Journal of Alzheimer's Disease Reports - Volume 6, issue 1

Authors: Carotenuto, Anna | Fasanaro, Angiola Maria | Manzo, Valentino | Amenta, Francesco | Traini, Enea

Article Type: Research Article

Abstract: Background: Depressive symptoms are common in Alzheimer’s disease (AD) patients and are associated with an increased functional decline. Selective serotonin reuptake inhibitor antidepressants showed a limited efficacy. Objective: The purpose of this work was to evaluate if a higher brain cholinergic stimulation induced by the association between the acetylcholinesterase inhibitor donepezil and the cholinergic precursor choline alphoscerate has any effect on depression in AD patients. Methods: Patients were selected among those recruited in the ASCOMALVA (association between the cholinesterase inhibitor donepezil and the cholinergic precursor choline alphoscerate in AD) trial. Depressive symptoms were investigated in 90 …AD patients through the neuropsychiatric inventory at baseline and after 3, 6, 9, 12, 18, and 24 months of treatment. Patients were randomized in a group association therapy (45 subjects) receiving donepezil 10 mg plus choline alphoscerate 1,200 mg/day, and a group monotherapy (45 subjects) receiving donepezil 10 mg/day plus placebo. Based on the results of the MMSE at the recruitment patients were divided into 3 groups: severely impaired (score < 15); moderately impaired (score 19-16); mild-moderately impaired (score 24-20). Results: Depression symptoms were significantly lower (p  < 0.05) in patients treated with donepezil plus choline alphoscerate compared to patients treated with donepezil alone. Subjects of the group having mild to moderate cognitive impairment were those more sensitive to the association treatment. Conclusion: Depression symptoms of AD patients in the mild to moderate stage probably could to benefit of a stronger cholinergic stimulation induced by associating donepezil with the cholinergic precursor choline alphoscerate. Show more

Keywords: Alzheimer’s disease, association, choline alphoscerate, depression, donepezil

DOI: 10.3233/ADR-200269

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 235-243, 2022

Authors: Hu, Wen | Dai, Chun-Ling | Niu, Jiahui | Iqbal, Khalid

Article Type: Research Article

Abstract: Background: The triple transgenic mouse model of Alzheimer’s disease (3×Tg-AD) has gained popularity in Alzheimer’s research owing to the progressive development of both amyloid-β and tau pathologies in its brain. Prior handling-habituation, a necessary preparation procedure that reduces anxiety and stress in rodents, was seldom described in the literature involving these mice and needs to be addressed. Objective: We sought to determine whether 3×Tg-AD mice differ from B6;129 genetic control mice in terms of tameness and prior habituation to handling. Methods: We devised hand-staying and hand-boarding assays to evaluate tameness in 3×Tg-AD and B6;129 genetic …control mice at 2.5, 7, and 11.5 months of age, representing cognitively pre-symptomatic, early symptomatic and advanced symptomatic stages of the disease, respectively. We monitored the progress of handling-habituation across 8–15 daily handling sessions and assessed the animal behaviors in elevated plus maze. Results: We found that 3×Tg-AD mice were markedly tamer than age-matched control mice at the baseline. Whereas it took 2–3 days for 3×Tg-AD mice to reach the criteria for full tameness, it took an average of 7–9 days for young genetic control mice to do so. Prior handling-habituation enhanced risk assessment and coping strategy in mice in elevated plus maze. Completely handling-habituated mice exhibited comparable anxiety indices in the maze regardless of genotype and age. Conclusion: These findings collectively point to inherently heightened tameness and accelerated handling-habituation in 3×Tg-AD mice on a B6;129 genetic background. These traits should be carefully considered when behaviors are compared between 3×Tg-AD and the genetic control mice. Show more

Keywords: 3×Tg-AD, anxiety, mouse models of Alzheimer’s disease, prior handling-habituation, tameness

DOI: 10.3233/ADR-220007

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 245-255, 2022

Authors: Ahmed, Heba A. | Ishrat, Tauheed

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) has become a worldwide crisis with no effective therapeutic options. The medications currently available for AD are only palliative; their effect is temporary, and they are associated with unfavorable side effects. Even the newest medication aducanumab, granted accelerated FDA approval in 2021, failed to show cognitive benefits in clinical trials and continued approval requires verification in subsequent clinical trials. There is an urgent need for safe and effective therapies to preserve cognition and effectively manage AD. Generally, a new drug product takes several years for FDA approval and exceeds 2.5 billion dollars in research and development, …with most new drug products never even reaching the market. This has led to a recent shift for repurposing/repositioning existing FDA-approved medications, to new therapeutic indications. Objective: To investigate the effects of long-term treatment with candesartan, an FDA-approved angiotensin-II type-1 receptor blocker (ARB), on the development of cognitive impairment associated with premature aging. Methods: Candesartan was given at a dose of 1 mg/kg/d in an AD model of senescence-accelerated mouse prone-8 (SAMP8) and senescence-accelerated mouse resistant (SAMR1) mice. Oral treatment with candesartan or vehicle was started, in 2-month-old mice and administered continuously for 4-months. Results: Low-dose candesartan prevented the development of cognitive impairment, otherwise associated with accelerated aging, in SAMP8 mice, by reducing inflammation and nitro-oxidative stress. Candesartan did not affect the cognitive function of control SAMR1 mice. Conclusion: Early ARB treatment might be beneficial in preventing age-related cognitive deficits in AD-prone individuals. Show more

Keywords: Angiotensin receptor blocker, candesartan, cognitive impairment, oxidative stress, sporadic Alzheimer’s disease

DOI: 10.3233/ADR-220016

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 257-269, 2022

Authors: Tsamou, Maria | Roggen, Erwin L.

Article Type: Review Article

Abstract: The adverse outcome pathway (AOP) concept was first proposed as a tool for chemical hazard assessment facilitating the regulatory decision-making in toxicology and was more recently recommended during the BioMed21 workshops as a tool for the characterization of crucial endpoints in the human disease development. This AOP framework represents mechanistically based approaches using existing data, more realistic and relevant to human biological systems. In principle, AOPs are described by molecular initiating events (MIEs) which induce key events (KEs) leading to adverse outcomes (AOs). In addition to the individual AOPs, the network of AOPs has been also suggested to beneficially support …the understanding and prediction of adverse effects in risk assessment. The AOP-based networks can capture the complexity of biological systems described by different AOPs, in which multiple AOs diverge from a single MIE or multiple MIEs trigger a cascade of KEs that converge to a single AO. Here, an AOP network incorporating a recently proposed tau-driven AOP toward memory loss (AOP429) related to sporadic (late-onset) Alzheimer’s disease is constructed. This proposed AOP network is an attempt to extract useful information for better comprehending the interactions among existing mechanistic data linked to memory loss as an early phase of sporadic Alzheimer’s disease pathology. Show more

Keywords: Adverse outcome pathway, AOP-wiki, memory loss, network

DOI: 10.3233/ADR-220015

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 271-296, 2022

Authors: Bohlken, Jens | Weber, Kerstin | Riedel Heller, Steffi | Michalowsky, Bernhard | Kostev, Karel

Article Type: Research Article

Abstract: Background: Little is known about the impact of COVID-19 on mild cognitive disorder. Objective: The aim of this retrospective cohort study was to investigate whether COVID-19 diagnosis is associated with subsequent mild cognitive disorder (MCD) compared to acute upper respiratory infections (AURI). Methods: This retrospective cohort study used data from the Disease Analyzer database (IQVIA) and included 67,046 patients with first-time symptomatic or asymptomatic COVID-19 diagnoses in 1,172 general practices in Germany between March 2020 and September 2021. Diagnoses were based on ICD-10 codes. Patients diagnosed with AURI were matched to 67,046 patients with COVID-19 using …propensity scores based on sex, age, index month, and comorbidities. The index date was the diagnosis date for either COVID-19 or AURI. Associations between the COVID-19 and MCD were studied using conditional Poisson regression models. Results: The incidence of MCD was 7.6 cases per 1,000 person-years in the COVID-19 group and 5.1 cases per 1,000 person-years in the AURI group (IRR = 1.49, 95% CI = 1.22–1.82). The incidence rate ratio decreased strongly with increasing age from 10.08 (95% CI = 4.00–24.42) in the age group≤50 to 1.03 (95% CI = 0.81–1.31) in the age group > 70. In addition, the association between COVID-19 and MCD was significant in women (IRR: 1.70, 95% CI: 1.34–2.16) but not in men (IRR: 1.08, 95% CI: 0.75–1.56). Conclusion The incidence of MCD was low but significantly higher in COVID-19 than in AURI patients, especially among younger patients. If a cognitive disorder is suspected, referral to a specialist is recommended. Show more

Keywords: COVID-19 pandemic, general practices, Germany, mild cognitive disorder, post-COVID

DOI: 10.3233/ADR-220020

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 297-305, 2022

Authors: Koppelmans, Vincent | Silvester, Benjamin | Duff, Kevin

Article Type: Systematic Review

Abstract: Background: Despite the prevalence of motor symptoms in mild cognitive impairment (MCI) and Alzheimer’s disease (AD), their underlying neural mechanisms have not been thoroughly studied. Objective: This review summarizes the neural underpinnings of motor deficits in MCI and AD. Methods: We searched PubMed up until August of 2021 and identified 37 articles on neuroimaging of motor function in MCI and AD. Study bias was evaluated based on sample size, availability of control samples, and definition of the study population in terms of diagnosis. Results: The majority of studies investigated gait, showing that slower gait …was associated with smaller hippocampal volume and prefrontal deactivation. Less prefrontal activation was also observed during cognitive-motor dual tasking, while more activation in cerebellar, cingulate, cuneal, somatosensory, and fusiform brain regions was observed when performing a hand squeezing task. Excessive subcortical white matter lesions in AD were associated with more signs of parkinsonism, poorer performance during a cognitive and motor dual task, and poorer functional mobility. Gait and cognitive dual-tasking was furthermore associated with cortical thickness of temporal lobe regions. Most non-gait motor measures were only reported in one study in relation to neural measures. Conclusion: Cross-sectional designs, lack of control groups, mixing amnestic- and non-amnestic MCI, disregard of sex differences, and small sample sizes limited the interpretation of several studies, which needs to be addressed in future research to progress the field. Show more

Keywords: Alzheimer’s disease, diffusion tensor imaging, functional MRI, functional near-infrared spectroscopy, magnetic resonance imaging, mild cognitive impairment, motor function

DOI: 10.3233/ADR-210065

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 307-344, 2022

Authors: Padala, Sanjana P. | Yarns, Brandon C.

Article Type: Article Commentary

Abstract: Despite controversy about the efficacy and safety of aducanumab, the FDA’s fast-tracking of this medicine is truly historic. However, structural problems leading to socioeconomic disparities and systemic racism in science, healthcare, and society have left out under-represented populations. This perspective outlines the racial and socioeconomic health disparities in aducanumab treatment: 1) Disparities in the risk of Alzheimer’s disease (AD), 2) Limited participation from under-represented groups in AD trials raising concerns about the generalizability of the results, 3) Questionable applicability of the amyloid hypothesis in groups under-represented in AD research, and 4) Aducanumab’s initial sticker price that unfairly singled out those …with lower socioeconomic backgrounds. Potential solutions are discussed. Show more

Keywords: Aducanumab, Alzheimer’s disease, bioethics, ethics

DOI: 10.3233/ADR-220023

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 345-348, 2022

Authors: Patel, Vishvas N. | Chorawala, Mehul R. | Shah, Maitri B. | Shah, Kashvi C. | Dave, Bhavarth P. | Shah, Manal P. | Patel, Tanvi M.

Article Type: Review Article

Abstract: Type-2 diabetes mellitus (T2DM) is a chronic immuno-inflammatory and metabolic disease characterized by hyperglycemia and insulin resistance with corresponding hyperinsulinemia. On the other hand, Alzheimer’s disease (AD) is a neurodegenerative disease involving cognitive impairment, neuronal dysfunction, and memory loss. Several recently published literatures suggest a causal relationship between T2DM and AD. In this review, we have discussed several potential mechanisms underlying diabetes-induced cognitive impairment which include, abnormal insulin signaling, amyloid-β accumulation, oxidative stress, immuno-inflammation, mitochondrial dysfunction, advanced glycation end products, acetylcholinesterase and butyrylcholinesterase, advanced lipid peroxidation products, and apolipoprotein E. All these interconnected mechanisms may act either individually or synergistically …which eventually leads to neurodegeneration and AD. Show more

Keywords: Alzheimer’s disease, diabetes mellitus, hyperphosphorylation of tau, insulin resistance, neurodegeneration, oxidative stress

DOI: 10.3233/ADR-220021

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 349-357, 2022

Authors: Styck, Abigail C. | George, Daniel R.

Article Type: Research Article

Abstract: Background: Gardening has been shown to have positive effects on persons living with dementia, but no studies have explored the effects of gardening on sense of purpose. Objective: Explore how gardening may influence sense of purpose for people with dementia. Methods: Ten residents with dementia diagnoses living in a skilled care facility participated in hour-long gardening sessions twice weekly at outdoor raised beds over a two-month duration. One group (n  = 5) donated vegetables to a food pantry while the other (n  = 5) harvested produce for personal use. Semi-structured interviews with participants and their caregivers conducted post-intervention …were analyzed for themes. Results: Participants and caregivers reported biopsychosocial benefits of gardening, identifying four main themes: 1) Gardening outdoors provided specific physical benefits that improved quality of life; 2) Working on a project in a group setting improved mood and fostered a sense of community; 3) Gardening promoted reminiscence and reinforced a sense of self; 4) Gardening provided participants with a sense of purpose and pride. Conclusion: Gardening has biopsychosocial benefits for persons living with dementia, and there appears to be additive benefit linked to improved sense of purpose via charitable giving. Show more

Keywords: Arts, dementia, medical humanities, nature, psychosocial

DOI: 10.3233/ADR-220018

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 359-367, 2022

Authors: Volloch, Vladimir | Rits-Volloch, Sophia

Article Type: Research Article

Abstract: We posit that Alzheimer’s disease (AD) is driven by amyloid-β (Aβ) generated in the amyloid-β protein precursor (AβPP) independent pathway activated by AβPP-derived Aβ accumulated intraneuronally in a life-long process. This interpretation constitutes the Amyloid Cascade Hypothesis 2.0 (ACH2.0). It defines a tandem intraneuronal -Aβ (i Aβ)-anchored cascade occurrence: intraneuronally-accumulated, AβPP-derived i Aβ triggers relatively benign cascade that activates the AβPP-independent i Aβ-generating pathway, which, in turn, initiates the second, devastating cascade that includes tau pathology and leads to neuronal loss. The entire output of the AβPP-independent i Aβ-generating pathway is retained intraneuronally and perpetuates the pathway’s operation. This process …constitutes a self-propagating, autonomous engine that drives AD and ultimately kills its host cells. Once activated, the AD Engine is self-reliant and independent from Aβ production in the AβPP proteolytic pathway; operation of the former renders the latter irrelevant to the progression of AD by relegating its i Aβ contribution to insignificant, and brands its manipulation for therapeutic purposes, such as BACE (beta-site AβPP-cleaving enzyme) inhibition, as futile. In the proposed AD paradigm, the only valid direct therapeutic strategy is targeting the engine’s components, and the most effective feasible approach appears to be the activation of BACE1 and/or of its homolog BACE2, with the aim of exploiting their Aβ-cleaving activities. Such treatment would collapse the i Aβ population and ‘reset’ its levels below those required for the operation of the AD Engine. Any sufficiently selective i Aβ-depleting treatment would be equally effective. Remarkably, this approach opens the possibility of a short-duration, once-in-a-lifetime-only or very infrequent, preventive or curative therapy for AD; this therapy would be also effective for prevention and treatment of the ‘common’ pervasive aging-associated cognitive decline. The ACH2.0 clarifies all ACH-unresolved inconsistencies, explains the widespread ‘resilience to AD’ phenomenon, predicts occurrences of a category of AD-afflicted individuals without excessive Aβ plaque load and of a novel type of familial insusceptibility to AD; it also predicts the lifespan-dependent inevitability of AD in humans if untreated preventively. The article details strategy and methodology to generate an adequate AD model and validate the hypothesis; the proposed AD model may also serve as a research and drug development platform. Show more

Keywords: the Amyloid Cascade Hypothesis 2.0, intraneuronal Aβ (iAβ), AβPP-independent generation of iAβ, PKR and HRI kinases, integrated stress response, iAβ depletion therapy for AD, BACE activators as AD drugs

DOI: 10.3233/ADR-220031

Citation: Journal of Alzheimer's Disease Reports, vol. 6, no. 1, pp. 369-399, 2022