Journal of Alzheimer's Disease - Volume 64, issue s1

Authors: Kulmala, Jenni | Ngandu, Tiia | Kivipelto, Miia

Article Type: Research Article

Abstract: During the last few years, dementia prevention based on modifiable lifestyle factors has gained increasing attention. Cohort studies with follow-ups extending up to decades have identified several risk and protective factors, and very recently new randomized controlled trials with multidomain approach have provided promising evidence by showing that modifying simultaneously several risk factors, it is possible to maintain and improve cognitive capacity among older at-risk persons. Several lifestyle-based multidomain trials are under preparation or ongoing and to facilitate international collaboration and effective worldwide dementia prevention, the World Wide FINGERS interdisciplinary network (http://wwfingers.com ) was recently initiated. Additionally, several new implementation …projects are taking the first steps from trial setting to real-life implementation of a dementia prevention program. This paper highlights the recent perspectives from the field of Alzheimer’s disease and reflects the implications and importance of current achievements. Finally, predictions for the future work especially in terms of global collaboration and implementation will be discussed. Show more

Keywords: Dementia, implementation, intervention, prevention, risk reduction

DOI: 10.3233/JAD-179919

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S191-S198, 2018

Authors: Chételat, Gaël

Article Type: Review Article

Abstract: Over the last ten years, we have conducted research in Alzheimer’s disease (AD) using multimodal neuroimaging techniques to improve diagnosis, further our understanding of the pathological mechanisms underlying the disease, and support the development of innovative non-pharmacological preventive strategies. Our works emphasized the interest of hippocampal subfield volumetry in early diagnosis and the need for further development in this field including optimization, standardization, and automatization of the techniques. Also, we conducted several studies in cognitively intact at-risk elderly (e.g., subjective cognitive decline patients and APOE4 carriers) to better identify biomarkers associated with increased risk of developing AD. Regarding the physiopathological …mechanisms, specific multimodal neuroimaging techniques allowed us to highlight the relevance of diaschisis, the mismatch between neurodegeneration and local Aβ deposition and the regional variation in the mechanisms underlying structural or functional alterations. Further works integrating other biomarkers known to play a role in the physiopathology of AD (tau, TDP-43, inflammation, etc.) in a longitudinal design would be useful to get a comprehensive understanding of their relative role, sequence, and causal relationships. Our works also highlighted the relevance of functional connectivity in further understanding the specificity of cognitive deficits in AD and how connectivity differentially influences the propagation of the different AD biomarkers. Finally, we conducted several studies on the links between lifestyle factors and neuroimaging biomarkers to unravel mechanisms of reserve. Further efforts are needed to better understand which lifestyle factor, or combination of factors, impact on AD pathology, and when, to help translating our knowledge to training programs that might prevent or delay brain and cognitive changes leading to AD dementia. Show more

Keywords: Aging, Alzheimer’s disease, diagnosis, disconnection, FDG-PET, lifestyle, meditation, multimodal neuroimaging, prevention, structural MRI

DOI: 10.3233/JAD-179920

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S199-S211, 2018

Authors: Vos, Stephanie J.B. | Visser, Pieter Jelle

Article Type: Review Article

Abstract: Increasing interest in clinical trials and clinical research settings to identify Alzheimer’s disease (AD) in the earliest stages of the disease has led to the concept of preclinical AD. Individuals with preclinical AD have AD pathology without clinical symptoms yet. Accumulating evidence has shown that biomarkers can identify preclinical AD and that preclinical AD is associated with a poor clinical outcome. Little is known yet about the role of vascular and lifestyle risk factors in the development of preclinical AD. In order to better understand preclinical AD pathology and clinical progression rates, there is a need to refine the concept …of preclinical AD. This will be of great value for advancements in future research, clinical trials, and eventually clinical practice. Show more

Keywords: Amyloid, biomarkers, clinical trials, cognition, diagnosis, lifestyle, neuronal injury, preclinical Alzheimer’s disease, prognosis, vascular risk

DOI: 10.3233/JAD-179943

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S213-S227, 2018

Authors: Solfrizzi, Vincenzo | Agosti, Pasquale | Lozupone, Madia | Custodero, Carlo | Schilardi, Andrea | Valiani, Vincenzo | Sardone, Rodolfo | Dibello, Vittorio | Di Lena, Luca | Lamanna, Angela | Stallone, Roberta | Bellomo, Antonello | Greco, Antonio | Daniele, Antonio | Seripa, Davide | Sabbà, Carlo | Logroscino, Giancarlo | Panza, Francesco

Article Type: Research Article

Abstract: The link diet-cognitive function/dementia has been largely investigated in observational studies; however, there was a lack of evidence from randomized clinical trials (RCTs) on the prevention of late-life cognitive disorders though dietary intervention in cognitively healthy older adults. In the present article, we systematically reviewed RCTs published in the last four years (2014–2017) exploring nutritional intervention efficacy in preventing the onset of late-life cognitive disorders and dementia in cognitively healthy subjects aged 60 years and older using different levels of investigation (i.e., dietary pattern changes/medical food/nutraceutical supplementation/multidomain approach and dietary macro- and micronutrient approaches) as well as possible underlying mechanisms …of nutritional prevention. From the 35 included RCTs, there was moderate evidence that intervention through dietary pattern changes, medical food/nutraceutical supplementation, and multidomain approach improved specific cognitive domains or cognitive-related blood biomarkers. There was high evidence that protein supplementation improved specific cognitive domains or functional status in prefrail older adults without effect Show more

Keywords: Alzheimer’s disease, dementia, dietary pattern, healthy diet, macronutrients, medical food, Mediterranean diet, micronutrients, mild cognitive impairment, nutraceuticals, prevention

DOI: 10.3233/JAD-179940

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S229-S254, 2018

Authors: Andrade, Andreia G. | Bubu, Omonigho M. | Varga, Andrew W. | Osorio, Ricardo S.

Article Type: Review Article

Abstract: Obstructive sleep apnea (OSA) and Alzheimer’s disease (AD) are highly prevalent conditions with growing impact on our aging society. While the causes of OSA are now better characterized, the mechanisms underlying AD are still largely unknown, challenging the development of effective treatments. Cognitive impairment, especially affecting attention and executive functions, is a recognized clinical consequence of OSA. A deeper contribution of OSA to AD pathogenesis is now gaining support from several lines of research. OSA is intrinsically associated with disruptions of sleep architecture, intermittent hypoxia and oxidative stress, intrathoracic and hemodynamic changes as well as cardiovascular comorbidities. All of these …could increase the risk for AD, rendering OSA as a potential modifiable target for AD prevention. Evidence supporting the relevance of each of these mechanisms for AD risk, as well as a possible effect of AD in OSA expression, will be explored in this review. Show more

Keywords: AD risk, Alzheimer’s disease, amyloid, obstructive sleep apnea, OSA phenotypes

DOI: 10.3233/JAD-179936

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S255-S270, 2018

Authors: Zetterberg, Henrik | Blennow, Kaj

Article Type: Review Article

Abstract: The past five years have seen an enormous development in the field of fluid biomarkers for Alzheimer’s disease (AD) and related disorders. The proteins that constitute the foundation for the cerebrospinal fluid (CSF) tests for the classical AD pathologies are now being explored as potential blood-based biomarkers, thanks to the recent implementation of ultrasensitive measurement technologies in academic and clinical laboratories worldwide. The current blood-derived data are still less clear than those obtained using CSF as the sample type, but independent research suggests that there are biomarker signals in blood that relate to plaque and tangle pathologies in AD, which …are relevant to explore further. Additionally, neurofilament light has emerged as the first robust blood-based biomarker for neurodegeneration in a broad range of central nervous system disorders, as well as for acute brain injuries. Here, we briefly recapitulate the first and second waves of fluid biomarker analysis in AD, i.e., the development and validation of established and novel CSF biomarkers for the disorder, followed by a focused discussion on blood-based biomarkers for AD, which we describe as the third wave of fluid biomarker analysis that hopefully will gain further momentum during the coming five years. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, plasma, serum, tau

DOI: 10.3233/JAD-179926

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S271-S279, 2018

Authors: Parnetti, Lucilla | Eusebi, Paolo

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disorder, affecting around 35 million people worldwide. Cerebrospinal fluid (CSF) biomarkers entered the diagnostic criteria as support for early diagnosis. The classical biochemical signature of AD includes total tau (T-tau), phosphorylated tau (P-tau), and the 42 amino acid peptide (Aβ42 ) of amyloid-β. Recent observations suggest that the use of CSF Aβ42 :Aβ40 ratio rather than CSF Aβ42 alone could contribute to reduce inter-laboratory variation in Aβ values and increasing diagnostic performance of the CSF AD biomarkers in routine practice. However, research efforts aimed at enriching the CSF biomarker panel …are ongoing. The CSF AD signature is also crucial for the design of clinical trials for AD, since it best guarantees AD pathology as the cause of cognitive impairment. Accordingly, CSF biomarkers have been now reported in the inclusion criteria of Phase I, Phase II, and Phase III clinical trials as enrichment strategy. So far, one of the most important reasons for the failure of AD clinical trials was the inclusion of participants with unlikely AD pathology. In order to implement the use of CSF biomarkers in AD routine diagnostic work-up and as accepted strategy for enriching trial populations, inter-laboratory variability should be minimized. Increasing efforts should also be devoted to promote data sharing practices, encouraging individual participant data meta-analyses. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid biomarkers, early diagnosis, tau

DOI: 10.3233/JAD-179910

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S281-S287, 2018

Authors: Kiddle, Steven J. | Voyle, Nicola | Dobson, Richard J.B.

Article Type: Review Article

Abstract: Ever since the discovery of APOE ɛ 4 around 25 years ago, researchers have been excited about the potential of a blood test for Alzheimer’s disease (AD). Since then researchers have looked for genetic, protein, metabolite, and/or gene expression markers of AD and related phenotypes. However, no blood test for AD is yet being used in the clinical setting. We first review the trends and challenges in AD blood biomarker research, before giving our personal recommendations to help researchers overcome these challenges. While some degree of consistency and replication has been seen across independent studies, several high-profile studies have …seemingly failed to replicate. Partly due to academic incentives, there is a reluctance in the field to report predictive ability, to publish negative findings, and to independently replicate the work of others. If this can be addressed, then we will know sooner whether a blood test for AD or related phenotypes with clinical utility can be developed. Show more

Keywords: Alzheimer’s disease, blood proteins, blood tests, cohort studies, data reporting, genetics, gene expression, metabolomics, research design

DOI: 10.3233/JAD-179904

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S289-S297, 2018

Authors: Drummond, Eleanor | Goñi, Fernando | Liu, Shan | Prelli, Frances | Scholtzova, Henrieta | Wisniewski, Thomas

Article Type: Review Article

Abstract: There is growing genetic and proteomic data highlighting the complexity of Alzheimer’s disease (AD) pathogenesis. Greater use of unbiased “omics” approaches is being increasingly recognized as essential for the future development of effective AD research, that need to better reflect the multiple distinct pathway abnormalities that can drive AD pathology. The track record of success in AD clinical trials thus far has been very poor. In part, this high failure rate has been related to the premature translation of highly successful results in animal models that mirror only limited aspects of AD pathology to humans. We highlight our recent efforts …to increase use of human tissue to gain a better understanding of the AD pathogenesis subtype variety and to develop several distinct therapeutic approaches tailored to address this diversity. These therapeutic approaches include the blocking of the Aβ/apoE interaction, stimulation of innate immunity, and the simultaneous blocking of Aβ/tau oligomer toxicity. We believe that future successful therapeutic approaches will need to be combined to better reflect the complexity of the abnormal pathways triggered in AD pathogenesis. Show more

Keywords: Apolipoprotein E, chronic traumatic encephalopathy, immunomodulation, innate immunity, oligomer, prion, Toll-like receptor 9, unbiased proteomics

DOI: 10.3233/JAD-179909

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S299-S312, 2018

Authors: Selles, M. Clara | Oliveira, Mauricio M. | Ferreira, Sergio T.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the main form of dementia in the elderly and affects greater than 47 million people worldwide. Care for AD patients poses very significant personal and economic demands on individuals and society, and the situation is expected to get even more dramatic in the coming decades unless effective treatments are found to halt the progression of the disease. Although AD is most commonly regarded as a disease of the memory, the entire brain is eventually affected by neuronal dysfunction or neurodegeneration, which brings about a host of other behavioral disturbances. AD patients often present with apathy, depression, …eating and sleeping disorders, aggressive behavior, and other non-cognitive symptoms, which deeply affect not only the patient but also the caregiver’s health. These symptoms are usually associated with AD pathology but are often neglected as part of disease progression due to the early and profound impact of disease on memory centers such as the hippocampus and entorhinal cortex. Yet, a collection of findings offers biochemical insight into mechanisms underlying non-cognitive symptoms in AD, and indicate that, at the molecular level, such symptoms share common mechanisms. Here, we review evidence indicating mechanistic links between memory loss and non-cognitive symptoms of AD. We highlight the central role of the pro-inflammatory activity of microglia in behavioral alterations in AD patients and in experimental models of the disease. We suggest that a deeper understanding of non-cognitive symptoms of AD may illuminate a new beginning in AD research, offering a fresh approach to elucidate mechanisms involved in disease progression and potentially unveiling yet unexplored therapeutic targets. Show more

Keywords: Alzheimer, depression, amyloid- β, inflammation, microglia, TNF-α

DOI: 10.3233/JAD-179925

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S313-S327, 2018