Journal of Alzheimer's Disease - Volume 68, issue 1

Authors: Hampel, Harald | Vergallo, Andrea | Perry, George | Lista, Simone | Alzheimer Precision Medicine Initiative (APMI)

Collaborators: AGUILAR, Lisi Flores | BABILONI, Claudio | BALDACCI, Filippo | BENDA, Norbert | BLACK, Keith L. | BOKDE, Arun L.W. | BONUCCELLI, Ubaldo | BROICH, Karl | CACCIOLA, Francesco | CASTRILLO†, Juan | CAVEDO, Enrica | CERAVOLO, Roberto | CHIESA, Patrizia A. | CORVOL, Jean-Christophe | CUELLO, Augusto Claudio | CUMMINGS, Jeffrey L. | DEPYPERE, Herman | DUBOIS, Bruno | DUGGENTO, Andrea | ESCOTT-PRICE, Valentina | FEDEROFF, Howard | FERRETTI, Maria Teresa | FIANDACA, Massimo | FRANK, Richard A. | GARACI, Francesco | GEERTS, Hugo | GIORGI, Filippo S. | GRAZIANI, Manuela | HABERKAMP, Marion | HABERT, Marie-Odile | HAMPEL, Harald | HERHOLZ, Karl | KARRAN, Eric | KIM, Seung H. | KORONYO, Yosef | KORONYO-HAMAOUI, Maya | LANGEVIN, Todd | LEHÉRICY, Stéphane | LISTA, Simone | LORENCEAU, Jean | MANGO, Dalila | MAPSTONE, Mark | NERI, Christian | NISTICÓ, Robert | O’BRYANT, Sid E. | PERRY, George | RITCHIE, Craig | ROSSI, Simone | SAIDI, Amira | SANTARNECCHI, Emiliano | SCHNEIDER, Lon S. | SPORNS, Olaf | TOSCHI, Nicola | VERDOONER, Steven R. | VERGALLO, Andrea | VILLAIN, Nicolas | WELIKOVITCH, Lindsay A. | WOODCOCK, Janet | YOUNESI, Erfan

Article Type: Review Article

Abstract: Precision medicine (PM) is an evolving scientific renaissance movement implementing key breakthrough technological and scientific advances to overcome the limitations of traditional symptom- and sign-based phenotypic diagnoses and clinical “one-size-fits-all, magic bullet drug development” in these largely heterogeneous target populations. It is a conceptual shift from ineffective treatments for biologically heterogeneous “population averages” to individually-tailored biomarker-guided targeted therapies. PM is defining which therapeutic approach will be the most effective for a specific individual, at a determined disease stage, across multiple medical research fields, including neuroscience, neurology and psychiatry. The launch of the Alzheimer Precision Medicine Initiative (APMI) and its associated …cohort program in 2016—facilitated by the academic core coordinating center run by the Sorbonne University Clinical Research Group in Alzheimer Precision Medicine (Sorbonne University GRC n°21 APM)”—is geared at transforming healthcare, conventional clinical diagnostics, and drug development research in Alzheimer’s disease. Ever since the commencement of the APMI, the international interdisciplinary research network has introduced groundbreaking translational neuroscience programs on the basis of agnostic exploratory genomics, systems biology, and systems neurophysiology applying innovative “big data science”, including breakthrough artificial intelligence-based algorithms. Here, we present the scientific breakthrough advances and the pillars of the theoretical and conceptual development leading to the APMI. Show more

Keywords: Alzheimer’s disease, APMI, All of Us Research Program, artificial intelligence, big data, biomarker-guided therapies, precision medicine, systems biology, systems neurophysiology, translational research programs.

DOI: 10.3233/JAD-181121

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 1-24, 2019

Authors: Shen, Liang | Ji, Hong-Fang

Article Type: Review Article

Abstract: Developing novel agents for unexplored targets to combat Alzheimer’s disease (AD) represents an urgent task due to its increasing prevalence worldwide. The present paper summarizes the latest studies emerged in the past few years investigating the associations between the “forgotten organ” gut microbiota and AD from the following two aspects: 1) the associations between gut microbiota and AD development by animal models and human studies; and 2) the effects of gut microbiota modulation-based intervention for AD. Then, we propose future perspectives in two promising research areas: 1) developing gut microbiota modulation-based intervention; and 2) developing gut microbiota-associated diagnostic biomarkers for …AD. Knowledge gaps and potential barriers to overcome towards these two goals are also discussed. Show more

Keywords: Alzheimer’s disease, gut microbiota, therapy

DOI: 10.3233/JAD-181143

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 25-31, 2019

Authors: Wang, Xin | Zimmermann, Helena R. | Ma, Tao

Article Type: Review Article

Abstract: Currently there is no cure or effective disease-modifying therapy for Alzheimer’s disease (AD), the most common form of dementia that is becoming a global threat to public health. It is important to develop novel therapeutic strategies targeting AD pathophysiology particularly synaptic failure and cognitive impairments. Recent studies revealed several molecular signaling pathways potentially linked to brain pathology and synaptic failure in AD, including AMP-activated protein kinase (AMPK), a master kinase that plays a central role in the maintenance of cellular energy homeostasis. Particularly, hyperactive AMPK via phosphorylation has been linked to AD-associated synaptic plasticity impairments, indicating suppression of AMPK activity …might be beneficial for cognitive deficiency in AD. In this review, we will discuss how targeting dysregulation of AMPK signaling could be a feasible therapeutic approach for AD. Show more

Keywords: Alzheimer’s disease, AMPK, protein synthesis, signaling transduction, synaptic plasticity

DOI: 10.3233/JAD-181043

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 33-38, 2019

Authors: Marston, Kieran J. | Brown, Belinda M. | Rainey-Smith, Stephanie R. | Peiffer, Jeremiah J.

Article Type: Review Article

Abstract: The global population is aging at an unprecedented rate giving rise to a greater prevalence of age-related illnesses such as dementia and vascular disease. Dementia affects approximately 47 million individuals globally with projections of 130 million by the year 2050. Late-onset Alzheimer’s disease is the most common form of dementia, accounting for approximately 75% of all cases and is characterized by a progressive decline in cognitive function, memory, and cerebral volume. The pathogenesis of Alzheimer’s disease is poorly understood; however, aging, genetics, and an individual’s diet and lifestyle over several decades appear to be key determinants. As there is no …current cure for Alzheimer’s disease, postponing or preventing the onset of Alzheimer’s disease and dementia through therapeutic methods should, therefore, be targeted at individuals decades prior to an individual showing signs or symptoms of decline. As a preventative tool, resistance exercise improves memory, attention, spatial awareness, reaction time, planning, and information processing. Improvements in cognitive performance following resistance exercise and training may be mediated by peripheral elevations in the physiological biomarkers (i.e., neural and vascular) explored in this review. The purpose of this review is to discuss vascular and neuronal degeneration as a cause or consequence of dementia and Alzheimer’s disease, and the biological markers of neurogenesis and blood vessel growth, function, and regulation. We will also explore the merits of acute and chronic resistance training as a strategy to postpone the onset of cognitive decline, dementia, and Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, cognitive decline, physiology, prevention, resistance training

DOI: 10.3233/JAD-181079

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 39-64, 2019

Authors: Tiepolt, Solveig | Luthardt, Julia | Patt, Marianne | Hesse, Swen | Hoffmann, Karl Titus | Weise, David | Gertz, Hermann Josef | Sabri, Osama | Barthel, Henryk

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) and [18 F]FDG PET are established as amyloid pathology and neuronal injury biomarkers. Early after administration Aβ PET images have the potential to replace [18 F]FDG PET images allowing dual biomarker delivery by the administration of a single tracer. For [18 F]FDG PET data, a correlation with cognitive performance is known. Objective: The aim of this study was to investigate whether early after administration [11 C]PiB PET data also correlate with cognitive performance. Methods: The early after administration [11 C]PiB PET data of 31 patients with cognitive impairment were evaluated. CERAD subtests were …summarized to five cognitive domains. The resulting z scores were correlated with the PET data on a voxel- and VOI-based approach. Additional subgroup analyses (MCI versus dementia, Aβ-positive versus Aβ-negative subjects) were performed. Results: Significant correlations between cognitive performance and early after administration [11 C]PiB PET data were found between left temporo-parietal SUVR and language domain, bilateral occipital as well as left temporal SUVR and executive function, left pre- and postcentral SUVRs, and visuospatial abilities. For the episodic and immediate memory domains, the analysis at the high significance level did not show any correlated cluster, however, the exploratory analysis did. Conclusion: Our study revealed correlations between deficits in different cognitive domains and regional early after administration [11 C]PiB PET data similar to those known from [18 F]FDG PET studies. Thus, our data support the assumption that early [11 C]PiB PET data have a potential as neuronal injury biomarker. Head-to-head double-tracer studies of larger cohorts are needed to confirm this assumption. Show more

Keywords: Alzheimer’s disease, CERAD, cognition, dual time-point, early amyloid-β PET, PiB

DOI: 10.3233/JAD-180217

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 65-76, 2019

Authors: Ashford, J. Wesson

Article Type: Article Commentary

Abstract: In this issue, an article by Tiepolt et al. shows that PET scanning using [11 C]PiB can demonstrate both cerebral blood flow (CBF) changes and amyloid-β (Aβ) deposition in patients with mild cognitive dysfunction or mild dementia of Alzheimer’s disease (AD). The CBF changes can be determined because the early scan counts (1–9 minutes) reflect the flow of the radiotracer in the blood passing through the brain, while the Aβ levels are measured by later scan counts (40–70 minutes) after the radiotracer has been cleared from regions to which the radiotracer did not bind. Thus, two different diagnostic measures are …obtained with a single injection. Unexpectedly, the mild patients with Aβ positivity had scan data with only a weak relationship to memory, while the relationships to executive function and language function were relatively strong. This divergence of findings from studies of severely impaired patients highlights the importance of determining how AD pathology affects the brain. A possibility suggested in this commentary is that Aβ deposits occur early in AD and specifically in critical areas of the neocortex affected only later by the neurofibrillary pathology indicating a different role of the amyloid-β protein precursor (AβPP) in the development of those neocortical regions, and a separate component of AD pathology may selectively impact functions of these neocortical regions. The effects of adverse AβPP metabolism in the medial temporal and brainstem regions occur later possibly because of different developmental issues, and the later, different pathology is clearly more cognitively and socially devastating. Show more

Keywords: Alzheimer’s disease, amyloid, cerebral blood flow, cognition, neuroplasticity, pathology

DOI: 10.3233/JAD-181198

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 77-83, 2019

Authors: Lussier, Maxime | Adam, Stéphane | Chikhaoui, Belkacem | Consel, Charles | Gagnon, Mathieu | Gilbert, Brigitte | Giroux, Sylvain | Guay, Manon | Hudon, Carol | Imbeault, Hélène | Langlois, Francis | Macoir, Joel | Pigot, Hélène | Talbot, Lise | Bier, Nathalie

Article Type: Research Article

Abstract: Background: Functional assessment is of paramount importance when mild cognitive impairment is suspected, but common assessment tools such as questionnaires lack sensitivity. An alternative and innovative approach consists in using sensor technology in smart apartments during scenario-based assessments of instrumental activities of daily living (IADL). However, studies that investigate this approach are scarce and the technology used is not always transposable in healthcare settings. Objective: To explore whether simple and wireless technology used in two different smart environments could add value to performance and rater-based measures of IADL when it comes to predicting mild cognitive impairment (MCI) in …older adults. Methods: Twenty-six (26) cognitively healthy older adults (CH) and 22 older adults with MCI were recruited. Functional performance in a set of five scripted tasks was evaluated with sensor-based observations (motion, contact, and electric sensors) and performance-based measures (rated with videotapes). The five tasks could be performed in any order and were detailed on an instruction sheet given to participants. Results: Sensor-based observations showed that participants with MCI spent more time in the kitchen and looking into the fridge and kitchen cabinets than CH participants. Moreover, these measures were negatively associated with memory and executive performances of participants and significantly contributed to the prediction of MCI. Conclusion: Simple, wireless, and sensor-based technology holds potential for the detection of MCI in older adults as they perform daily tasks. However, some limits are discussed and we offer recommendations to improve the usefulness of this innovative approach. Show more

Keywords: Activities of daily living, memory, mild cognitive impairment, neurocognitive disorders, older adults, smart homes, technology, wireless technology

DOI: 10.3233/JAD-180652

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 85-96, 2019

Authors: Jacob, Louis | Bohlken, Jens | Kostev, Karel

Article Type: Research Article

Abstract: Background: Previous research has found a positive association between the use of antiepileptic drugs (AEDs) and dementia. However, there have been some concerns about the generalizability of its findings. Objective: The goal of this case-control study was to analyze the association between AED use and dementia risk in Germany. Methods: This study included patients who had received a first dementia diagnosis from one of 1,203 general practitioners or 202 neuropsychiatrists between 2013 and 2017 (index date). Controls without dementia were matched (1:1) to dementia cases by age, gender, physician, diagnosis of mild cognitive …impairment, and observation time prior to the index date. Two regression models were used to analyze the association between AED use and dementia risk after adjusting for comorbidities and co-prescribed drugs. AEDs were included as a dichotomous variable in Model 1 (ever versus never use) and as a continuous variable in Model 2 (duration of treatment in years). Results: A total of 50,575 cases with dementia and 50,575 controls without dementia were included in this study. Model 1 (odds-ratio [OR] = 0.99) and Model 2 (OR = 1.00) showed no significant association between AED use and dementia risk. However, prescriptions for levetiracetam generic brands (Model 1: OR = 1.70; Model 2: OR = 1.36) were associated with an increased dementia risk. Conclusions: Overall, AED use was not significantly associated with dementia risk in patients followed by general practitioners and neuropsychiatrists in Germany between 2013 and 2017. Nonetheless, the potential deleterious effects of levetiracetam generic brands on cognition deserve further investigation. Show more

Keywords: Antiepileptic drug, case-control study, dementia, Germany, risk factor

DOI: 10.3233/JAD-181194

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 97-103, 2019

Authors: Szoeke, Cassandra | Goodwill, Alicia M. | Gorelik, Alexandra | Dennerstein, Lorraine | Caeyenberghs, Karen | Simpson Jr. , Steven | Hill, Edward | Campbell, Stephen

Article Type: Research Article

Abstract: Cerebral amyloid-β (Aβ) plaques are the hallmark biomarker of Alzheimer’s disease (AD) and are detectable decades before clinical symptoms. Modifying risk factors associated with Aβ accrual offers an opportunity for AD prevention. While midlife vascular health is linked to AD; there is minimal longitudinal evidence regarding the effect of midlife lipids on Aβ. We examined the association between midlife lipids and Aβ 20 years later. One hundred and twenty-two women had serum lipid profiles in midlife (1992, 45–57 years), and cerebral imaging, genotyping, and cognition measured 20 years later (2012/13, 66–77 years). Imaging was performed in 2012/13 via F-18 Florbetaben …positron emission tomography (PET) and standard uptake value ratios (SUVR) were calculated. Lipid profiles and other predictors of high PET-SUVR levels (>1.2) were evaluated using multivariable logistic regression. Increases in low-density lipoprotein (LDL) cholesterol in midlife were associated with Aβ, adjusting for age, education, cholesterol medication, and cognition (AdjOR1.81, 95% CI 1.08–3.01, p  = 0.024), but attenuated on adjustment for apolipoprotein E4 (APOE ɛ 4). Aβ risk increased in women with APOE ɛ 4 and midlife cholesterol >6.2 mmol/L (AdjOR9.59, 95% CI 2.94–31.31, p  < 0.001), APOE ɛ 4 and LDL >3.3 mmol/L (AdjOR9.00, 95% CI 2.89–28.03, p  < 0.001), and APOE ɛ 4 and cholesterol to high-density lipoprotein ratio ≥3.25 (AdjOR8.32, 95% CI 2.32–29.89, p  < 0.001). Presence of APOE ɛ 4 and midlife dyslipidemia compounded the risk for Aβ deposition, although no independent effect of midlife lipids was found. Lipid-modifying treatment in midlife could mitigate the risk of Aβ in women with a genetic predisposition for AD. To better inform prevention, future consideration should be given toward managing dyslipidemia in women carrying the APOE ɛ 4 allele. Show more

Keywords: Amyloid burden, apolipoprotein, cerebral amyloid, dementia, dyslipidemia, positron emission tomography, prevention, serum lipid profile, vascular health

DOI: 10.3233/JAD-180815

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 105-114, 2019

Authors: Duffy, Kara B. | Ray, Balmiki | Lahiri, Debomoy K. | Tilmont, Edward M. | Tinkler, Gregory P. | Herbert, Richard L. | Greig, Nigel H. | Ingram, Donald K. | Ottinger, Mary Ann | Mattison, Julie A.

Article Type: Research Article

Abstract: The degeneration in the locus coeruleus associated with Alzheimer’s disease suggests an involvement of the noradrenergic system in the disease pathogenesis. The role of depleted norepinephrine was tested in adult and aged rhesus macaques to develop a potential model for testing Alzheimer’s disease interventions. Monkeys were injected with the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) or vehicle at 0, 3, and 6 months; brains were harvested at 9 months. Reduced norepinephrine in the locus coeruleus was accompanied by decreased dopamine β-hydroxylase staining and increased amyloid-β load in the aged group, and the proportion of potentially toxic amyloid-β42 peptide was increased. Immunohistochemistry …revealed no effects on microglia or astrocytes. DSP4 treatment altered amyloid processing, but these changes were not associated with the induction of chronic neuroinflammation. These findings suggest norepinephrine deregulation is an essential component of a nonhuman primate model of Alzheimer’s disease, but further refinement is necessary. Show more

Keywords: Alzheimer’s disease, DSP4, locus coeruleus, neurotoxin, nonhuman primate, norepinephrine

DOI: 10.3233/JAD-180487

Citation: Journal of Alzheimer's Disease, vol. 68, no. 1, pp. 115-126, 2019