Journal of Alzheimer's Disease - Volume 62, issue 3

Authors: Butterfield, D. Allan | Boyd-Kimball, Debra

Article Type: Review Article

Abstract: Oxidative stress is implicated in the pathogenesis and progression of Alzheimer’s disease (AD) and its earlier stage, amnestic mild cognitive impairment (aMCI). One source of oxidative stress in AD and aMCI brains is that associated with amyloid-β peptide, Aβ1-42 oligomers. Our laboratory first showed in AD elevated oxidative stress occurred in brain regions rich in Aβ1-42 , but not in Aβ1-42 -poor regions, and was among the first to demonstrate Aβ peptides led to lipid peroxidation (indexed by HNE) in AD and aMCI brains. Oxidatively modified proteins have decreased function and contribute to damaged key biochemical and metabolic pathways …in which these proteins normally play a role. Identification of oxidatively modified brain proteins by the methods of redox proteomics was pioneered in the Butterfield laboratory. Four recurring altered pathways secondary to oxidative damage in brain from persons with AD, aMCI, or Down syndrome with AD are interrelated and contribute to neuronal death. This “Quadrilateral of Neuronal Death” includes altered: glucose metabolism, mTOR activation, proteostasis network, and protein phosphorylation. Some of these pathways are altered even in brains of persons with preclinical AD. We opine that targeting these pathways pharmacologically and with lifestyle changes potentially may provide strategies to slow or perhaps one day, prevent, progression or development of this devastating dementing disorder. This invited review outlines both in vitro and in vivo studies from the Butterfield laboratory related to Aβ1-42 and AD and discusses the importance and implications of some of the major achievements of the Butterfield laboratory in AD research. Show more

Keywords: Alzheimer’s disease, amyloid beta-peptide 1–42, glucose metabolism, mTOR activation, oxidative stress, protein phosphorylation, proteostasis

DOI: 10.3233/JAD-170543

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1345-1367, 2018

Authors: Adlard, Paul A. | Bush, Ashley I.

Article Type: Review Article

Abstract: It is estimated that by the year 2050 there will be more than 1.5 billion people globally over the age of 65 years. Aging is associated with changes to a number of different cellular processes which are driven by a variety of factors that contribute to the characteristic decline in function that is seen across multiple physiological domains/tissues in the elderly (including the brain). Importantly, aging is also the primary risk factor for the development of neurodegenerative disorders such as Alzheimer’s disease. As such, there is an urgent need to provide a greater understanding of both the pathogenesis and treatment …of these devastating neurodegenerative disorders. One of the key cellular processes that becomes dysregulated with age and participates both directly and indirectly in age-related dysfunction, is metal homeostasis and the neurochemistry of metalloproteins, the basic science of which has been extensively reviewed in the past. In this review, we will focus on the human clinical intervention trials that have been conducted over approximately the last four decades that have attempted to establish the efficacy of targeting metal ions in the treatment of AD. Show more

Keywords: Alzheimer’s disease, clinical trials, copper, iron, metals, therapeutic, zinc

DOI: 10.3233/JAD-170662

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1369-1379, 2018

Authors: de la Monte, Suzanne M. | Tong, Ming | Wands, Jack R.

Article Type: Review Article

Abstract: The Journal of Alzheimer ’s Disease (JAD), founded in 1998, played a pivotal role in broadening the field of research on Alzheimer’s disease (AD) by publishing a diverse range of clinical, pathological, molecular, biochemical, epidemiological, experimental, and review articles from its birth. This article recounts my own journey as an author who contributed articles to JAD over the 20 years of the journal’s existence. In retrospect, it seems remarkable that a considerable body of work that originated from our group marks a trail that began with studies of vascular, stress, and mitochondrial factors in AD pathogenesis, exploded into the …concept of ‘Type 3 Diabetes’, and continued with the characterization of how environmental, exposure, and lifestyle factors promote neurodegeneration and which therapeutic strategies could reverse the neurodegeneration cascade. Show more

Keywords: Ceramides, dementia, diabetes, insulin resistance, neuroinflammation, nitrosamines, obesity, streptozotocin, Type 3 diabetes, vascular steatohepatitis

DOI: 10.3233/JAD-170829

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1381-1390, 2018

Authors: Moreira, Paula I.

Article Type: Review Article

Abstract: A growing body of evidence supports a clear association between Alzheimer’s disease and diabetes and several mechanistic links have been revealed. This paper is mainly devoted to the discussion of the role of diabetes-associated mitochondrial defects in the pathogenesis of Alzheimer’s disease. The research experience and views of the author on this subject will be highlighted.

Keywords: Alzheimer’s disease, diabetes, mechanistic link, mitochondria

DOI: 10.3233/JAD-170931

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1391-1401, 2018

Authors: Swerdlow, Russell H.

Article Type: Review Article

Abstract: Decades of research indicate mitochondria from Alzheimer’s disease (AD) patients differ from those of non-AD individuals. Initial studies revealed structural differences, and subsequent studies showed functional deficits. Observations of structure and function changes prompted investigators to consider the consequences, significance, and causes of AD-related mitochondrial dysfunction. Currently, extensive research argues mitochondria may mediate, drive, or contribute to a variety of AD pathologies. The perceived significance of these mitochondrial changes continues to grow, and many currently believe AD mitochondrial dysfunction represents a reasonable therapeutic target. Debate continues over the origin of AD mitochondrial changes. Some argue amyloid-β (Aβ) induces AD mitochondrial …dysfunction, a view that does not challenge the amyloid cascade hypothesis and that may in fact help explain that hypothesis. Alternatively, data indicate mitochondrial dysfunction exists independent of Aβ, potentially lies upstream of Aβ deposition, and suggest a primary mitochondrial cascade hypothesis that assumes mitochondrial pathology hierarchically supersedes Aβ pathology. Mitochondria, therefore, appear at least to mediate or possibly even initiate pathologic molecular cascades in AD. This review considers studies and data that inform this area of AD research. Show more

Keywords: Alzheimer’s disease, bioenergetics, cascade, cytochrome oxidase, mitochondria

DOI: 10.3233/JAD-170585

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1403-1416, 2018

Authors: Wallin, Anders | Román, Gustavo C. | Esiri, Margaret | Kettunen, Petronella | Svensson, Johan | Paraskevas, George P. | Kapaki, Elisabeth

Article Type: Review Article

Abstract: Subcortical small-vessel disease (SSVD) is a disorder well characterized from the clinical, imaging, and neuropathological viewpoints. SSVD is considered the most prevalent ischemic brain disorder, increasing in frequency with age. Vascular risk factors include hypertension, diabetes, hyperlipidemia, elevated homocysteine, and obstructive sleep apnea. Ischemic white matter lesions are the hallmark of SSVD; other pathological lesions include arteriolosclerosis, dilatation of perivascular spaces, venous collagenosis, cerebral amyloid angiopathy, microbleeds, microinfarcts, lacunes, and large infarcts. The pathogenesis of SSVD is incompletely understood but includes endothelial changes and blood-brain barrier alterations involving metalloproteinases, vascular endothelial growth factors, angiotensin II, mindin/spondin, and the mammalian target …of rapamycin pathway. Metabolic and genetic conditions may also play a role but hitherto there are few conclusive studies. Clinical diagnosis of SSVD includes early executive dysfunction manifested by impaired capacity to use complex information, to formulate strategies, and to exercise self-control. In comparison with Alzheimer’s disease (AD), patients with SSVD show less pronounced episodic memory deficits. Brain imaging has advanced substantially the diagnostic tools for SSVD. With the exception of cortical microinfarcts, all other lesions are well visualized with MRI. Diagnostic biomarkers that separate AD from SSVD include reduction of cerebrospinal fluid amyloid-β (Aβ)42 and of the ratio Aβ42 /Aβ40 often with increased total tau levels. However, better markers of small-vessel function of intracerebral blood vessels are needed. The treatment of SSVD remains unsatisfactory other than control of vascular risk factors. There is an urgent need of finding targets to slow down and potentially halt the progression of this prevalent, but often unrecognized, disorder. Show more

Keywords: Cerebral small vessel disease, classification, cerebrospinal fluid, diagnostic imaging, genetics, metabolism, pathology, pathophysiology, symptoms, cognitive impairment

DOI: 10.3233/JAD-170803

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1417-1441, 2018

Authors: Kehoe, Patrick Gavin

Article Type: Review Article

Abstract: There is wide recognition of a complex association between midlife hypertension and cardiovascular disease and later development of Alzheimer’s disease (AD) and cognitive impairment. While significant progress has been made in reducing rates of mortality and morbidity due to cardiovascular disease over the last thirty years, progress towards effective treatments for AD has been slower. Despite the known association between hypertension and dementia, research into each disease has largely been undertaken in parallel and independently. Yet over the last decade and a half, the emergence of converging findings from pre-clinical and clinical research has shown how the renin angiotensin system …(RAS), which is very important in blood pressure regulation and cardiovascular disease, warrants careful consideration in the pathogenesis of AD. Numerous components of the RAS have now been found to be altered in AD such that the multifunctional and potent vasoconstrictor angiotensin II, and similarly acting angiotensin III, are greatly altered at the expense of other RAS signaling peptides considered to contribute to neuronal and cognitive function. Collectively these changes may contribute to many of the neuropathological hallmarks of AD, as well as observed progressive deficiencies in cognitive function, while also linking elements of a number of the proposed hypotheses for the cause of AD. This review discusses the emergence of the RAS and its likely importance in AD, not only because of the multiple facets of its involvement, but also perhaps fortuitously because of the ready availability of numerous RAS-acting drugs, that could be repurposed as interventions in AD. Show more

Keywords: ACE acetylcholine, Alzheimer’s disease, amyloid-β, angiotensin, cognitive decline, dementia, drug repurposing, epidemiology, hypertension, treatment, vascular

DOI: 10.3233/JAD-171119

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1443-1466, 2018

Authors: Hodges, John R. | Piguet, Olivier

Article Type: Review Article

Abstract: The landscape of frontotemporal dementia (FTD) has evolved remarkably in recent years and is barely recognizable from two decades ago. Knowledge of the clinical phenomenology, cognition, neuroimaging, genetics, pathology of the different subtypes of FTD, and their relations to other neurodegenerative conditions, has increased rapidly, due in part, to the growing interests into these neurodegenerative brain conditions. This article reviews the major advances in the field of FTD over the past 20 years, focusing primarily on the work of Frontier, the frontotemporal dementia clinical research group, based in Sydney, Australia. Topics covered include clinical presentations (cognition, behavior, neuroimaging), pathology, genetics, …and disease progression, as well as interventions and carer directed research. This review demonstrates the improvement in diagnostic accuracy and capacity to provide advice on genetic risks, prognosis, and outcome. The next major challenge will be to capitalize on these research findings to develop effective disease modifying drugs, which are currently lacking. Show more

Keywords: Behavioral variant frontotemporal dementia, diagnosis, genetics, interventions, pathology, prognosis, progressive nonfluent aphasia, semantic dementia

DOI: 10.3233/JAD-171087

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1467-1480, 2018