Journal of Alzheimer's Disease - Volume 84, issue 4

Authors: Torres, Angie K. | Jara, Claudia | Park-Kang, Han S. | Polanco, Catalina M. | Tapia, Diego | Alarcón, Fabián | de la Peña, Adely | Llanquinao, Jesus | Vargas-Mardones, Gabriela | Indo, Javiera A. | Inestrosa, Nibaldo C. | Tapia-Rojas, Cheril

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is characterized by cognitive impairment and the presence of neurofibrillary tangles and senile plaques in the brain. Neurofibrillary tangles are composed of hyperphosphorylated tau, while senile plaques are formed by amyloid-β (Aβ) peptide. The amyloid hypothesis proposes that Aβ accumulation is primarily responsible for the neurotoxicity in AD. Multiple Aβ-mediated toxicity mechanisms have been proposed including mitochondrial dysfunction. However, it is unclear if it precedes Aβ accumulation or if is a consequence of it. Aβ promotes mitochondrial failure. However, amyloid β precursor protein (AβPP) could be cleaved in the mitochondria producing Aβ peptide. Mitochondrial-produced Aβ could interact …with newly formed ones or with Aβ that enter the mitochondria, which may induce its oligomerization and contribute to further mitochondrial alterations, resulting in a vicious cycle. Another explanation for AD is the tau hypothesis, in which modified tau trigger toxic effects in neurons. Tau induces mitochondrial dysfunction by indirect and apparently by direct mechanisms. In neurons mitochondria are classified as non-synaptic or synaptic according to their localization, where synaptic mitochondrial function is fundamental supporting neurotransmission and hippocampal memory formation. Here, we focus on synaptic mitochondria as a primary target for Aβ toxicity and/or formation, generating toxicity at the synapse and contributing to synaptic and memory impairment in AD. We also hypothesize that phospho-tau accumulates in mitochondria and triggers dysfunction. Finally, we discuss that synaptic mitochondrial dysfunction occur in aging and correlates with age-related memory loss. Therefore, synaptic mitochondrial dysfunction could be a predisposing factor for AD or an early marker of its onset. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, cognitive impairment, mitochondria, neurofibrillary tangles, synapses, synaptic mitochondria

DOI: 10.3233/JAD-215139

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1391-1414, 2021

Authors: Schultz, Bruna | Taday, Jéssica | Menezes, Leonardo | Cigerce, Anderson | Leite, Marina C. | Gonçalves, Carlos-Alberto

Article Type: Review Article

Abstract: One of the changes found in the brain in Alzheimer’s disease (AD) is increased calpain, derived from calcium dysregulation, oxidative stress, and/or neuroinflammation, which are all assumed to be basic pillars in neurodegenerative diseases. The role of calpain in synaptic plasticity, neuronal death, and AD has been discussed in some reviews. However, astrocytic calpain changes sometimes appear to be secondary and consequent to neuronal damage in AD. Herein, we explore the possibility of calpain-mediated astroglial reactivity in AD, both preceding and during the amyloid phase. We discuss the types of brain calpains but focus the review on calpains 1 and …2 and some important targets in astrocytes. We address the signaling involved in controlling calpain expression, mainly involving p38/mitogen-activated protein kinase and calcineurin, as well as how calpain regulates the expression of proteins involved in astroglial reactivity through calcineurin and cyclin-dependent kinase 5. Throughout the text, we have tried to provide evidence of the connection between the alterations caused by calpain and the metabolic changes associated with AD. In addition, we discuss the possibility that calpain mediates amyloid-β clearance in astrocytes, as opposed to amyloid-β accumulation in neurons. Show more

Keywords: Alzheimer’s disease, astrocyte, calcineurin, calpain, CDK5, GFAP, S100B

DOI: 10.3233/JAD-215182

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1415-1430, 2021

Authors: Swerdlow, Neal R. | Kotz, Juliana E. | Joshi, Yash B. | Talledo, Jo | Sprock, Joyce | Molina, Juan L. | Huisa, Branko | Huege, Steven F. | Romero, Jairo Alberto | Walsh, Michael J. | Delano-Wood, Lisa | Light, Gregory A.

Article Type: Short Communication

Abstract: Memantine’s benefits in Alzheimer’s disease (AD) are modest and heterogeneous. We tested the feasibility of using sensitivity to acute memantine challenge to predict an individual’s clinical response. Eight participants completed a double-blind challenge study of memantine (placebo versus 20 mg) effects on autonomic, subjective, cognitive, and neurophysiological measures, followed by a 24-week unblinded active-dose therapeutic trial (10 mg bid). Study participation was well tolerated. Subgroups based on memantine sensitivity on specific laboratory measures differed in their clinical response to memantine, some by large effect sizes. It appears feasible to use biomarkers to predict clinical sensitivity to memantine.

Keywords: Alzheimer’s disease, event-related potentials, memantine, neurocognition, prepulse inhibition

DOI: 10.3233/JAD-215029

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1431-1438, 2021

Authors: Vrillon, Agathe | Deramecourt, Vincent | Pasquier, Florence | Magnin, Éloi | Wallon, David | Lozeron, Pierre | Bouaziz-Amar, Élodie | Paquet, Claire

Article Type: Short Communication

Abstract: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia have a strong clinical, genetic, and pathological connection but association of ALS with Alzheimer’s disease (AD) is seldom reported. We report a series of 5 cases of AD associated with ALS. Our patients presented with cognitive deterioration with episodic memory impairment meeting criteria for AD. ALS occurred subsequently in all cases and its phenotype was not homogenous. Amyloid process was confirmed in four cases with cerebrospinal fluid biomarkers. One case underwent postmortem exam, demonstrating hallmarks lesions of both diseases. This series highlights that ALS-AD phenotype could be a specific underexplored entity.

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, cerebrospinal fluid biomarkers, neurodegenerative disorders, neuropathology

DOI: 10.3233/JAD-215226

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1439-1446, 2021

Authors: Zhang, Qiang | Schultz, Jordan L. | Aldridge, Georgina M. | Simmering, Jacob E. | Kim, Youngcho | Ogilvie, Amy C. | Narayanan, Nandakumar S.

Article Type: Short Communication

Abstract: Previous studies have identified dementia as a risk factor for death from coronavirus disease 2019 (COVID-19). However, it is unclear whether Alzheimer’s disease (AD) is an independent risk factor for COVID-19 case fatality rate. In a retrospective cohort study, we identified 387,841 COVID-19 patients through TriNetX. After adjusting for demographics and comorbidities, we found that AD patients had higher odds of dying from COVID-19 compared to patients without AD (Odds Ratio: 1.20, 95%confidence interval: 1.09–1.32, p  < 0.001). Interestingly, we did not observe increased mortality from COVID-19 among patients with vascular dementia. These data are relevant to the evolving COVID-19 pandemic.

Keywords: Alzheimer’s disease, case fatality, Coronavirus disease 2019 (COVID-19), dementia with Lewy bodies, frontotemporal dementia, Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), vascular dementia

DOI: 10.3233/JAD-215161

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1447-1452, 2021

Authors: Clute-Reinig, Nicholas | Jayadev, Suman | Rhoads, Kristoffer | Le Ny, Anne-Laure

Article Type: Article Commentary

Abstract: Dementia and Alzheimer’s disease (AD) are global health crises, with most affected individuals living in low- or middle-income countries. While research into diagnostics and therapeutics remains focused exclusively on high-income populations, recent technological breakthroughs suggest that low-cost AD diagnostics may soon be possible. However, as this disease shifts onto those with the least financial and structural ability to shoulder its burden, it is incumbent on high-income countries to develop accessible AD healthcare. We argue that there is a scientific and ethical mandate to develop low-cost diagnostics that will not only benefit patients in low-and middle-income countries but the AD field …as a whole. Show more

Keywords: Alzheimer’s disease diagnostics, dementia, developing countries, global health, health equity, healthcare disparities, neurological diagnostic techniques

DOI: 10.3233/JAD-210663

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1453-1455, 2021

Authors: Høilund-Carlsen, Poul F. | Alavi, Abass

Article Type: Article Commentary

Abstract: According to the FDA, aducanumab (Aduhelm), the recently approved anti-Alzheimer drug, reduces the level of cerebral amyloid plaques—a hallmark finding in patients with Alzheimer’s disease—and this will result in a reduction in clinical decline. The authors of this article are not convinced that amyloid deposits are a hallmark of Alzheimer’s disease and are of the opinion that the apparent reduction in amyloid accumulation following aducanumab treatment is likely instead a result of continued and advanced cerebral cell death and, thus, not a sign of improvement but of an even more advanced disease.

Keywords: Aducanumab, aduhelm, Alzheimer’s disease, amyloid PET, dementia

DOI: 10.3233/JAD-215275

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1457-1460, 2021

Authors: Foucard, Cendrine | Palisson, Juliette | Belin, Catherine | Bereaux, Chloé | Dumurgier, Julien | Paquet, Claire | Degos, Bertrand | Bouaziz-Amar, Elodie | Maillet, Didier | Houot, Marion | Garcin, Béatrice

Article Type: Research Article

Abstract: Background: The TNI-93 is a quick memory test designed for all patients regardless of their education level. A significant proportion of patients with Alzheimer’s disease (AD) are illiterate or poorly educated, and only a few memory tests are adapted for these patients. Objective: In this study we aimed at assessing the diagnostic value of the TNI-93 for diagnosis of patients with biologically confirmed amyloid status. Methods: We included all patients who had an analysis of AD cerebrospinal fluid biomarkers, a neuropsychological assessment including a TNI-93 and an anatomical brain imaging at Avicenne Hospital between January 2009 …and November 2019. We compared the TNI-93 scores in patients with amyloid abnormalities (A+) and patients without amyloid abnormalities (A-) according to the AT(N) diagnostic criteria. Results: 108 patients were included (mean age: 66.9±8.5 years old, mean education level: 8.9±5.2 years). Patients from the A + group (N= 80) were significantly more impaired than patients from the A- group (N= 28) on immediate recall (A+: 5.9±2.8; A-: 7.4±2.6; p = 0.001), free recall (A+: 3.5±2.7; A-: 5.9±2.8; p ≤ 0.001), total recall (A+: 5.7±3.5; A-:7.8±2.8; p ≤ 0.001), and on number of intrusions during the recall phase (A+: 1±1.8; A-: 0.1±0.3; p = 0.002). ROC curves revealed that the best scores to discriminate A + from A- patients were immediate recall (Area under curve (AUC): 0.70), number of encoding trials (AUC: 0.73), free recall (AUC: 0.74), and total recall (AUC: 0.74). Conclusion: The TNI-93’s immediate, free, and total recalls are valuable tools for the 39 diagnosis of AD. Show more

Keywords: Alzheimer’s disease, AT(N), cerebrospinal fluid biomarkers, illiteracy, memory test, neuropsychology

DOI: 10.3233/JAD-210546

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1461-1471, 2021

Authors: Ismael, Saifudeen | Mirzahosseini, Golnoush | Ahmed, Heba A. | Yoo, Arum | Kassan, Modar | Malik, Kafait U. | Ishrat, Tauheed

Article Type: Research Article

Abstract: Background: Understanding Alzheimer’s disease (AD) in terms of its various pathophysiological pathways is essential to unravel the complex nature of the disease process and identify potential therapeutic targets. The renin-angiotensin system (RAS) has been implicated in several brain diseases, including traumatic brain injury, ischemic stroke, and AD. Objective: This study was designed to evaluate the protein expression levels of RAS components in postmortem cortical and hippocampal brain samples obtained from AD versus non-AD individuals. Methods: We analyzed RAS components in the cortex and hippocampus of postmortem human brain samples by western blotting and immunohistochemical techniques in …comparison with age-matched non-demented controls. Results: The expression of AT1 R increased in the hippocampus, whereas AT2 R expression remained almost unchanged in the cortical and hippocampal regions of AD compared to non-AD brains. The Mas receptor was downregulated in the hippocampus. We also detected slight reductions in ACE-1 protein levels in both the cortex and hippocampus of AD brains, with minor elevations in ACE-2 in the cortex. We did not find remarkable differences in the protein levels of angiotensinogen and Ang II in either the cortex or hippocampus of AD brains, whereas we observed a considerable increase in the expression of brain-derived neurotrophic factor in the hippocampus. Conclusion: The current findings support the significant contribution of RAS components in AD pathogenesis, further suggesting that strategies focusing on the AT1 R and AT2 R pathways may lead to novel therapies for the management of AD. Show more

Keywords: Alzheimer’s disease, angiotensin-converting enzyme, angiotensin type 1 receptor, angiotensin type 2 receptor, renin-angiotensin system

DOI: 10.3233/JAD-215051

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1473-1484, 2021

Authors: Bruus, Anna E. | Waldemar, Gunhild | Vogel, Asmus

Article Type: Research Article

Abstract: Background: Autobiographical memory (AM) is a personal form of memory that becomes impaired in the early, clinical stages of Alzheimer’s disease (AD). In the “preclinical” phase of AD, neuropathological hallmarks are present (especially in a brain network underpinning AM), but performance on standardized neuropsychological tests is normal. Even so, some patients have subjective cognitive decline (SCD). Objective: The aim was to 1) investigate AM performance on two tests with different approaches in SCD, and in prodromal and mild AD, and 2) examine the association between the AM tests. Methods: We included 17 SCD patients with heightened …risk of AD, 17 amnestic mild cognitive impairment (aMCI) patients, 17 patients with mild dementia due to AD, and 30 healthy controls. Patients were diagnosed according to international criteria, and all participants had MMSE scores≥24. AM was assessed using the Columbia Autobiographical Memory Interview-Short Form (CAMI-SF) and the Three Events Test. These tests measure the production of contextual details. Results: Significant group effects were found for the Three Events Test and the CAMI-SF. All patient groups produced significantly fewer contextual details than the controls on the Three Events Test. On CAMI-SF, the aMCI and mild AD groups were able to answer fewer questions or gave significantly less detailed answers than the other groups. The SCD patients performed below the controls on CAMI-SF, but the difference was not significant. Conclusion: AM may be impaired in very early AD, even in the phases where standardized episodic memory tests show no decline. Show more

Keywords: Alzheimer’s disease, autobiographical memory, dementia, memory disorder, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-215113

Citation: Journal of Alzheimer's Disease, vol. 84, no. 4, pp. 1485-1496, 2021