Journal of Alzheimer's Disease - Volume 78, issue 1

Authors: Schneider, Julie A. | Aggarwal, Neelum T.

Article Type: Obituary

DOI: 10.3233/JAD-201123

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 1-2, 2020

Authors: Anstey, Kaarin J. | Peters, Ruth | Zheng, Lidan | Barnes, Deborah E. | Brayne, Carol | Brodaty, Henry | Chalmers, John | Clare, Linda | Dixon, Roger A. | Dodge, Hiroko | Lautenschlager, Nicola T. | Middleton, Laura E. | Qiu, Chengxuan | Rees, Glenn | Shahar, Suzana | Yaffe, Kristine

Article Type: Article Commentary

Abstract: In the past decade a large body of evidence has accumulated on risk factors for dementia, primarily from Europe and North America. Drawing on recent integrative reviews and a consensus workshop, the International Research Network on Dementia Prevention developed a consensus statement on priorities for future research. Significant gaps in geographical location, representativeness, diversity, duration, mechanisms, and research on combinations of risk factors were identified. Future research to inform dementia risk reduction should fill gaps in the evidence base, take a life-course, multi-domain approach, and inform population health approaches that improve the brain-health of whole communities.

Keywords: Multi-domain, primary prevention, risk factor, risk reduction

DOI: 10.3233/JAD-200674

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 3-12, 2020

Authors: Pietroboni, Anna M. | Colombi, Annalisa | Carandini, Tiziana | Scarpini, Elio | Galimberti, Daniela | Bozzali, Marco

Article Type: Review Article

Abstract: Just as multiple sclerosis (MS) has long been primarily considered a white matter (WM) disease, Alzheimer’s disease (AD) has for decades been regarded only as a grey matter disorder. However, convergent evidences have suggested that WM abnormalities are also important components of AD, at the same extent as axonal and neuronal loss is critically involved in MS pathophysiology since early clinical stages. These observations have motivated a more thorough investigation about the possible mechanisms that could link neuroinflammation and neurodegeneration, focusing on amyloid-β (Aβ). Neuroimaging studies have found that patients with AD have widespread WM abnormalities already at the earliest …disease stages and prior to the presence of Aβ plaques. Moreover, a correlation between cerebrospinal fluid (CSF) Aβ levels and WM lesion load was found. On the other hand, recent studies suggest a predictive role for CSF Aβ levels in MS, possibly due in the first instance to the reduced capacity for remyelination, consequently to a higher risk of WM damage progression, and ultimately to neuronal loss. We undertook a review of the recent findings concerning the involvement of CSF Aβ levels in the MS disease course and of the latest evidence of AD related WM abnormalities, with the aim to discuss the potential causes that may connect WM damage and amyloid pathology. Show more

Keywords: Amyloid-β , inflammation, neurodegeneration, white matter damage

DOI: 10.3233/JAD-200868

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 13-22, 2020

Authors: Blanken, Anna E. | Nation, Daniel A.

Article Type: Research Article

Abstract: Background: Gender differences have been noted in studies linking blood pressure to all-cause dementia, and the two most common forms of dementia: Alzheimer’s disease (AD) and vascular dementia (VaD). However, how gender modifies the relationship between blood pressure and dementia remains unclear. Objective: To review evidence for a gender modifying effect on the link between blood pressure and all-cause dementia. Methods: A systematic review was conducted according to PRISMA guidelines. Sixteen out of 256 reviewed articles met inclusion criteria. Results: For women, higher midlife systolic blood pressure (SBP) and hypertension were both associated with …greater risk of all-cause dementia, AD, and VaD, in six out of seven studies. Two of these studies reported higher midlife SBP/hypertension were associated with greater risk for all-cause dementia in women, but not men. One study reported higher midlife SBP associated with greater AD risk in women, but not men. However, another study reported that midlife hypertension associated with AD risk in men, but not women. No clear gender differences were reported in the relationship between late-life high blood pressure/hypertension with all-cause dementia or AD. Conclusion: Studies rarely, and inconsistently, analyzed or reported gender effects. Therefore, interpretation of available evidence regarding the role of gender in blood pressure associated dementia was difficult. Several studies indicated higher midlife SBP was associated with greater risk of all-cause dementia for women, compared to men. Future studies should evaluate women-specific aging processes that occur in midlife when considering the association between blood pressure and dementia risk. Show more

Keywords: Aging, Alzheimer type, blood pressure, dementia, female, gender, hypertension, neurobiology, sex, systematic review, vascular

DOI: 10.3233/JAD-200245

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 23-48, 2020

Authors: Harris, Christopher J. | Gray, Nora E. | Caruso, Maya | Hunter, Marguex | Ralle, Martina | Quinn, Joseph F.

Article Type: Research Article

Abstract: Background: Environmental copper has been implicated in the pathogenesis of Alzheimer’s disease based on evidence that: 1) brain copper levels increase with age, 2) copper promotes misfolding and toxicity of amyloid-β in vitro , 3) copper-modulating interventions reduce amyloid pathology in animal models. However, the effect of copper upon non-amyloid Alzheimer’s pathology is relatively under-explored. Objective: To determine if modulation of brain copper level affects brain tau pathology and/or associated cognitive impairment. Methods: We tested the hypothesis that brain copper modulates tau pathology by manipulating brain levels of copper in the PS19 transgenic mouse model of …tau pathology. We treated PS19 and wild-type mice with oral zinc acetate, an established therapy for long term control of excess brain copper, and examined treatment effects upon brain copper, brain tau, NFT-like pathology, and spatial memory. We treated a second cohort of mice with exogenous dietary copper in order to evaluate whether excess environmental copper promotes brain tau pathology. Results: Copper-lowering with oral zinc attenuated spatial memory impairment in female but not male PS19 mice, without a significant effect upon tau pathology. Copper loading increased brain copper, but did not have an effect on brain tau pathology or spatial memory function. Conclusion: These findings suggest that a strategy to lower brain copper may be viable for symptomatic benefit in the setting of tau neuropathology, but unlikely to have robust effects on the underlying pathology. These findings are consistent with dietary or other exogenous copper being unlikely to promote tau pathology. Show more

Keywords: Copper, neurofibrillary tangles, tau, zinc

DOI: 10.3233/JAD-200002

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 49-60, 2020

Authors: Gu, Yebo | Wu, Zhou | Zeng, Fan | Jiang, Muzhou | Teeling, Jessica L. | Ni, Junjun | Takahashi, Ichiro

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and bone loss are clinically exacerbated. However, the mechanism of exacerbation remains understood. Objective: We tested our hypothesis that periodontitis is involved in the exacerbation, contributing to AD pathologies. Methods: The bone, memory, and inflammation in bone and brain were examined in 12-month-old mice after systemic exposure to lipopolysaccharide from Porphyromonas gingivalis (P g LPS) for 3 consecutive weeks. Results: Compared with control mice, bone loss in tibia (26% decrease) and memory decline (47% decrease) were induced in mice with a positive correlation after exposure to P g LPS …(r  = 0.7378, p  = 0.0011). The IL-6 and IL-17 expression in tibia was negatively correlated with the bone volume/total tissue volume (r  = –0.6619, p  = 0.0052; r  = –0.7129, p  = 0.0019), while that in the cortex was negatively correlated with the memory test latency (r  = –0.7198, p  = 0.0017; p  = 0.0351, r  = –0.5291). Furthermore, the IL-17 expression in microglia was positively correlated with Aβ42 accumulation in neurons (r  = 0.8635, p  < 0.0001). In cultured MG6 microglia, the P g LPS-increased IL-6 expression was inhibited by a PI3K-specific inhibitor (68% decrease), and that of IL-17 was inhibited by IL-6 antibody (41% decrease). In cultured N2a neurons, conditioned medium from P g LPS-stimulated microglia (MCM) but not P g LPS increased the productions of AβPP, CatB, and Aβ42 , which were significantly inhibited by pre-treatment with IL-17 antibody (67%, 51%, and 41% decrease). Conclusion: These findings demonstrated that chronic systemic exposure to P g LPS simultaneously induces inflammation-dependent bone loss and AD-like pathologies by elevating IL-6 and IL-17 from middle age, suggesting that periodontal bacteria induce exacerbation of bone loss and memory decline, resulting in AD progression. Show more

Keywords: Alzheimer’s disease, amyloid-β, bone loss, interleukin-6, interleukin-17, lipopolysaccharide from Porphyromonas gingivalis, memory decline, microglia, systemic inflammation

DOI: 10.3233/JAD-200689

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 61-74, 2020

Authors: Stephen, Ruth | Solomon, Alina | Ngandu, Tiia | Levälahti, Esko | Rinne, Juha O. | Kemppainen, Nina | Parkkola, Riitta | Antikainen, Riitta | Strandberg, Timo | Kivipelto, Miia | Soininen, Hilkka | Liu, Yawu | for the FINGER study group

Article Type: Research Article

Abstract: Background: Early pathological changes in white matter microstructure can be studied using the diffusion tensor imaging (DTI). It is not only important to study these subtle pathological changes leading to cognitive decline, but also to ascertain how an intervention would impact the white matter microstructure and cognition in persons at-risk of dementia. Objectives: To study the impact of a multidomain lifestyle intervention on white matter and cognitive changes during the 2-year Finnish Geriatric Intervention Study to prevent Cognitive Impairment and Disability (FINGER), a randomized controlled trial in at-risk older individuals (age 60–77 years) from the general population. …Methods: This exploratory study consisted of a subsample of 60 FINGER participants. Participants were randomized to either a multidomain intervention (diet, exercise, cognitive training, and vascular risk management, n  = 34) or control group (general health advice, n  = 26). All underwent baseline and 2-year brain DTI. Changes in fractional anisotropy (FA), diffusivity along domain (F1) and non-domain (F2) diffusion orientations, mean diffusivity (MD), axial diffusivity (AxD), radial diffusivity (RD), and their correlations with cognitive changes during the 2-year multidomain intervention were analyzed. Results: FA decreased, and cognition improved more in the intervention group compared to the control group (p  < 0.05), with no significant intergroup differences for changes in F1, F2, MD, AxD, or RD. The cognitive changes were significantly positively related to FA change, and negatively related to RD change in the control group, but not in the intervention group. Conclusion: The 2-year multidomain FINGER intervention may modulate white matter microstructural alterations. Show more

Keywords: Alzheimer’s disease, dementia, diffusion tensor imaging, randomized controlled trial

DOI: 10.3233/JAD-200423

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 75-86, 2020

Authors: Karki, Reagon | Madan, Sumit | Gadiya, Yojana | Domingo-Fernández, Daniel | Kodamullil, Alpha Tom | Hofmann-Apitius, Martin

Article Type: Research Article

Abstract: Background: Recent studies have suggested comorbid association between Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) through identification of shared molecular mechanisms. However, the inference is pre-dominantly literature-based and lacks interpretation of pre-disposed genomic variants and transcriptomic measurables. Objective: In this study, we aim to identify shared genetic variants and dysregulated genes in AD and T2DM and explore their functional roles in the comorbidity between the diseases. Methods: The genetic variants for AD and T2DM were retrieved from GWAS catalog, GWAS central, dbSNP, and DisGeNet and subjected to linkage disequilibrium analysis. Next, shared variants were …prioritized using RegulomeDB and Polyphen-2. Afterwards, a knowledge assembly embedding prioritized variants and their corresponding genes was created by mining relevant literature using Biological Expression Language. Finally, coherently perturbed genes from gene expression meta-analysis were mapped to the knowledge assembly to pinpoint biological entities and processes and depict a mechanistic link between AD and T2DM. Results: Our analysis identified four genes (i.e., ABCG1 , COMT , MMP9 , and SOD2 ) that could have dual roles in both AD and T2DM. Using cartoon representation, we have illustrated a set of causal events surrounding these genes which are associated to biological processes such as oxidative stress, insulin resistance, apoptosis and cognition. Conclusion: Our approach of using data as the driving force for unraveling disease etiologies eliminates literature bias and enables identification of novel entities that serve as the bridge between comorbid conditions. Show more

Keywords: Alzheimer’s disease, comorbidity, systems biology, type 2 diabetes mellitus

DOI: 10.3233/JAD-200752

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 87-95, 2020

Authors: de Oliveira, Jade | Engel, Daiane F. | de Paula, Gabriela C. | dos Santos, Danúbia B. | Lopes, Jadna B. | Farina, Marcelo | Moreira, Eduardo L.G. | de Bem, Andreza F.

Article Type: Research Article

Abstract: Background: Evidence has revealed an association between familial hypercholesterolemia and cognitive impairment. In this regard, a connection between cognitive deficits and hippocampal blood-brain barrier (BBB) breakdown was found in low-density lipoprotein receptor knockout mice (LDLr–/–), a mouse model of familial hypercholesterolemia. Objective: Herein we investigated the impact of a hypercholesterolemic diet on cognition and BBB function in C57BL/6 wild-type and LDLr–/–mice. Methods: Animals were fed with normal or high cholesterol diets for 30 days. Thus, wild-type and LDLr–/–mice were submitted to memory paradigms. Additionally, BBB integrity was evaluated in the mice’s prefrontal cortices and hippocampi. …Results: A tenfold elevation in plasma cholesterol levels of LDLr–/–mice was observed after a hypercholesterolemic diet, while in wild-type mice, the hypercholesterolemic diet exposure increased plasma cholesterol levels only moderately and did not induce cognitive impairment. LDLr–/–mice presented memory impairment regardless of the diet. We observed BBB disruption as an increased permeability to sodium fluorescein in the prefrontal cortices and hippocampi and a decrease on hippocampal claudin-5 and occludin mRNA levels in both wild-type and LDLr–/–mice treated with a hypercholesterolemic diet. The LDLr–/–mice fed with a regular diet already presented BBB dysfunction. The BBB-increased leakage in the hippocampi of LDLr–/–mice was related to high microvessel content and intense astrogliosis, which did not occur in the control mice. Conclusion: Therefore, LDLr–/–mice seem to be more susceptible to cognitive impairments and BBB damage induced by exposure to a high cholesterol diet. Finally, BBB disruption appears to be a relevant event in hypercholesterolemia-induced brain alterations. Show more

Keywords: Blood-brain barrier, familial hypercholesterolemia, LDLr–/– mice, memory impairment, mild cognitive impairment, neuroinflammation

DOI: 10.3233/JAD-200541

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 97-115, 2020

Authors: Turró-Garriga, Oriol | Viñas-Díez, Vanesa | Conde-Sala, Josep Lluís | Calvó-Perxas, Laia | Cullell-Juncà, Marta | Mas-Vall-llosera, Glòria | Flaqué, Margarida | Turon-Estrada, Antoni | Juvinyà-Canal, Dolors | Mioshi, Eneida | Garre-Olmo, Josep

Article Type: Research Article

Abstract: Background: Dementia care is associated with physical, emotional, and monetary impact on the informal carers providing unpaid care. Differences in the personal characteristics of caregivers may help explain the variations in the costs of dementia care. Objective: The aim of this study was to analyze the effect of caregivers’ sense of coherence (SOC) on direct and indirect costs in dementia care. Methods: A cross-sectional study was conducted in community dwelling caregivers of patients with Alzheimer’s disease. Data of healthcare services were obtained from clinical registries, and information was collected from caregivers regarding their use of social …care resources and time spent caregiving. The transformation of all costs into Euros was made assigning a fixed cost of 10.29 € /h and 16.24 € /h for assisting in instrumental and basic activities of daily living, respectively. Caregivers’ SOC was assessed using the Orientation to Life Questionnaire (OLQ-13). Adjusted regression models were developed, with different types of costs as dependent variables. Results: A sample of 147 caregivers was recruited. The mean OLQ-13 score was 73.3 points (SD = 11.6). The regression models showed a small association between caregivers’ SOC and direct costs, mainly linked to the use of social care resources (r2  = 0.429; β= –15.6 € /month), and a greater association between SOC and indirect costs (r2  = 0.562; β= –222.3 € /month). Conclusion: Increasing caregivers’ SOC could reduce dementia care costs by decreasing the use of social care resources and caregiving time. Show more

Keywords: Alzheimer’s disease, caregiver, cost of illness, dementia, direct service cost, healthcare cost, sense of coherence

DOI: 10.3233/JAD-200350

Citation: Journal of Alzheimer's Disease, vol. 78, no. 1, pp. 117-126, 2020