a Mendelian randomization (MR) study to investigate the causal association between vitamin …D levels and AD using a large-scale vitamin D genome-wide association study (GWAS) dataset and two large-scale AD GWAS datasets from the IGAP and UK Biobank with individuals aged 60 years and over. Our results showed that genetically increased 25OHD levels were significantly associated with reduced AD risk individuals aged 60 years and over. Hence, our findings in combination with previous literature indicate that maintaining adequate vitamin D status in older people especially aged 60 years and over, may contribute to slow down cognitive decline and to forestall AD. Long-term randomized controlled trials are required to test whether vitamin D supplementation may prevent AD in older people especially those aged 60 years and may be recommended as preventive agents. Show more

Keywords: Alzheimer’s disease, genome-wide association study, Mendelian randomization, vitamin D

DOI: 10.3233/JAD-190713

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019