Journal of Alzheimer's Disease - Volume 68, issue 2

Authors: Tobore, Tobore Onojighofia

Article Type: Review Article

Abstract: Alzheimers’ disease (AD) is the most common cause of dementia, with an estimated 5 million new cases occurring annually. Among the elderly, AD shortens life expectancy, results in disability, decreases quality of life, and ultimately, leads to institutionalization. Despite extensive research in the last few decades, its heterogeneous pathophysiology and etiopathogenesis have made it difficult to develop an effective treatment and prevention strategy. Aging is the biggest risk factor for AD and evidence suggest that the total number of older people in the population is going to increase astronomically in the next decades. Also, there is evidence that air pollution …and increasing income inequality may result in higher incidence and prevalence of AD. This makes the need for a comprehensive understanding of the etiopathogenesis and pathophysiology of the disease extremely critical. In this paper, a quintuple framework of thyroid dysfunction, vitamin D deficiency, sex hormones, and mitochondria dysfunction and oxidative stress are used to provide a comprehensive description of AD etiopathogenesis and pathophysiology. The individual role of each factor, their synergistic and genetic interactions, as well as the limitations of the framework are discussed. Show more

Keywords: Alzheimer’s disease, amyloid-β, dementia, hyperphosphorylated tau, melatonin, mitochondria dysfunction, oxidative stress, pathogenesis, sex hormones, thyroid hormone, vitamin D

DOI: 10.3233/JAD-181052

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 417-437, 2019

Authors: Bocai, Nadia I. | Marcora, María S. | Belfiori-Carrasco, Lautaro F. | Morelli, Laura | Castaño, Eduardo M.

Article Type: Review Article

Abstract: The accumulation and spreading of protein tau in the human brain are major features of neurodegenerative disorders known as tauopathies. In addition to several subcellular abnormalities, tau aggregation within neurons seems capable of triggering endoplasmic reticulum (ER) stress and the consequent unfolded protein response (UPR). In metazoans, full activation of a complex ER-UPR network may restore proteostasis and ER function or, if stress cannot be solved, commit cells to apoptosis. Due to these alternative outcomes (survival or death), the pharmacological manipulation of ER-UPR has become the focus of potential therapies in many human diseases, including tauopathies. Here we update and …analyze the experimental data from human brain, cellular, and animal models linking tau accumulation and ER-UPR. We further discuss mechanistic aspects and put the ER-UPR into perspective as a possible therapeutic target in this group of diseases. Show more

Keywords: Dementia, endoplasmic reticulum stress, tau proteins, tauopathies, unfolded protein response

DOI: 10.3233/JAD-181021

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 439-458, 2019

Authors: Roda, Alejandro R. | Montoliu-Gaya, Laia | Villegas, Sandra

Article Type: Review Article

Abstract: Alzheimer’s disease (AD), the most common type of dementia worldwide, is characterized by high levels of amyloid-β (Aβ) peptide and hyperphosphorylated tau protein. Genetically, the ɛ 4 allele of apolipoprotein E (ApoE) has been established as the major risk factor for developing late-onset AD (LOAD), the most common form of the disease. Although the role ApoE plays in AD is still not completely understood, a differential role of its isoforms has long been known. The current review compiles the involvement of ApoE isoforms in amyloid-β protein precursor transcription, Aβ aggregation and clearance, synaptic plasticity, neuroinflammation, lipid metabolism, mitochondrial function, …and tau hyperphosphorylation. Due to the complexity of LOAD, an accurate description of the interdependence among all the related molecular mechanisms involved in the disease is needed for developing successful therapies. Show more

Keywords: Aβ clearance, Aβ aggregation, AβPP transcription, AICD generation, Alzheimer’s disease, amyloid-β, apolipoprotein E, lipid metabolism, mitochondrial damage, neuroinflammation

DOI: 10.3233/JAD-180740

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 459-471, 2019

Authors: Takamatsu, Yoshiki | Ho, Gilbert | Waragai, Masaaki | Wada, Ryoko | Sugama, Shuei | Takenouchi, Takato | Masliah, Eliezer | Hashimoto, Makoto

Article Type: Research Article

Abstract: Alzheimer’s disease (AD), the most common neurodegenerative dementia, leads to memory dysfunction due to widespread neuronal loss associated with aggregation of amyloidogenic proteins (APs), while schizophrenia (SCZ) represents a major psychiatric disorder characterized by delusions, hallucinations, and other cognitive abnormalities, the underlying mechanisms of which remain obscure. Although AD and SCZ partially overlap in terms of psychiatric symptoms and some aspects of cognitive impairment, the causal relationship between AD and SCZ is unclear. Based on the similarity of APs with yeast prion in terms of stress-induced protein aggregation, we recently proposed that evolvability of APs might be an epigenetic phenomenon …to transmit stress information of parental brain to cope with the stressors in offspring. Although amyloid evolvability may be beneficial in evolution, AD might be manifested during parental aging as the mechanism of antagonistic pleiotropy phenomenon. Provided that accumulating evidence implicates stress as an important factor in SCZ, the main objective of this paper is to better understand the possible connection of AD and SCZ through amyloid evolvability. Hypothetically, the delivery of information of stress by APs may be less efficient under the decreased evolvability conditions such as disease-modifying treatment, leading to SCZ in offspring. Conversely, the increased evolvability conditions including gene mutations of APs are supposed to be beneficial for offspring, but might lead to AD in parents. Collectively, AD and SCZ might transgenerationally interfere with each other through amyloid evolvability, and this could explain why both AD and SCZ have not been selected out through evolution. Show more

Keywords: Alzheimer’s disease, amyloid-β , antagonistic pleiotropy, disease-modifying therapy, evolvability, natural selection, schizophrenia, transgenerational

DOI: 10.3233/JAD-180986

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 473-481, 2019

Authors: Regland, Björn | McCaddon, Andrew

Article Type: Research Article

Abstract: The ‘amyloid hypothesis’ dominates Alzheimer’s disease (AD) research but has failed to deliver effective therapies. Amyloid precursor protein (APP ) and presenilin-1 (PSEN1 ) genetic mutations are undoubtedly pathogenic, albeit by unclear mechanisms. Conversely, high dose B-vitamins convincingly slow brain atrophy in a pre-stage state of sporadic AD. Here we suggest a link between sporadic and genetic AD: 1) Increased serum homocysteine, a marker of B-vitamin deficiencies, is a significant risk factor for sporadic AD. It also correlates with elevated levels of antichymotrypsin, a serine protease inhibitor. 2) Family members with codon 717 APP mutations and dementia have low …serum vitamin B12 values. Overexpression of the APP domain coding for a Kunitz type serine protease inhibitor might explain this. 3) PSEN1 mutations disrupt lysosomal function due to reduced proteolytic activity. They also trap cobalamin (B12 ) within lysosomes, leading to intracellular deficiency of the vitamin. In summary, APP and PSEN1 mutations both confer a risk for reduced protease activity and B12 bio-availability. Comparably, sporadic AD features a constellation of increased protease inhibition and B-vitamin deficiencies, the central part of which is believed to be B12 . These concordant observations in three disparate AD etiologies suggest a common neuropathogenic pathway. This hypothesis is evaluable in laboratory and clinical trials. Show more

Keywords: Alzheimer’s disease, amyloid, proteolysis, vitamin B12 deficiency

DOI: 10.3233/JAD-181007

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 483-488, 2019

Authors: Becker, Robert E. | Greig, Nigel H.

Article Type: Research Article

Abstract: Neuronal death is the final step in the progression of preclinical Alzheimer’s disease (AD) pathologies into clinically evident AD and its profound dementia. As such, a drug candidate proposed to be effective in AD must successfully prevent neuronal losses. The lack of preclinical demonstrated abilities to prevent neuronal programmed cell death may explain the recent failure of 300–400 AD drug candidates, identify a flaw in the Amyloid Hypothesis, and a risk for subsequent drug candidate interventions against AD. We propose that investigators use either animal models or small early translational clinical trials to test for AD drug candidates’ efficacy against …clinically critical features of the disease, such as prevention of neuronal death. Such stringent testing would more effectively shelter AD patients from being recruited into clinical trials that are destined to fail in Phase II or III. Show more

Keywords: Alzheimer’s disease, amyloid hypothesis, animal models, clinical trial failures, neuronal death, programmed cell death, traumatic brain injury

DOI: 10.3233/JAD-181300

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 489-492, 2019

Authors: Paroni, Giulia | Bisceglia, Paola | Seripa, Davide

Article Type: Research Article

Abstract: The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer’s disease (IAD). However, despite the neuropathological overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, we suggested that amyloid-β (Aβ) peptides production and AP formation is a physiological aging process resulting …from a systemic age-related decrease in the efficiency of the proteins catabolism/clearance machinery. In this pathogenetic model Aβ peptides act as neurotoxic molecules, but only above a critical concentration [Aβ]c . A threshold mechanism triggers IAD/NIAD onset only when [Aβ]≥[Aβ]c . In this process, APOE modifies [Aβ]c threshold in an isoform-specific way. Consequently, all factors influencing Aβ anabolism, such as amyloid beta precursor protein (APP ), presenilin 1 (PSEN1 ), and presenilin 2 (PSEN2 ) gene mutations, and/or Aβ catabolism/clearance could contribute to exceed the threshold [Aβ]c , being characteristic of each individual. In this model, AP formation does not depend on [Aβ]c . The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be observed in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD. Show more

Keywords: Alpha-secretase, Alzheimer’s disease, amyloid hypothesis, amyloid plaque, amyloid-alpha peptide, amyloid-beta peptide, amyloid precursor protein, apolipoprotein E, beta-secretase, inherited Alzheimer’s disease, non-inherited Alzheimer’s disease

DOI: 10.3233/JAD-180802

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 493-510, 2019

Authors: Umstead, Andrew | Vega, Irving E.

Article Type: Short Communication

Abstract: The accumulation of tau protein aggregates is a pathological hallmark in Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the identity of the toxic tau conformation that propagates and induces neurodegeneration is still unknown. Anti-tau antibodies are a common tool used to differentiate between normal and pathological-associated tau forms or as passive immunotherapy in the quest to interfere with tau-mediated neurodegeneration. Here, we show that Tau13, a tau N-terminal antibody, preferentially enriches high molecular weight tau species produced in a tauopathy mouse model and AD. The data suggest that Tau13 has higher affinity to specific tau conformation presence in higher …molecular weight tau species. Show more

Keywords: Aggregation, Alzheimer’s disease, tau, tauopathy

DOI: 10.3233/JAD-181187

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 511-516, 2019

Authors: Rawlings, Andreea M. | Sharrett, A. Richey | Mosley, Thomas H. | Wong, Dean F. | Knopman, David S. | Gottesman, Rebecca F.

Article Type: Short Communication

Abstract: We examined associations between cognitive reserve and late-life amyloid-β deposition using florbetapir positron emission tomography (PET). We used data from the Atherosclerosis Risk in Communities (ARIC) and ARIC-PET Study. 330 dementia-free participants underwent PET scans. Mean global cortical standardized uptake value ratio (SUVR) >1.2 was defined as elevated. Midlife cognition was significantly associated with late-life cognition, but not with late-life elevated SUVR; education was not associated with late-life SUVR, but was strongly associated with late-life cognition. Cognitive reserve may reduce dementia risk by mitigating the impact of Alzheimer’s disease pathology on the clinical expression of dementia, rather than by altering …its pathogenesis. Show more

Keywords: Amyloid, cohort study, education, epidemiology, human, PET imaging

DOI: 10.3233/JAD-180785

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 517-521, 2019

Authors: Marcum, Zachary A. | Hohl, Sarah D. | Gray, Shelly L. | Barthold, Doug | Crane, Paul K. | Larson, Eric B.

Article Type: Short Communication

Abstract: We administered a mixed-method survey to 1,661 patients in a large health system to assess preferences toward antihypertensive use for dementia prevention. If a specific antihypertensive medication was shown to prevent or delay dementia, the vast majority (>90%) of respondents currently taking an antihypertensive reported that they would be willing to take that specific antihypertensive starting as early as mid-life. Concerns reported were potential side effects, lack of evidence of effectiveness, blood pressure being normal or low, and medication cost. Analysis of free-text responses revealed themes of concerns regarding evidence of effectiveness and health priorities.

Keywords: Alzheimer’s disease, antihypertensive agents, dementia, primary prevention

DOI: 10.3233/JAD-181080

Citation: Journal of Alzheimer's Disease, vol. 68, no. 2, pp. 523-529, 2019