Journal of Alzheimer's Disease - Volume 98, issue 4

Authors: Sachdeva, Punya | Narayanan, Kannan Badri | Sinha, Jitendra Kumar | Gupta, Saurabh | Ghosh, Shampa | Singh, Krishna Kumar | Bhaskar, Rakesh | Almutary, Abdulmajeed G. | Zothantluanga, James H. | Kotta, Kranthi Kumar | Nelson, Vinod Kumar | Paiva-Santos, Ana Cláudia | Abomughaid, Mosleh Mohammad | Kamal, Mehnaz | Iqbal, Danish | ALHarbi, Mohammed Hamoud | ALMutairi, Awadh Aedh | Dewanjee, Saikat | Nuli, Mohana Vamsi | Vippamakula, Shanmugam | Jha, Saurabh Kumar | Ojha, Shreesh | Jha, Niraj Kumar

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of neurofibrillary tangles and amyloid-β plaques. Recent research has unveiled the pivotal role of insulin signaling dysfunction in the pathogenesis of AD. Insulin, once thought to be unrelated to brain function, has emerged as a crucial factor in neuronal survival, synaptic plasticity, and cognitive processes. Insulin and the downstream insulin signaling molecules are found mainly in the hippocampus and cortex. Some molecules responsible for dysfunction in insulin signaling are GSK-3β, Akt, PI3K, and IRS. Irregularities in insulin signaling or insulin resistance may arise from changes in the phosphorylation …levels of key molecules, which can be influenced by both stimulation and inactivity. This, in turn, is believed to be a crucial factor contributing to the development of AD, which is characterized by oxidative stress, neuroinflammation, and other pathological hallmarks. Furthermore, this route is known to be indirectly influenced by Nrf2, NF-κB, and the caspases. This mini-review delves into the intricate relationship between insulin signaling and AD, exploring how disruptions in this pathway contribute to disease progression. Moreover, we examine recent advances in drug delivery systems designed to target insulin signaling for AD treatment. From oral insulin delivery to innovative nanoparticle approaches and intranasal administration, these strategies hold promise in mitigating the impact of insulin resistance on AD. This review consolidates current knowledge to shed light on the potential of these interventions as targeted therapeutic options for AD. Show more

Keywords: Alzheimer’s disease, amyloid-beta plaques, antidiabetics, drug delivery systems, insulin signaling, intranasal drug delivery, metformin, nanoparticles, neurodegeneration, tau phosphorylation

DOI: 10.3233/JAD-231181

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1169-1179, 2024

Authors: Gelfo, Francesca | Petrosini, Laura | Mandolesi, Laura | Landolfo, Eugenia | Caruso, Giulia | Balsamo, Francesca | Bonarota, Sabrina | Bozzali, Marco | Caltagirone, Carlo | Serra, Laura

Article Type: Review Article

Abstract:  Evidence in the literature indicates that aerobic physical activity may have a protective role in aging pathologies. However, it has not been clarified whether different types of aerobic exercise produce different effects. In particular, these potential differences have not been explored in patients with Alzheimer’s disease (AD). The present narrative review has the specific aim of evaluating whether land (walking/running) and water (swimming) aerobic activities exert different effects on cognitive functions and neural correlates in AD patients. In particular, the investigation is carried out by comparing the evidence provided from studies on AD animal models and on patients. On the …whole, we ascertained that both human and animal studies documented beneficial effects of land and water aerobic exercise on cognition in AD. Also, the modulation of numerous biological processes is documented in association with structural modifications. Remarkably, we found that aerobic activity appears to improve cognition per se , independently from the specific kind of exercise performed. Aerobic exercise promotes brain functioning through the secretion of molecular factors from skeletal muscles and liver. These molecular factors stimulate neuroplasticity, reduce neuroinflammation, and inhibit neurodegenerative processes leading to amyloid-β accumulation. Additionally, aerobic exercise improves mitochondrial activity, reducing oxidative stress and enhancing ATP production. Aerobic activities protect against AD, but implementing exercise protocols for patients is challenging. We suggest that health policies and specialized institutions should direct increasing attention on aerobic activity as lifestyle modifiable factor for successful aging and age-related conditions. Show more

Keywords: Aerobic activity, Alzheimer’s disease, animal models, brain/cognitive/neural reserve, cognition, humans, neural plasticity, physical exercise

DOI: 10.3233/JAD-231279

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1181-1197, 2024

Authors: Polis, Baruh | Samson, Abraham O.

Article Type: Review Article

Abstract: Animal models, particularly transgenic mice, are extensively used in Alzheimer’s disease (AD) research to emulate key disease hallmarks, such as amyloid plaques and neurofibrillary tangles formation. Although these models have contributed to our understanding of AD pathogenesis and can be helpful in testing potential therapeutic interventions, their reliability is dubious. While preclinical studies have shown promise, clinical trials often yield disappointing results, highlighting a notable gap and disparity between animal models and human AD pathology. Existing models frequently overlook early-stage human pathologies and other key AD characteristics, thereby limiting their application in identifying optimal therapeutic interventions. Enhancing model reliability necessitates …rigorous study design, comprehensive behavioral evaluations, and biomarker utilization. Overall, a nuanced understanding of each model’s neuropathology, its fidelity to human AD, and its limitations is essential for accurate interpretation and successful translation of findings. This article analyzes the discrepancies between animal models and human AD pathology that complicate the translation of findings from preclinical studies to clinical applications. We also delve into AD pathogenesis and attributes to propose a new perspective on this pathology and deliberate over the primary limitations of key experimental models. Additionally, we discuss several fundamental problems that may explain the translational failures and suggest some possible directions for more effective preclinical studies. Show more

Keywords: Aging, Alzheimer’s disease, animal models, validity

DOI: 10.3233/JAD-240058

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1199-1218, 2024

Authors: Widjaya, Michael Anekson | Lee, Shin-Da | Cheng, Wei-Chung | Wu, Bor-Tsang

Article Type: Systematic Review

Abstract: Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disease that affects the immune system due to the accumulation of amyloid-β (Aβ) and tau associated molecular pathology and other pathogenic processes. To address AD pathogenesis, various approaches had been conducted from drug development to lifestyle modification to reduce the prevalence of AD. Exercise is considered a prominent lifestyle modification to combat AD. Objective: This observation prompted us to review the literature on exercise related to immune genes in the cortex of animal models of AD. We focused on animal model studies due to their prevalence in this …domain. Methods: The systematic review was conducted according to PRISMA standards using Web of Science (WoS) and PubMed databases. Any kind of genes, proteins, and molecular molecules were included in this systematic review. The list of these immune-related molecules was analyzed in the STRING database for functional enrichment analysis. Results: We found that 17 research studies discussed immune-related molecules and 30 immune proteins. These studies showed that exercise had the ability to ameliorate dysfunction in AD-related pathways, which led to decreasing the expression of microglia-related pathways and Th17-related immune pathways. As a result of decreasing the expression of immune-related pathways, the expression of apoptosis-related pathways was also decreasing, and neuronal survival was increased by exercise activity. Conclusions: Based on functional enrichment analysis, exercise not only could reduce apoptotic factors and immune components but also could increase cell survival and Aβ clearance in cortex samples. PROSPERO ID: CRD42022326093. Show more

Keywords: Alzheimer’s disease, apoptosis-related pathway, brain, microglia-related pathway, physical activity, Th17-related pathway

DOI: 10.3233/JAD-230803

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1219-1234, 2024

Authors: Love, Robert W.B.

Article Type: Research Article

Abstract:  Alzheimer’s disease is the leading cause of dementia in the world. It affects 6 million people in the United States and 50 million people worldwide. Alzheimer’s disease is characterized by the accumulation of amyloid-β plaques (Aβ), an increase in tau protein neurofibrillary tangles, and a loss of synapses. Since the 1990s, removing and reducing Aβ has been the focus of Alzheimer’s treatment and prevention research. The accumulation of Aβ can lead to oxidative stress, inflammation, neurotoxicity, and eventually apoptosis. These insults impair signaling systems in the brain, potentially leading to memory loss and cognitive decline. Aniracetam is a safe, effective, …cognitive-enhancing drug that improves memory in both human and animal studies. Aniracetam may prevent the production and accumulation of Aβ by increasing α -secretase activity through two distinct pathways: 1) increasing brain derived neurotrophic factor expression and 2) positively modulating metabotropic glutamate receptors. This is the first paper to propose an evidence-based model for aniracetam reducing the accumulation and production of Aβ. Show more

Keywords: Aging, α-secretase, Alzheimer’s disease, amyloid plaques, aniracetam, BDNF, cognition, dementia, neurobiology, pharmacology

DOI: 10.3233/JAD-231247

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1235-1241, 2024

Authors: Area-Gomez, Estela | Schon, Eric A.

Article Type: Research Article

Abstract: The “amyloid cascade” hypothesis of Alzheimer’s disease (AD) pathogenesis invokes the accumulation in the brain of plaques (containing the amyloid-β protein precursor [AβPP] cleavage product amyloid-β [Aβ]) and tangles (containing hyperphosphorylated tau) as drivers of pathogenesis. However, the poor track record of clinical trials based on this hypothesis suggests that the accumulation of these peptides is not the only cause of AD. Here, an alternative hypothesis is proposed in which the AβPP cleavage product C99, not Aβ, is the main culprit, via its role as a regulator of cholesterol metabolism. C99, which is a cholesterol sensor, promotes the formation of …mitochondria-associated endoplasmic reticulum (ER) membranes (MAM), a cholesterol-rich lipid raft-like subdomain of the ER that communicates, both physically and biochemically, with mitochondria. We propose that in early-onset AD (EOAD), MAM-localized C99 is elevated above normal levels, resulting in increased transport of cholesterol from the plasma membrane to membranes of intracellular organelles, such as ER/endosomes, thereby upregulating MAM function and driving pathology. By the same token, late-onset AD (LOAD) is triggered by any genetic variant that increases the accumulation of intracellular cholesterol that, in turn, boosts the levels of C99 and again upregulates MAM function. Thus, the functional cause of AD is upregulated MAM function that, in turn, causes the hallmark disease phenotypes, including the plaques and tangles. Accordingly, the MAM hypothesis invokes two key interrelated elements, C99 and cholesterol, that converge at the MAM to drive AD pathogenesis. From this perspective, AD is, at bottom, a lipid disorder. Show more

Keywords: Amyloid, C99, cholesterol, endoplasmic reticulum, MAM, mitochondria

DOI: 10.3233/JAD-231318

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1243-1275, 2024

Authors: Calderón-Garcidueñas, Lilian | Ayala, Alberto | Mukherjee, Partha S.

Article Type: Short Communication

Abstract: Air pollution exposures ought to be of significant interest for the United States (US) public as health issues will play a role in the 2024 elections. Citizens are not aware of the harmful brain impact of exposures to ubiquitous anthropogenic combustion emissions and friction-derived nanoparticles, industrial nanoplastics, the growing risk of wildfires, and the smoke plumes of soot. Ample consideration of pediatric and early adulthood hallmarks of Alzheimer’s disease, Parkinson’s disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis and associations with neuropsychiatric and neurodevelopmental disorders in the process of setting, reviewing, and implementing standards for particulate matter (PM)2.5 , ultrafine …PM, and industrial nanoparticles must be of interest to US citizens. Show more

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, anthropogenic emissions control, frontotemporal lobar degeneration, nanoparticles, Parkinson’s disease, particulate air pollution, pediatric neurodegeneration, 2024 US elections, wildfires

DOI: 10.3233/JAD-231373

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1277-1282, 2024

Authors: Bragazzi, Nicola Luigi | Boulares, Ayoub | Garbarino, Sergio

Article Type: Article Commentary

Abstract:  In their article, Finch and Burstein explore the hypothesis that Alzheimer’s disease and related dementias (ADRD) may predominantly be phenomena of the modern era. Through a review of classical Greek and Latin literature, they found minimal reference to conditions akin to ADRD, suggesting a historical rarity of severe cognitive decline. Instead, ancient texts focused on physical aspects of aging, with cognitive changes, when noted, not resembling modern-day dementia. Finch and Burstein further extend their analysis by drawing parallels with the Tsimane people of Bolivia, known for their low prevalence of dementia and cardiovascular diseases, attributed to lifestyle factors such as …diet and physical activity. By comparing historical sleep patterns transitioning from segmented to monophasic sleep with those of the Tsimane community, we enriched Finch and Burstein’s research, highlighting the need to take into account a range of diverse factors, including sleep, in understanding the etiopathogenesis of ADRD in today’s society. Show more

Keywords: Alzheimer’s disease, ancient Greeks and Romans, paleopathology, segmented and monophasic sleep

DOI: 10.3233/JAD-240154

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1283-1286, 2024

Authors: Zhang, Mengxue | Qu, Yanjie | Li, Qian | Gu, Chao | Zhang, Limin | Chen, Hongxu | Ding, Minrui | Zhang, Tong | Zhen, Rongrong | An, Hongmei

Article Type: Research Article

Abstract: Background: The development of Alzheimer’s disease (AD) can be divided into subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia. Early recognition of pre-AD stages may slow the progression of dementia. Objective: This study aimed to explore functional connectivity (FC) changes of the brain prefrontal cortex (PFC) in AD continuum using functional near-infrared spectroscopy (fNIRS), and to analyze its correlation with cognitive function. Methods: All participants underwent 48-channel fNIRS at resting-state. Based on Brodmann partitioning, the PFC was divided into eight subregions. The NIRSIT Analysis Tool (v3.7.5) was used to analyze mean ΔHbO2 and FC. …Spearman correlation analysis was used to examine associations between FC and cognitive function. Results: Compared with HC group, the mean ΔHbO2 and FC were different between multiple subregions in the AD continuum. Both mean ΔHbO2 in the left dorsolateral PFC and average FC decreased sequentially from SCD to MCI to AD groups. Additionally, seven pairs of subregions differed in FC among the three groups: the differences between the MCI and SCD groups were in heterotopic connectivity; the differences between the AD and SCD groups were in left intrahemispheric and homotopic connectivity; whereas the MCI and AD groups differed only in homotopic connectivity. Spearman correlation results showed that FCs were positively correlated with cognitive function. Conclusions: These results suggest that the left dorsolateral PFC may be the key cortical impairment in AD. Furthermore, there are different resting-state prefrontal network patterns in AD continuum, and the degree of cognitive impairment is positively correlated with reduced FC strength. Show more

Keywords: Alzheimer’s disease, cognitive decline, functional connectivity, functional near-infrared spectroscopy, prefrontal cortex, resting-state

DOI: 10.3233/JAD-230648

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1287-1300, 2024

Authors: Ruan, Yiming | Zheng, Darui | Guo, Wenxuan | Cao, Xuan | Qi, Wenzhang | Yuan, Qianqian | Zhang, Xulian | Liang, Xuhong | Zhang, Da | Xue, Chen | Xiao, Chaoyong

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI), the prodromal stage of Alzheimer’s disease, has two distinct subtypes: stable MCI (sMCI) and progressive MCI (pMCI). Early identification of the two subtypes has important clinical significance. Objective: We aimed to compare the cortico-striatal functional connectivity (FC) differences between the two subtypes of MCI and enhance the accuracy of differential diagnosis between sMCI and pMCI. Methods: We collected resting-state fMRI data from 31 pMCI patients, 41 sMCI patients, and 81 healthy controls. We chose six pairs of seed regions, including the ventral striatum inferior, ventral striatum superior, dorsal-caudal putamen, dorsal-rostral putamen, …dorsal caudate, and ventral-rostral putamen and analyzed the differences in cortico-striatal FC among the three groups, additionally, the relationship between the altered FC within the MCI subtypes and cognitive function was examined. Results: Compared to sMCI, the pMCI patients exhibited decreased FC between the left dorsal-rostral putamen and right middle temporal gyrus, the right dorsal caudate and right inferior temporal gyrus, and the left dorsal-rostral putamen and left superior frontal gyrus. Additionally, the altered FC between the right inferior temporal gyrus and right putamen was significantly associated with episodic memory and executive function. Conclusions: Our study revealed common and distinct cortico-striatal FC changes in sMCIs and pMCI across different seeds; these changes were associated with cognitive function. These findings can help us understand the underlying pathophysiological mechanisms of MCI and distinguish pMCI and sMCI in the early stage potentially. Show more

Keywords: Alzheimer’s disease, classification, functional connectivity, mild cognitive impairment, resting-state functional magnetic resonance imaging, striatum

DOI: 10.3233/JAD-231174

Citation: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1301-1317, 2024