Journal of Alzheimer's Disease - Volume 67, issue 3

Authors: Cummings, Jeffrey L. | Tong, Gary | Ballard, Clive

Article Type: Review Article

Abstract: Although Alzheimer’s disease (AD) is the world’s leading cause of dementia and the population of patients with AD continues to grow, no new therapies have been approved in more than a decade. Many clinical trials of single-agent therapies have failed to affect disease progression or symptoms compared with placebo. The complex pathophysiology of AD may necessitate combination treatments rather than monotherapy. The goal of this narrative literature review is to describe types of combination therapy, review the current clinical evidence for combination therapy regimens (both symptomatic and disease-modifying) in the treatment of AD, describe innovative clinical trial study designs that …may be effective in testing combination therapy, and discuss the regulatory and drug development landscape for combination therapy. Successful combination therapies in other complex disorders, such as human immunodeficiency virus, may provide useful examples of a potential path forward for AD treatment. Show more

Keywords: Alzheimer’s disease, cholinesterase inhibitor, dementia, disease-modifying, memantine, symptomatic, treatment combination

DOI: 10.3233/JAD-180766

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 779-794, 2019

Authors: Serrano-Pozo, Alberto | Growdon, John H.

Article Type: Review Article

Abstract: Population-based clinic-pathological studies have established that the most common pathological substrate of dementia in community-dwelling elderly people is mixed, especially Alzheimer’s disease (AD) and cerebrovascular ischemic disease (CVID), rather than pure AD. While these could be just two frequent unrelated comorbidities in the elderly, epidemiological research has reinforced the idea that mid-life (age <65 years) vascular risk factors increase the risk of late-onset (age ≥ 65 years) dementia, and specifically AD. By contrast, healthy lifestyle choices such as leisure activities, physical exercise, and Mediterranean diet are considered protective against AD. Remarkably, several large population-based longitudinal epidemiological studies have recently indicated …that the incidence and prevalence of dementia might be decreasing in Western countries. Although it remains unclear whether these positive trends are attributable to neuropathologically definite AD versus CVID, based on these epidemiological data it has been estimated that a sizable proportion of AD cases could be preventable. In this review, we discuss the current evidence about modifiable risk factors for AD derived from epidemiological, preclinical, and interventional studies, and analyze the opportunities for therapeutic and preventative interventions. Show more

Keywords: Alcohol drinking, Alzheimer’s disease, dementia, diet, diabetes mellitus, education, exercise, hypertension, hyperlipidemia, smoking

DOI: 10.3233/JAD181028

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 795-819, 2019

Authors: Koop-Nieuwelink, Carolien | Sedaghat, Sanaz | Mutlu, Unal | Licher, Silvan | Franco, Oscar H. | Ikram, M. Arfan | Geerlings, Mirjam I. | Ikram, M. Kamran | Bos, Daniel

Article Type: Short Communication

Abstract: Longitudinal population-based data on effects of kidney dysfunction in the development of stroke and dementia remains inconclusive. We investigated associations of kidney function with risk of stroke and dementia in 5,993 community-dwelling individuals (mean age: 69.0 years, 57.2% women). We calculated estimated glomerular filtration rates based on creatinine, cystatin-C, and a combination of these two. During a mean follow-up of 11.6 years (69,790 person-years), 1,360 individuals suffered a stroke (n  = 601) or developed dementia (n  = 759). We found that an impaired kidney function was related to a higher risk of stroke, but not to dementia.

Keywords: Dementia, epidemiology, glomerular filtration rate, kidney function, stroke

DOI: 10.3233/JAD-181086

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 821-826, 2019

Authors: Lutski, Miri | Weinstein, Galit | Goldbourt, Uri | Tanne, David

Article Type: Research Article

Abstract: Background: Lipid levels are associated with an increased risk of cardiovascular disease. Objective: We investigated the association between plasma lipids, apolipoproteins levels, apolipoprotein B/low-density lipoprotein cholesterol (Apo-B/LDL-C), and Apo-B/Apo-A ratios and rate of cognitive decline two decades later in men with coronary heart disease (CHD). Methods: A subset of 337 men (mean age at baseline 56.6±6.4 years) who previously participated in the Bezafibrate Infarction Prevention (BIP) trial (1990–1997) underwent cognitive evaluations 15±3 years (T1) and 19.9±1 years after baseline (T2) as part of the BIP Neurocognitive study. Lipid and apolipoprotein fractions were measured …at baseline. Cognitive function for memory, executive function, visual spatial, attention domains, and composite score were assessed using the NeuroTrax Computerized Battery at T1 and T2 evaluations. Linear mixed models were used to assess change in cognitive function between the two cognitive evaluations. Results: Controlling for confounders, the decline in composite cognitive score (β = –0.161±0.06; p  = 0.013) as well as in memory (β = –0.269±0.10; p  = 0.009) and visual spatial function (β = –0.304±0.12; p  = 0.010) was greater among patients in the upper (≥105 mg/dL) Apo-B tertile as compared to counterparts with < 105 mg/dL. The decline in the composite cognitive score (β = –0.124±0.06; p  = 0.043) was also greater among patients in the estimated LDL-C≥160 mg/dL group compared to counterparts with LDL-C<160 mg/dL. Upper tertile of Apo-B/LDL-C ratio (≥0.75) compared to the lower tertiles was significantly associated with change in memory score (β = –0.210±0.10; p  = 0.041). Conclusion: Our findings suggest that the plasma concentrations of Apo-B, LDL-C, and Apo-B/LDL-C ratio are potential predictors of accelerated late-life cognitive decline among men with CHD. Show more

Keywords: Apolipoproteins, cognitive decline, coronary heart disease, lipid ratios, plasma lipids

DOI: 10.3233/JAD-180849

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 827-837, 2019

Authors: Ben Jemaa, Sonia | Marzouki, Yousri | Fredj, Mohamed | Le Gall, Didier | Bellaj, Tarek

Article Type: Research Article

Abstract: Background: Depression is a major disorder that can be ttriggering, exacerbating, or co-occurring with dementia symptoms. Its assessment is paramount to achieve diagnostic, prognostic, and therapeutic decisions. The Cornell Scale for Depression in Dementia (CSDD) is purposely designed to address clinically this issue. Objective: To examine the reliability and validity of an Arabic version of the CSDD (A-CSDD) in the Tunisian population. Methods: Fifty-seven participants took part in this study: 20 as a control group (NC), 18 as dementia patients with depression (DD), and 19 as depressed patients without dementia (DND); all patients met the DSM …IV criteria for depression and/or dementia. A translated, back-translated and adapted Arabic version of the CSDD was administered in parallel with the Geriatric Depression Scale (GDS), the non-cognitive part of the Alzheimer’s disease Assessment Scale, and the Mini-Mental State Examination. Results: The A-CSDD had good internal consistency (Cronbach’s alpha = 0.85) and high test-retest reliability (Rho  = 0.897, p  < 0.001). The A-CSDD had excellent discriminatory power to diagnose depression in dementia patients (AUC = 0.90, p  < 0.001) and good concurrent validity with the GDS (Rho  = 0.70, p  < 0.001). A principal component analysis with varimax rotation, performed on the DD group, led to a configuration of five factors explaining 75% of the variance. Conclusions: The results showed that this Arabic-Tunisian version of the A-CSDD is reliable and valid for diagnosing depression in an elderly Tunisian population with dementia and can be used in clinical and research settings. Show more

Keywords: Arabic version, Cornell Scale for Depression in Dementia, culture, dementia, depression, normative data, reliability, test adaptation, validity

DOI: 10.3233/JAD-180448

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 839-848, 2019

Authors: Hornung, Karen | Zampar, Silvia | Engel, Nadine | Klafki, Hans | Liepold, Thomas | Bayer, Thomas A. | Wiltfang, Jens | Jahn, Olaf | Wirths, Oliver

Article Type: Research Article

Abstract: In sporadic Alzheimer’s disease (AD), an imbalance between production and clearance of amyloid-β (Aβ) peptides seems to account for enhanced Aβ accumulation. The metalloprotease neprilysin (NEP) is an important Aβ degrading enzyme as shown by a variety of in vitro and in vivo studies. While the degradation of full-length Aβ peptides such as Aβ1-40 and Aβ1-42 is well established, it is less clear whether NEP is also capable of degrading N-terminally truncated Aβ species such as the common variant Aβ4-42 . In the present report, we confirmed the degradation of Aβ4-x species by neprilysin using in vitro …digestion and subsequent analysis using gel-based assays and mass spectrometry. By crossing Tg4-42 mice expressing only Aβ4-42 peptides with homozygous NEP-knock-out mice (NEP-/- ), we were able to demonstrate that NEP deficiency increased hippocampal intraneuronal Aβ levels and aggravated neuron loss in the Tg4-42 transgenic mouse model of AD. Show more

Keywords: Alzheimer’s disease, AβPP, intraneuronal amyloid-β, mass spectrometry, neprilysin, neuron loss, transgenic mice, stereology

DOI: 10.3233/JAD-181134

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 849-858, 2019

Authors: Cross, Donna J. | Meabon, James S. | Cline, Marcella M. | Richards, Todd L. | Stump, Amanda J. | Cross, Chloe G. | Minoshima, Satoshi | Banks, William A. | Cook, David G.

Article Type: Research Article

Abstract: Repetitive mild traumatic brain injury (rmTBI) is known to disturb axonal integrity and may play an important role in the pathogenic cascades leading to neurodegeneration. One critical approach to reduce the future onset of neurodegeneration is to intervene in this process at an early stage following a brain injury. Previously we showed that direct application of the microtubule-stabilizing drug, paclitaxel, on the brain following controlled cortical impact improved motor function and reduced lesion size. Herein, we extended these findings to a model of mild brain injury induced by repeated closed-skull impacts. Paclitaxel was administered intranasally to circumvent its …poor transport across the blood-brain barrier. Mice received five mild closed-skull impacts (one per day for five days). Intranasal paclitaxel was administered once only, immediately after the first impact. We found that paclitaxel prevented injury-induced deficits in a spatial memory task in a water tread maze. In vivo magnetic resonance imaging (MRI) and positron emission tomography with 18F-flurodeoxyglucose (FDG-PET) revealed that paclitaxel prevented structural injury and hypometabolism. On MRI, apparent, injury-induced microbleeds were observed in 100% of vehicle-treated rmTBI mice, but not in paclitaxel -treated subjects. FDG-PET revealed a 42% increase in whole brain glucose metabolism in paclitaxel-treated mice as compared to vehicle-treated rmTBI. Immunohistochemistry found reduced evidence of axonal injury and synaptic loss. Our results indicate that intranasal paclitaxel administration imparts neuroprotection against brain injury and cognitive impairment in mice. The results from this study support the idea that microtubule-stabilization strategies hold therapeutic promise in mitigating traumatic brain injury. Show more

Keywords: Axonal injury, imaging, microtubule-stabilizing drug, repeat mild traumatic brain injury, synaptic preservation

DOI: 10.3233/JAD-180871

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 859-874, 2019

Authors: Wiedrick, Jack T. | Phillips, Jay I. | Lusardi, Theresa A. | McFarland, Trevor J. | Lind, Babett | Sandau, Ursula S. | Harrington, Christina A. | Lapidus, Jodi A. | Galasko, Douglas R. | Quinn, Joseph F. | Saugstad, Julie A.

Article Type: Research Article

Abstract: We previously discovered microRNAs (miRNAs) in cerebrospinal fluid (CSF) that differentiate Alzheimer’s disease (AD) patients from Controls. Here we examined the performance of 37 candidate AD miRNA biomarkers in a new and independent cohort of CSF from 47 AD patients and 71 Controls on custom TaqMan arrays. We employed a consensus ranking approach to provide an overall priority score for each miRNA, then used multimarker models to assess the relative contributions of the top-ranking miRNAs to differentiate AD from Controls. We assessed classification performance of the top-ranking miRNAs when combined with apolipoprotein E4 (APOE4) genotype status or CSF amyloid-β42 …(Aβ42 ):total tau (T-tau) measures. We also assessed whether miRNAs that ranked higher as AD markers correlate with Mini-Mental State Examination (MMSE) scores. We show that of 37 miRNAs brought forth from the discovery study, 26 miRNAs remained viable as candidate biomarkers for AD in the validation study. We found that combinations of 6–7 miRNAs work better to identify AD than subsets of fewer miRNAs. Of 26 miRNAs that contribute most to the multimarker models, 14 have higher potential than the others to predict AD. Addition of these 14 miRNAs to APOE4 status or CSF Aβ42 :T-tau measures significantly improved classification performance for AD. We further show that individual miRNAs that ranked higher as AD markers correlate more strongly with changes in MMSE scores. Our studies validate that a set of CSF miRNAs serve as biomarkers for AD, and support their advancement toward development as biomarkers in the clinical setting. Show more

Keywords: Alzheimer’s disease, amyloid-β42 , apolipoprotein E, biomarkers, cerebrospinal fluid, microRNA, Mini-Mental State Examination, total tau

DOI: 10.3233/JAD-180539

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 875-891, 2019

Authors: Foveau, Bénédicte | Correia, Ana Sofia | Hébert, Sébastien S. | Rainone, Sara | Potvin, Olivier | Kergoat, Marie-Jeanne | Belleville, Sylvie | Duchesne, Simon | LeBlanc, Andréa C. | and the CIMA-Q Consortium for the early identification of Alzheimer’s disease-Québec

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) occurs as either an autosomal dominant inherited disease or sporadically. While familial mutant genes can be expressed in cells or in animal models to assess dysregulated functions, sporadic AD cannot be replicated in models given our lack of understanding of causality. Furthermore, the study of sporadic forms of AD is difficult given the inaccessibility of brain tissues in living individuals and the manifestation of symptoms years after the onset of disease. Here, the objective was to assess if induced pluripotent stem cell-derived neurons from well-ascertained sporadic AD individuals could represent potential cellular models to determine the underlying …molecular mechanisms of disease. We used cryopreserved peripheral blood mononuclear cells from three well-ascertained sporadic AD and three non-cognitively impaired (NCI) individuals of the CIMA-Q cohort to obtain iPSC-derived neurons. Microtubule associated protein 2 was decreased in AD neurons, whereas expression of AD-associated amyloid precursor protein, tau, and amyloid-β peptide was similar in AD and NCI individuals. RNA sequencing identified several upregulated and downregulated mRNAs in AD relative to NCI neurons. Of these, complement Factor H (CFH), signal regulatory protein beta1 (SIRPB1), and insulin like growth factor binding protein 5 (IGFBP5) were previously associated with AD. In addition, several transcription factors not previously associated with AD, but involved in neuronal proliferation and differentiation were differentially expressed. The results identify novel avenues for the study of the underlying causes of sporadic AD and support the establishment of additional lines to identify mechanisms of disease in sporadic AD individuals. Show more

Keywords: Alzheimer’s disease, cholinergic neurons, cryopreserved cell, gene expression, induced pluripotent stem cells

DOI: 10.3233/JAD-180833

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 893-910, 2019

Authors: La, Alice L. | Walsh, Christine M. | Neylan, Thomas C. | Vossel, Keith A. | Yaffe, Kristine | Krystal, Andrew D. | Miller, Bruce L. | Karageorgiou, Elissaios

Article Type: Research Article

Abstract: Background: Recent studies reveal an association between slow-wave sleep (SWS), amyloid-β aggregation, and cognition. Objective: This retrospective study examines whether long-term use of trazodone, an SWS enhancer, is associated with delayed cognitive decline. Methods: We identified 25 regular trazodone users (mean age 75.4±7.5; 9 women, 16 men) who carried a diagnosis of Alzheimer’s dementia, mild cognitive impairment, or normal cognition, and 25 propensity-matched trazodone non-users (mean age 74.5±8.0; 13 women, 12 men), accounting for age, sex, education, type of sleep deficit (hypersomnia, insomnia, parasomnia), diagnosis, and baseline Mini-Mental State Examination (MMSE). Longitudinal …group differences in cognitive testing were evaluated through repeated measures tests over an average inter-evaluation interval of four years. Results: Trazodone non-users had 2.6-fold faster decline MMSE (primary outcome) compared to trazodone users, 0.27 (95% confidence interval [CI]: 0.07–0.48) versus 0.70 (95% CI: 0.50–0.90) points per year (p  = 0.023). The observed effects were especially associated with subjective improvement of sleep complaints in post-hoc analyses (p  = 0.0006). Secondary outcomes of other cognitive and functional scores had variable worsening in non-users and varied in significance when accounting for co-administered medications and multiple comparisons. Trazodone effects on MMSE remained significant within participants with AD-predicted pathology, with 2.4-fold faster decline in non-users (p  = 0.038). Conclusions: These results suggest an association between trazodone use and delayed cognitive decline, adding support for a potentially attractive and cost-effective intervention in dementia. Whether the observed relationship of trazodone to cognitive function is causal or an indirect marker of other effects, such as treated sleep disruption, and if such effects are mediated through SWS enhancement requires confirmation through prospective studies. Show more

Keywords: Alzheimer’s disease, dementia, hypnotics, mild cognitive impairment, sleep, treatment

DOI: 10.3233/JAD-181145

Citation: Journal of Alzheimer's Disease, vol. 67, no. 3, pp. 911-921, 2019