Journal of Alzheimer's Disease Reports - Volume 2, issue 1

Authors: Ralph, Stephen J. | Espinet, Anthony J.

Article Type: Research Article

Abstract: It is almost ten years since the Banerjee 2009 report established that inappropriate prescribing of antipsychotics in the elderly was occurring in the UK and such patients had an 85% increased risk of adverse events and greater mortality. This report was a critical analysis addressing the outcomes of treatment practices for dementia in UK patients and globally, aimed at reducing prescribing of antipsychotic drugs for dementia. Since 2009, many significant studies worldwide (including several more recent large retrospective studies) provide more extensive longitudinal data for the adverse impacts of antipsychotic drugs in dementia. We have used the data in these …studies including from over 380,000 dementia patients, with 85,069 prescribed antipsychotic agents as well as from 359,235 non-dementia antipsychotic drug users to provide an up-dated meta-analysis. This is the first meta-analysis to include evidence from general mental health studies showing that antipsychotic drugs precipitate excessive mortality across the spectrum. Prescribing of antipsychotic drugs for dementia or for other mental health care should be avoided and alternative means sought for handling behavioral disorders of such patients. Show more

Keywords: Antipsychotic agents, causes of death, clinical governance, dementia, deprescriptions, excess mortality, health care reform, meta-analysis, psychotropic drugs, review, risk

DOI: 10.3233/ADR-170042

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 1-26, 2018

Authors: Dolfe, Lisa | Tambaro, Simone | Tigro, Helene | Del Campo, Marta | Hoozemans, Jeroen J.M. | Wiehager, Birgitta | Graff, Caroline | Winblad, Bengt | Ankarcrona, Maria | Kaldmäe, Margit | Teunissen, Charlotte E. | Rönnbäck, Annica | Johansson, Jan | Presto, Jenny

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common form of dementia and there is no successful treatment available. Evidence suggests that fibril formation of the amyloid β-peptide (Aβ) is a major underlying cause of AD, and treatment strategies that reduce the toxic effects of Aβ amyloid are sought for. The BRICHOS domain is found in several proteins, including Bri2 (also called integral membrane protein 2B (ITM2B)), mutants of which are associated with amyloid and neurodegeneration, and Bri3 (ITM2C). We have used mouse hippocampal neurons and brain tissues from mice and humans and show Bri3 deposits dispersed on AD plaques. In contrast …to what has been shown for Bri2, Bri3 immunoreactivity is decreased in AD brain homogenates compared to controls. Both Bri2 and Bri3 BRICHOS domains interact with Aβ40 and Aβ42 present in neurons and reduce Aβ42 amyloid fibril formation in vitro , but Bri3 BRICHOS is less efficient. These results indicate that Bri2 and Bri3 BRICHOS have different roles in relation to Aβ aggregation. Show more

Keywords: Alzheimer’s disease, amyloid, amyloid β-peptide, BRICHOS, chaperone

DOI: 10.3233/ADR-170051

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 27-39, 2018

Authors: Lee, Wonseok | Lee, Sang Won | Lee, Gyudo | Yoon, Dae Sung

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptides can be aggregated into β-sheet rich fibrils or plaques and deposited on the extracellular matrix of brain tissues, which is a hallmark of Alzheimer’s disease. Several drug candidates have been designed to retard the progression of the neurodegenerative disorder or to eliminate toxic Aβ aggregates. Recently, 4-(2-Hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS) has emerged as a promising drug candidates for elimination of toxic Aβ aggregates. However, the effect of EPPS on the degradation of Aβ aggregates such as fibrils has not yet been fully elucidated. In this article, we investigate the EPPS-driven degradative behavior of Aβ aggregates at the …molecular level by using high-resolution atomic force microscopy. We synthesized Aβ fibrils and observed degradation of fibrils following treatment with various concentrations (1–50 mM) of EPPS for various time periods. We found that degradation of Aβ fibrils by EPPS increased as a function of concentration and treatment duration. Intriguingly, we also found regeneration of Aβ aggregates with larger sizes than original aggregates at high concentrations (10 and 50 mM) of EPPS. This might be attributed to a shorter lag phase that facilitates reformation of Aβ aggregates in the absence of clearance system. Show more

Keywords: Aβ aggregates, Alzheimer’s disease, amyloid-β, atomic force microscopy, 4-(2-Hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS), fibril degradation

DOI: 10.3233/ADR-170024

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 41-49, 2018

Authors: Villalba, Noel Lorenzo | Laboulbene, Stephane | Merzouki, Tawoufik | Méndez Bailon, Manuel | Kechida, Melek | Sigonney, Vanessa | Tabue Teguo, Maturin

Article Type: Research Article

Abstract: A 66-year-old woman presented with slowly progressive cognitive decline. MRI showed bi-frontotemporal atrophy, but the 14.3.3 protein was not present in cerebrospinal fluid. Electroencephalogram was irrelevant. Interview with relatives led doctors to search for a genetic cause and confirmed the diagnosis of Gerstmann–Sträussler–Scheinker syndrome.

Keywords: Cognitive decline, Gerstmann–Sträussler–Scheinker syndrome, prion protein

DOI: 10.3233/ADR-170050

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 51-53, 2018

Authors: Cruz-Aguilar, Manuel Alejandro | Ramírez-Salado, Ignacio | Guevara, Miguel Angel | Hernández-González, Marisela | Benitez-King, Gloria

Article Type: Research Article

Abstract: There is evidence demonstrating that 5-mg of fast-release melatonin significantly reduces nocturnal sleep onset in patients with mild-to-moderate Alzheimer’s disease (AD). However, the physiological mechanism that could promote sleep installation by melatonin in patients with AD is still poorly understood. The present pilot study was designed to analyze the effects of melatonin on cortical activity during the sleep onset period (SOP) in eight mild-to-moderate AD patients treated with 5-mg of fast-release melatonin. Electroencephalographic recordings were obtained from C3-A1, C4-A2, F7-T3, F8-T4, F3-F4, and O1-O2. The relative power (RP), interhemispheric, intrahemispheric, and fronto-posterior correlations of six electroencephalographic bands were calculated and …compared between two conditions: placebo and melatonin. Results show that at F7-T3, F3-F4, and C3-A1, melatonin induced an increase of the RP of the delta band. Likewise, in F7-T3, melatonin induced a decrease of the RP in the alpha1 band. Similarly, results show a lower interhemispheric correlation between the F7-T3 and F8-T4 derivations in the alpha1 band compared to the placebo condition. We conclude that the short sleep onset related to melatonin intake in AD patients was associated with a lower RP of the alpha1, a higher RP of the delta band (mainly in the left hemisphere) and a decreased interhemispheric EEG coupling in the alpha1 band. The possible role of the GABAergic neurotransmission as well as of the cascade of neurochemical events that melatonin triggers on sleep onset are discussed. Show more

Keywords: Alzheimer’s disease, EEG correlation, electroencephalography, melatonin, relative power, sleep onset, suprachiasmatic nucleus

DOI: 10.3233/ADR-170019

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 55-65, 2018

Authors: de Bellis, Alberto | de Bellis, Massimo | Aloe, Luigi

Article Type: Research Article

Abstract: Background: Nerve growth factor (NGF) is known for playing a critical protective role on a number of brain neurons in mammals, including humans. NGF can be delivered to the CNS via nasal route and has a neuroprotective action in case of neurodegenerative diseases. Objective: The aim of this study is to investigate for the first time whether purified NGF can play a neuroprotective role on human brain neurons affected by neurodegenerative diseases when administered via nasal route. Methods: Two female patients, both affected by frontotemporal dementia (FTD) associated with corticobasal syndrome (CBS) at different stages of …disease progression, received a daily intranasal NGF spray for one year. Clinical/neurological aspects were observed over time. The follow-up study was performed using 18 FDG PET. Results: This case study seems to demonstrate that IN-NGF slows down the common decline caused by FTD/CBS. Conclusions: These findings suggest the potential neuroprotective role of IN-NGF administered in case of neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, intranasal delivery, nerve growth factor, neurodegenerative diseases, neuroprotection, non-invasive

DOI: 10.3233/ADR-180055

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 67-77, 2018

Authors: Mazi, Aise Rumeysa | Arzuman, Aysegul Sumeyye | Gurel, Busra | Sahin, Betul | Tuzuner, Mete Bora | Ozansoy, Mehmet | Baykal, Ahmet Tarik

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive disorder characterized by a variety of molecular pathologies causing cortical dementia with a prominent memory deficit. Formation of the pathology, which begins decades before the diagnosis of the disease, is highly correlated with the clinical symptoms. Several proteomics studies were performed using animal models to monitor the alterations of the brain tissue proteome at different stages of AD. However, proteome changes in the brain regions of newborn transgenic mouse model have not been investigated yet. To this end, we analyzed protein expression alterations in cortex, hippocampus and cerebellum of transgenic mice carrying five familial …AD mutations (5XFAD) at neonatal day-1. Our results indicate a remarkable difference in protein expression profile of newborn 5XFAD brain with region specific variations. Additionally, the proteins, which show similar expression alteration pattern in postmortem human AD brains, were determined. Bioinformatics analysis showed that the molecular alterations were mostly related to the cell morphology, cellular assembly and organization, and neuroinflammation. Moreover, morphological analysis revealed that there is an increase in neurite number of 5XFAD mouse neurons in vitro . We suggest that, molecular alterations in the AD brain exist even at birth, and perhaps the disease is silenced until older ages when the brain becomes vulnerable. Show more

Keywords: Alzheimer’s disease, cerebellum, cortex, hippocampus, neonatal neurodegeneration, proteomics

DOI: 10.3233/ADR-170049

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 79-91, 2018

Authors: Younan, Ben

Article Type: Research Article

Abstract: Older adults engaging in regular physical activity can help create a buffer toward cognitive decline. The main aim of this study was to assess the effects of physical activity and cognitive functioning on a sample of young-old and old-old physically active adults and young-old and old-old sedentary adults. Cognitive functioning was examined using the digit span test, Wisconsin card sorting task. The National Task Group-Early Detection Screen for Dementia measure was used explore the relationship between scores and physical activity and sedentary adults. Findings from the study showed partial support for physical activity has a positive relationship with cognitive functioning. …The results found Young-old adults did better on the DST than all other groups regardless of being sedentary or physically active. Young-old physically active adults, however, did better on the DST latency measure than sedentary adults while old-old physically active adults did worse on the DST latency measure compared with old-old sedentary adults. The results also found that Physically active adults had a better score on the NTG-EDSD measure compared to the sedentary adults. Findings showed no significant differences for the WCST. Future research exploring the relationship between physical activity and cognitive functioning should do so by having more control over the extraneous variables. Show more

Keywords: Alzheimer’s disease, cognitive decline, old-old, older adults, physically active, young-old

DOI: 10.3233/ADR-180053

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 93-101, 2018

Authors: Picher, Ángel J. | Hernández, Félix | Budeus, Bettina | Soriano, Eduardo | Avila, Jesús

Article Type: Review Article

Abstract: Genetic factors may be involved in the onset of neurodegenerative diseases like Alzheimer’s disease. In the case of the familial type, the disease is due to an inherited mutation at specific sites in three genes. Also, there are some genetic risk factors that facilitate the development of sporadic Alzheimer’s disease. All of these genetic analyses were performed using blood samples as a source of DNA. However, the presence of somatic mutations in the brain can be identified only using brain samples. In this review, we comment on a method that correctly identifies single nucleotide variations in the human brain and …that can be used to validate high-through sequencing techniques. This method involves selective enrichment of the DNA population bearing the nucleotide variations, thereby facilitating posterior validation of the data by Sanger’s sequencing. Show more

Keywords: Brain somatic mutations, DNA sequencing, neurodegeneration

DOI: 10.3233/ADR-170039

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 103-109, 2018

Authors: Lehrer, Steven | Rheinstein, Peter H.

Article Type: Research Article

Abstract: Background: Studies of Alzheimer’s disease suggest that neuroinflammation or deranged brain wound healing may be a cause of some cases. But a placebo controlled study showed no effect at all on Alzheimer’s disease of low dose oral prednisone after one year. Introducing the steroid directly into the hippocampus and rhinencephalon via the nose, as happens in hay fever subjects, could be more effective. Objective: In the present study, we analyzed FDA MedWatch data for intranasal fluticasone propionate (Flonase) to determine the frequency of Alzheimer’s disease as an adverse event reported after use of the medication. Methods: …Machine-readable data from MedWatch, including adverse drug reaction reports from manufacturers, are part of a public database. We used the online tool eHealthMe to query the database. Results: By September 20, 2017, 35,221 people reported side effects to MedWatch after taking Flonase. Among them, 9 people (0.03%) had Dementia Alzheimer’s type. By October 3, 2017, 185,636 people reported side effects after taking Lipitor. Among them, 243 people (0.13%) had Dementia Alzheimer’s type. The lower incidence of Alzheimer’s dementia in the Flonase group compared to the Lipitor group was significant (p  <  0.001, Fisher exact test, two tailed). Conclusion: Long term use of oral non-steroidal anti-inflammatory drugs (NSAIDs) is linked with reduced risk of developing Alzheimer’s disease. Data from MedWatch suggest that fluticasone propionate administered intranasally might have a similar preventive effect to ibuprofen. Perhaps combining ibuprofen and Flonase could be therapeutic. Further studies would be desirable. Show more

Keywords: Alzheimer’s disease, brain, dementia, intranasal, steroids

DOI: 10.3233/ADR-170033

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 111-115, 2018

Authors: Sarikaya, Sevda | Sarikaya, Basar

Article Type: Research Article

Abstract: Although inappropriate sexual behavior in dementia is not common, it can be extremely troublesome for healthcare professionals and caregivers as well as patients themselves. There is paucity of data in the literature for the management of these behaviors, but the limited available data suggest efficiency of some commonly used treatment modalities. Herein, we present a 74-year old Alzheimer’s disease (AD) patient, known to be heterosexual throughout her past life, presenting with a recent display of same-sex inappropriate sexual behavior six years after the initial diagnosis of her disease. This new clinical picture of hypersexuality responded well to aripiprazole and her …symptoms gradually diminished and eventually disappeared after onset of medication. This report also constitutes the first reported case of an AD patient in the published literature presenting with hypersexuality of shifted sexual orientation during the course of the disease. Show more

Keywords: Alzheimer’s disease, antipsychotic agents, aripiprazole, dementia, frontotemporal dementia, sexuality

DOI: 10.3233/ADR-170041

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 117-121, 2018

Authors: Lehrer, Steven | Rheinstein, Peter H. | Rosenzweig, Kenneth E.

Article Type: Research Article

Abstract: Background: Two large studies suggest that risk is not increased. But other studies have found increased risk of Alzheimer’s disease and impaired cognition. Objective: To determine whether androgen deprivation therapy increases the risk of impaired cognition or Alzheimer’s disease in men with prostate cancer. Methods: We used data from MedWatch, the Food and Drug Administration (FDA) Safety Information and Adverse Event Reporting Program. Machine-readable data from MedWatch, including adverse drug reaction reports from manufacturers, are part of a public database. We used the online tool OpenVigil 2.1 to query the database. OpenVigil calculates proportional reporting ratios …(PRRs) from adverse drug reaction reports to determine whether the combination of drug and adverse event are related. For example, PRR = 2 indicates that the adverse reaction is two times more frequent in users of the drug than in the general population. Results: We analyzed adverse event reporting data for these androgen-deprivation drugs: The luteinizing hormone releasing hormone (LHRH) agonists leuprolide, goserelin triptorelin, histrelin; the anti-androgens flutamide, nilutamide, enzalutamide, and bicalutamide; the LHRH antagonist degarelix; the CYP17 inhibitor abiraterone; the anti-fungal ketoconazole, which is also an anti-androgen administered to men with advanced prostate cancer. Conclusion: Our analysis of FDA MedWatch adverse event data reports does not support the idea that androgen deprivation therapy per se is associated with Alzheimer’s disease or cognitive dysfunction. Perhaps the prostate cancer itself, or the stress it imposes on the man who has it, may be detrimental to mood and intellect, increasing susceptibility to Alzheimer’s disease and cognitive disorder. Show more

Keywords: Alzheimer’s disease, androgen deprivation, cognitive, MedWatch, OpenVigil

DOI: 10.3233/ADR-180052

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 123-127, 2018

Authors: Bennett, James P. | Keeney, Paula M.

Article Type: Research Article

Abstract: Background: Neuropathological changes of Alzheimer’s disease (AD) and Parkinson’s disease (PD) can coexist in the same sample, suggesting possible common degenerative mechanisms. Objective: The objective of this study was to use RNA-sequencing to compare gene expression in AD and PD vulnerable brain regions and search for co-expressed genes. Methods: Total RNA was isolated from AD/CTL frontal cortex and PD/CTL ventral midbrain. Sequencing libraries were prepared, multiplex paired-end RNA sequencing was carried out, and bioinformatics analyses of gene expression used both publicly available (tophat2/bowtie2/Cufflinks) and commercial (Qlucore Omics Explorer) algorithms. Results: Both AD (frontal cortex, …n = 10) and PD (ventral midbrain, n = 14) samples showed extensive heterogeneity of gene expression. Hierarchical clustering of heatmaps revealed two gene populations (AD, 376 genes; PD, 351 genes) that separated AD or PD from control samples at false-discovery rates (q) of <5% and fold changes of at least 1.3 (AD) or 1.5 (PD). 10,124 genes were co-expressed in our AD and PD samples. A very small group of these genes (n = 23) showed both low variances (<150; variance = standard deviation squared) and reduced expressions (>1.5-fold under-expression) in both AD and PD. Ingenuity Pathways Analyses (IPA, Qiagen) revealed loss of NAD biosynthesis and salvage as the major canonical pathway significantly altered in both AD and PD. Conclusions: AD and PD in vulnerable brain regions appear to arise from and result in independent molecular genetic abnormalities, but we identified several under-expressed genes with potential to treat both diseases. NAD supplementation shows particular promise. Show more

Keywords: Alzheimer’s disease, gene expression, Parkinson’s disease, RNA-sequencing

DOI: 10.3233/ADR-180072

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 129-137, 2018

Authors: Parady, Bodo

Article Type: Review Article

Abstract: Various fungi and bacteria can colonize in the brain and produce physical alterations seen in Alzheimer’s disease (AD). Environmental and genetic factors affect the occurrence of fungal colonization, and how fungi can grow, enter the brain, and interact with the innate immune system. The essence of AD development is the defeat of the innate immune system, whether through vulnerable patient health status or treatment that suppresses inflammation by suppressing the innate immune system. External and mechanical factors that lead to inflammation are a door for pathogenic opportunity. Current research associates the presence of fungi in the etiology of AD and …is shown in cerebral tissue at autopsy. From the time of the discovery of AD, much speculation exists for an infective cause. Identifying any AD disease organism is obscured by processes that can take place over years. Amyloid protein deposits are generally considered to be evidence of an intrinsic response to stress or imbalance, but instead amyloid may be evidence of the innate immune response which exists to destroy fungal colonization through structural interference and cytotoxicity. Fungi can remain ensconced for a long time in niches or inside cells, and it is the harboring of fungi that leads to repeated reinfection and slow wider colonization that eventually leads to a grave outcome. Although many fungi and bacteria are associated with AD affected tissues, discussion here focuses on Candida albicans as the archetype of human fungal pathology because of its wide proliferation as a commensal fungus, extensive published research, numerous fungal morphologies, and majority proliferation in AD tissues. Show more

Keywords: Alzheimer’s disease, APOE, Candida albicans, fungi, innate immune system, LCAT

DOI: 10.3233/ADR-180073

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 139-152, 2018

Authors: Beishon, Lucy C. | Panerai, Ronney B. | Robinson, Thompson G. | Subramaniam, Hari | Haunton, Victoria J.

Article Type: Research Article

Abstract: Background: The incidence of dementia is predicted to rise rapidly, but sensitive diagnostic tests remain elusive. Changes in cerebral blood flow velocity (CBFv) can occur at an early stage of cognitive decline, and can be measured by transcranial Doppler ultrasonography (TCD). Objective: The aim of this study was to characterize the CBFv changes that occur in healthy older adults (HC), mild cognitive impairment (MCI), and Alzheimer’s disease (AD), in response to a language task from the Addenbrooke’s cognitive examination (ACE-III). Methods: Participants underwent bilateral TCD, continuous heart rate (ECG), end-tidal CO2 (capnography, ETCO2 ), …and beat-to-beat blood pressure (Finometer, MAP), monitoring, during a 5-minute baseline, followed by cognitive tasks from the ACE-III. Data are presented for a language task (repeating words and phrases aloud), as peak percentage change in CBFv, HR, MAP, and ETCO2 from a normalized baseline. Results: 30 participants (mean age 73.2 years, 20% female) were recruited; HC (n  = 10), MCI (n  = 10), AD (n  = 10). Language scores did not differ between groups (p  = 0.16). Peak percentage change in CBFv differed between groups with the language task (HC: 15.9 (7.5)%, MCI: 6.7 (4.5)%, AD: 0.1 (7.1)%; p  < 0.005). However, changes in MAP (HC: 7.9 (4.6)%, MCI: –0.1 (0.9)%, AD: 0.9 (4.4)%; p  < 0.005), HR (HC: 8.8 (8.2)%, MCI: 0.7 (4.3)%, AD: –0.5 (5.6)%; p  = 0.005), and ETCO2 (HC: –0.9 (3.2)%, MCI: 0.9 (3.2)%, AD: –5.2 (5.7)%; p  = 0.006), also occurred. Conclusions: TCD measured CBFv changes to a language task from the ACE-III was feasible in a cognitively impaired population, further work is required in a larger population. Show more

Keywords: Alzheimer’s disease, cerebral blood flow, dementia imaging, mild cognitive impairment

DOI: 10.3233/ADR-180068

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 153-164, 2018

Authors: Pomara, Nunzio | Bruno, Davide

Article Type: Article Commentary

Abstract: In spite of compelling evidence linking amyloid-β (Aβ) disturbances to the pathophysiology of Alzheimer’s disease (AD), Aβ-based treatments have consistently failed to produce any beneficial effects both in mild cognitive impairment (MCI) and AD, even with successful reductions of toxic aggregated and soluble Aβ species. Before abandoning both the hypothesis and approach, there is a need to examine some overlooked factors that may have contributed to the lack of efficacy, such as the potential drug-induced increases in neuronal hyperactivity leading to adverse cognitive effects. In particular, we posit that selective cholinergic and noradrenergic pathways will be especially vulnerable to this …adverse effect. If confirmed, this idea could help identify a potentially preventable and treatable obstacle for enhancing the efficacy of therapeutic agents in MCI and AD. Show more

Keywords: Alzheimer’s disease, amyloid-β-based treatments, cognitive dysfunction, mild cognitive impairment, neuronal hyperactivity

DOI: 10.3233/ADR-180077

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 165-167, 2018

Authors: Dewji, Nazneen N. | Azar, Marc R. | Hanson, Leah R. | Frey II, William H. | Morimoto, Bruce H. | Johnson, David

Article Type: Research Article

Abstract: Strategies to achieve a therapy for Alzheimer’s disease (AD) aimed at reducing the effects of amyloid-β (Aβ) have largely involved inhibiting or modifying the activities of the β- or γ -secretases or by the use of monoclonal antibodies (MAb). We previously offered the potential for a new, early and effective approach for the treatment of AD by a strategy that does not target the secretases. We showed that a family of peptides containing the DEEEDEEL sequence and another independent peptide, all derived from the amino terminus of PS-1, are each capable of markedly reducing the production of Aβ in vitro …and in mThy1-hAPP transgenic mice. These peptides gave a strong and specific binding with the ectodomain of amyloid-β protein precursor (AβPP) and did not affect the catalytic activities of β- or γ -secretase, or the level of AβPP. Critical to the development of any therapeutic for AD is the requirement that it is stable and can be delivered to the brain. We report here data on the metabolic stability and delivery to the rat brain of our lead candidate P8 by intravenous (IV), intranasal (IN), and subcutaneous (SC) administration. Pharmacokinetics (PK) of P8 in rat plasma and CSF following a single dose of P8 demonstrate that SC administration gives better absorption compared to IN and is the delivery method of choice for the further development of P8 as a clinical candidate. Show more

Keywords: Alzheimer’s disease, amyloid-β, Aβ, amyloid-β protein precursor, presenilin, peptide drug, pharmacokinetic

DOI: 10.3233/ADR-180078

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 169-179, 2018

Authors: Galzitskaya, Oxana V. | Surin, Alexey K. | Glyakina, Anna V. | Rogachevsky, Vadim V. | Selivanova, Olga M.

Article Type: Research Article

Abstract: Aβ40 and Aβ42 peptides are believed to be associated with Alzheimer’s disease. Aggregates (plaques) of Aβ fibrils are found in the brains of humans affected with this disease. The mechanism of formation of Aβ fibrils has not been studied completely, which hinders the development of a correct strategy for therapeutic prevention of this neurodegenerative disorder. It has been found that the most toxic samples upon generation of fibrils are different oligomeric formations. Based on different research methods used for studying amyloidogenesis of Aβ40 and Aβ42 peptides and its amyloidogenic fragments, we have proposed a new mechanism …of formation of amyloid fibrils. In accord with this mechanism, the main building unit for fibril generation is a ring-like oligomer. Association of ring-like oligomers results in the formation of fibrils of different morphologies. Our model implies that to prevent development of Alzheimer’s disease a therapeutic intervention is required at the earliest stages of amyloidogenesis—at the stage of formation of ring-like oligomers. Therefore, the possibility of a personified approach for prevention not only of Alzheimer’s disease development but also of other neurodegenerative diseases associated with the formation of fibrils is argued. Show more

Keywords: Amyloidogenic regions, fibril, isoform, nucleus, oligomer, polymorphism

DOI: 10.3233/ADR-180063

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 181-199, 2018

Authors: Shea, Thomas B. | Remington, Ruth

Article Type: Research Article

Abstract: Executive function was assayed following a nutritional supplementation in healthy adults using the Trail Making Test. Comparison with published normative scores demonstrated that cohorts from 35–74 years of age displayed similar relative improvement compared to their own baseline performance. These findings support early, pro-active lifestyle modifications to maintain cognitive performance during aging and further demonstrate the persistence of cognitive reserve in healthy older adults.

Keywords: Aging, cognitive performance, executive function, lifestyle modification, nutritional supplementation

DOI: 10.3233/ADR-180056

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 201-205, 2018

Authors: Bature, Fidelia | Guinn, Barbara | Pang, Dong | The Luton, Dunstable, Milton Keynes General Practise consortium | Pappas, Yannis

Article Type: Research Article

Abstract: We set out to investigate the insights general practitioners (GPs) have into the early signs and symptoms of Alzheimer’s disease (AD), factors that may be responsible for the late diagnosis, as well as their recommendations for early diagnosis of AD. This was a semi-structured, qualitative and audio-recorded interview of seven GPs, from five GP surgeries in Milton Keynes and Luton, using the framework analysis. GPs reported challenges with the current patient’s consultation time, a lack of continuity of care, inadequate training, limited support for patients after diagnosis, and poor treatment of the UK’s aging population. The study highlights important changes …that would facilitate the earlier diagnosis of AD. Show more

Keywords: Alzheimer’s disease, general practice, GP interviews, qualitative study, semi-structured

DOI: 10.3233/ADR-180064

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 207-212, 2018

Authors: Lehrer, Steven

Article Type: Short Communication

Abstract: Background: Cancer mortality and Alzheimer’s disease (AD) mortality increase with age, but some studies have shown an inverse relationship of the two diseases, that is, older persons with cancer have a reduced risk of AD and vice versa. However, other analyses suggest that AD and brain tumor might be positively correlated. Objective: In the current study, we wished to determine the relationship of AD mortality to malignant brain tumor mortality in US states and counties. Methods: Data and maps of malignant brain tumor mortality and Alzheimer’s disease mortality (1999–2016) are from the CDC …Wonder tool (https://wonder.cdc.gov/cmf-icd10.html). Data on malignant brain tumor types and their frequencies are from the Surveillance, Epidemiology, and End Results Program (SEER, https://seer.cancer.gov). Data on the genetics of lower grade glioma are from the TCGA Lower Grade Glioma (LGG) dataset in TCGA (The Cancer Genome Atlas). Results: SEER data indicate that astrocytomas make up 58.2% of malignant brain tumors in patients 65 and older; glioblastoma and anaplastic astrocytoma make up 41.6%. We found a significant positive correlation between AD mortality rate and malignant brain tumor mortality rate 1999–2016 in persons age 65 and older in A) 1,101 US counties, p  <  0.001 and B) 50 US states, p  <  0.001. Conclusion: Adult malignant brain tumors may share some environmental risks with AD. Malignant brain tumors and AD also have some genes in common: TREM2, SPI1, CD33, and INPP5D. The interaction of environment and genetics is complex and overlaps in malignant brain tumors and AD. Show more

Keywords: The cancer genome atlas, glioma

DOI: 10.3233/ADR-180084

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 213-218, 2018

Authors: Singhrao, Sim K. | Olsen, Ingar

Article Type: Article Commentary

Abstract: Our research into Alzheimer’s disease (AD) focuses on the oral cavity and the brain, from which key evaluations of prospective and retrospective population-based data have shown that chronic periodontal disease existing for ten-years or over doubles the risk for the sporadic form of AD. Furthermore, Porphyromonas gingivalis (P. gingivalis ) mono-infections in established periodontal lesions, or introducing its lipopolysachharide (LPS), as demonstrated in in vivo studies, show hallmark pathology inclusive of extracellular amyloid plaques and phospho-tau bound neurofibrillary tangles with AD-like phenotype. Other studies have shown that if periodontitis remains untreated in human AD patients, cognitive decline ensues. …This is a bi-directional relationship meaning that the converse is also true; treating periodontal disease in AD patients improves memory. Bacterial cultures and established oral biofilms generate vast numbers of microvesicles and P. gingivalis outer membrane vesicles encase key virulence factors (LPS, gingipains, capsule, fimbriae) as though they are complete destructive “microbullets” when shed in the host. This provides P. gingivalis additional arsenal to manipulate its entry into disparate organs, hijack phagocytosis, destroy tissues, and affect complement related genes while transducing the onset of proinflammatory signaling cascades. The resulting inflammatory mediators may be the cause of disease defining lesions and cognitive decline typical of clinical AD. Show more

Keywords: Alzheimer’s disease, microbullets, outer membrane vesicles, P. gingivalis , periodontitis

DOI: 10.3233/ADR-180080

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 219-228, 2018

Authors: Guadagni, Veronica | Clark, Cameron M. | Tyndall, Amanda | Raneri, Jill K. | Parboosingh, Jillian S. | Hogan, David B. | Hanly, Patrick J. | Poulin, Marc J.

Article Type: Research Article

Abstract: Background: Sleep disturbances have been shown to be associated with the presence of the apolipoprotein (APOE ) ɛ 4 allele, the well-known genetic risk factor for late-onset sporadic Alzheimer’s disease (AD). Objective: This study quantifies the effects of a six-month aerobic exercise intervention on objective and subjective sleep quality in middle-aged to older individuals including those at increased genetic risk for late-onset sporadic Alzheimer’s disease (AD), who carry the apolipoprotein (APOE ) ɛ 4 risk allele. Methods: 199 sedentary men and women without significant cognitive impairments were enrolled in the Brain in Motion …study, a quasi-experimental single group pre-test/post-test study with no control group. Participants completed a six-month aerobic exercise intervention and consented to genetic testing. Genotyping of APOE confirmed that 54 individuals were carriers of the ɛ 4 allele. Participants’ subjective quality of sleep was assessed with the Pittsburgh Sleep Quality Index (PSQI) pre- and post-intervention. A convenience sample of participants (n  = 29, APOE ɛ 4+ = 7) consented to undergo two nights of in-home polysomnography (PSG) pre- and post intervention. Sleep architecture and respiratory variables were assessed. Results: The six-month aerobic exercise intervention significantly improved participants’ total PSQI score, sleep efficiency, and sleep latency in the full sample (n  = 199). PSG results showed that total sleep time and sleep onset latency significantly improved over the course of the exercise intervention only in individuals who carried the APOE ɛ 4 allele. These results are, however, exploratory and need to be carefully interpreted due to the rather small number of APOE ɛ 4+ in the PSG subgroup. Conclusions: The six-month aerobic exercise intervention significantly improved participants’ sleep quality with beneficial effects on PSG shown in individuals at increased genetic risk for late-onset sporadic AD. Show more

Keywords: Alzheimer’s disease, APOE ɛ4, dementia, polysomnography

DOI: 10.3233/ADR-180079

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 229-238, 2018

Authors: Witter, Steffi | Witter, Raiker | Vilu, Raivo | Samoson, Ago

Article Type: Research Article

Abstract: Plaque formation due to amyloid-β oligomerization and fibrillation is a key issue for its deposition in the brains of dementia and Alzheimer’s disease patients. Related drugs preventing this peptide fibril accumulation bear the potential of considerable medical and social value. In this study, we performed in vitro fibrillation inhibition tests with eight different medical plant extracts and nutraceuticals using fluorescence spectroscopy. Successful inhibition of the following plant extracts and nutraceuticals were obtained: Withania somnifera , Centella asiatica , Bacopa monnieri, and Convolvulus pluricaulis , providing new drug candidates for the prevention and treatment of Alzheimer’s disease.

Keywords: Alzheimer’s disease, amyloid-β, Bacopa monnieri, Centella asiatica, Convolvulus pluricaulis, medical plants, nutraceutical, Withania somnifera

DOI: 10.3233/ADR-180066

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 239-252, 2018