Journal of Alzheimer's Disease - Volume 100, issue s1

Authors: Pickert, Lena | Dias, Irundika H.K. | Thimm, Alexander | Weber, Johann | Abdullah, Sewa | Deelen, Joris | Polidori, M. Cristina

Article Type: Research Article

Abstract: Background: Among preventive strategies against dementia, nutrition is considered a powerful one and the recently established “nutritional cognitive neuroscience of aging” is a highly active research field. Objective: The present study was designed to deeply characterize older adults across the continuum from cognitive integrity to mild cognitive impairment (MCI) and better elucidate the prognostic role of lipophilic micronutrients within their lipidomic signature. Methods: 123 participants older than 65 years across the continuum from cognitive integrity to MCI were included [49 with subjective cognitive impairment, 29 women, 72.5±5.4 years, 26 MCI, 9 women, 74.5±5.8 years and 50 …without cognitive impairment, 21 women, 70.8±4.3 years]. All participants underwent neuropsychological and nutritional examination as well as comprehensive geriatric assessment with calculation of the Multidimensional Prognostic Index (MPI) as a proxy of frailty and biological age and blood withdrawal for the analyses of lipophilic micronutrients, metabolomics and oxylipidomics. One year after the evaluation, same tests are ongoing. Results: After adjustment for age, sex, daily fruit and vegetable intake and cholesterol, we found a significant positive correlation between lutein and the number of correct words in category fluency (p  = 0.016). Conclusions: This result supports the importance of carotenoids as robust biomarkers of cognitive performance independent of the nutritional status and frailty of the participants, as the entire present study collective was robust (MPI 0–0.33). The complete analyses of the metabolome and the oxylipidome will hopefully shed light on the metabolic and prognostic signature of cognitive decline in the rapidly growing population at risk of frailty. Show more

Keywords: Alzheimer’s disease, frailty, micronutrients, mild cognitive impairment, subjective cognitive impairment

DOI: 10.3233/JAD-240654

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S251-S263, 2024

Authors: Avila, Jesús

Article Type: Short Communication

Abstract: Aging is the main risk for neurodegenerative disorders like Alzheimer’s disease. In this short review, I will comment on how delaying brain aging through the addition of Yamanaka Factors or small compounds that bind to the folate receptor alpha, which promote the expression of the Yamanaka Factors or by the decrease tau levels in brain cells from older subjects could serve as strategies to prevent Alzheimer’s disease.

Keywords: Aging, Alzheimer’s disease, tau protein, therapies

DOI: 10.3233/JAD-240500

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S265-S270, 2024

Authors: Boccardi, Virginia | Ruggiero, Carmelinda | Cecchetti, Roberta | Mecocci, Patrizia

Article Type: Editorial

Abstract:  Aging is associated with a gradual decline in cellular stability, leading to a decrease in overall health. In the brain, this process is closely linked with an increased risk of neurodegenerative diseases, including Alzheimer’s disease. Understanding the mechanisms of brain aging is crucial for developing strategies aimed at enhancing both lifespan and health span. Recent advancements in geroscience, the study of the relationship between aging and age-related diseases, have begun to redefine our understanding of Alzheimer’s disease, guiding the development of preventive medical strategies that target the aging process itself rather than merely addressing the symptomatic manifestations of the disease.

Keywords: Aging, Alzheimer’s disease, geroscience, healthspan, longevity

DOI: 10.3233/JAD-240582

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S271-S276, 2024

Authors: Butterfield, D. Allan

Article Type: Review Article

Abstract: Activation of cell-cycle machinery in Alzheimer’s disease (AD) brain was reported by Mark Smith and colleagues and by other researchers. Among other biochemical processes underlying this activation, the notion that AD brain, under the onslaught of oxidative and nitrosative damage leading to neuronal loss, neurons would attempt to replenish their numbers by entering the cell cycle. However, being post-mitotic, neurons entering the cell cycle would become trapped therein, ultimately leading to death of these neurons. Yang and co-workers and the Butterfield laboratory first reported that similar activation of the cell cycle was present in the brains of individuals with amnestic …mild cognitive impairment (MCI), arguably the earliest clinical stage of AD, but who demonstrate normal activities of daily living and no dementia. Activation of the cell cycle in MCI brain is consonant with the concept that this process is an early aspect in the progression of AD. This brief review article discusses these findings and recognizes the contribution of Dr. Mark Smith to the investigation of cell-cycle activation in AD brain and other aspects of AD neuropathology. Show more

Keywords: Alzheimer’s disease, cell-cycle activation, mild cognitive impairment, oxidative damage, Pin1

DOI: 10.3233/JAD-240615

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S277-S281, 2024

Authors: Rosen, Allyson C. | Lavacot, James A. | Klee, Victoria | Luria, Yuval | Rumbaugh, Malia

Article Type: Review Article

Abstract: Ethics Review began a decade ago with a mission to identify ethical concerns that hold back innovation and to promote solutions that would move the field forward. Over this time, blood biomarkers for brain pathology and medications that treat that pathology promise to transform research and care. A central problem is that the evidence needed to guide test interpretation and practice is accumulating and there are unanswered questions. At the same time, people living with and at risk for dementia want access to their test results and involvement in their care. We promote dialog among diverse people across many institutions …through collaboration with the Advisory Group on Risk Evidence Education for Dementia (AGREEDementia.org). Over the years Ethics Review continues to publish these dialogs and solutions to overcome the paralysis of indecision and ethical concerns. Show more

Keywords: Alzheimer’s disease, amyloid-beta, blood biomarker, diagnostics, ethics

DOI: 10.3233/JAD-240634

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S283-S290, 2024

Authors: Kohler, Katharina | Macheda, Teresa | Hobbs, Misty M. | Maisel, M. Tyler | Rodriguez, Antonela | Farris, Lindsey | Wessel, Caitlin R. | Infantino, Christopher | Niedowicz, Dana M. | Helman, Alex M. | Beckett, Tina L. | Unrine, Jason M. | Murphy, M. Paul

Article Type: Research Article

Abstract: Background: Exposure to lead (Pb) is a major public health problem that could occur through contaminated soil, air, food, or water, either during the course of everyday life, or while working in hazardous occupations. Although Pb has long been known as a neurodevelopmental toxicant in children, a recent and growing body of epidemiological research indicates that cumulative, low-level Pb exposure likely drives age-related neurologic dysfunction in adults. Environmental Pb exposure in adulthood has been linked to risk of late-onset Alzheimer’s disease (AD) and dementia. Objective: Although the biological mechanism underlying this link is unknown, it has been proposed …that Pb exposure may increase the risk of AD via altering the expression of AD-related genes and, possibly, by activating the molecular pathways underlying AD-related pathology. Methods: We investigated Pb exposure using a line of genetically modified mice with AD-causing knock-in mutations in the amyloid precursor protein and presenilin 1 (APP ΔNL/ΔNL x PS1 P264 L/P264 L ) that had been crossed with Leprdb/db mice to impart vulnerability to vascular pathology. Results: Our data show that although Pb exposure in adult mice impairs cognitive function, this effect is not related to either an increase in amyloid pathology or to changes in the expression of common AD-related genes. Pb exposure also caused a significant increase in blood pressure, a well known effect of Pb. Interestingly, although the increase in blood pressure was unrelated to genotype, only mice that carried AD-related mutations developed cognitive dysfunction, in spite of showing no significant change in cerebrovascular pathology. Conclusions: These results raise the possibility that the increased risk of dementia associated with Pb exposure in adults may be tied to its subsequent interaction with either pre-existing or developing AD-related neuropathology. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, amyloid precursor protein, hypertension, presenilin 1, vascular contributions to cognitive impairment and dementia

DOI: 10.3233/JAD-240640

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S291-S304, 2024

Authors: Iban-Arias, Ruth | Wang, Shu-Han | Soares Dias Portela, Ariana | Yang, Eun-Jeong | Griggs, Elizabeth | Masieri, Sibilla | Hu, Wen | Chen, Lung-Chi | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: Background: The September 11, 2001, catastrophe unleashed widespread destruction beyond the World Center (WTC), with fires and toxic gases leaving lasting impacts. First responders at Ground Zero faced prolonged exposure to hazardous particulate matter (PM), resulting in chronic health challenges. Among the multitude of health concerns, the potential association between the WTCPM and Alzheimer’s disease (AD) has emerged as an area of intense inquiry, probing the intricate interplay between environmental factors and neurodegenerative diseases. Objective: We posit that a genetic predisposition to AD in mice results in dysregulation of the gut-brain axis following chronic exposure to WTCPM. …This, in turn, may heighten the risk of AD-like symptoms in these individuals. Methods: 3xTg-AD and WT mice were intranasally administered with WTCPM collected at Ground Zero within 72 hours after the attacks. Working memory and learning and recognition memory were monitored for 4 months. Moreover, brain transcriptomic analysis and gut barrier permeability along with microbiome composition were examined. Results: Our findings underscore the deleterious effects of WTCPM on cognitive function, as well as notable alterations in brain genes associated with synaptic plasticity, pro-survival, and inflammatory signaling pathways. Complementary, chronic exposure to the WTCPM led to increased gut permeability in AD mice and altered bacteria composition and expression of functional pathways in the gut. Conclusions: Our results hint at a complex interplay between gut and brain axis, suggesting potential mechanisms through which WTCPM exposure may exacerbate cognitive decline. Identifying these pathways offers opportunities for tailored interventions to alleviate neurological effects among first responders. Show more

Keywords: Alzheimer’s disease, cognitive decline, gut microbiome, World Center particulate matter

DOI: 10.3233/JAD-240635

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S305-S325, 2024

Authors: Wang, Wenzhang | Zhao, Fanpeng | Torres, Sandy | Harris, Peggy L.R. | Wang, Xinglong | Peng, Lihua | Siedlak, Sandra L. | Zhu, Xiongwei

Article Type: Research Article

Abstract: Background: Space radiation was linked to neurological damage and behavioral deficits which raised concerns of increased degenerative risk on the brain and development of Alzheimer’s disease following space travel. Objective: In this study, we investigated the effects of irradiation by 56 Fe and 28 Si in CRND8 mice, an Alzheimer’s disease mouse model. Methods: Six-month-old CRND8 mice were exposed to whole body irradiation by 56 Fe and 28 Si at 0.5 Gy and 2 Gy doses. Behavior tests were administered 1-month to 3-months post-irradiation. Amyloid deposition and other pathological changes were analyzed 3-months and/or 6-months post-irradiation. …Results: The Novel Object Recognition test showed some decline in 8-month-old mice compared to non-irradiated CRND8 mice. Male mice also showed a loss of freezing behavior in the fear conditioning contextual test following irradiation. Golgi staining revealed a loss of spines in hippocampal neurons after irradiation. Total amyloid immunohistochemistry showed a robust increase in 3-months post-irradiation 56 Fe groups which became normalized to non-irradiated group by 6-months post-irradiation. However, 2 Gy 28 Si caused a trend towards increased plaque load at 3-months post-irradiation which became significant at 6-months post irradiation only in male CRND8 mice. While 0.5 Gy Fe did not induce obvious changes in the total number of iba-1 positive microglia, more hippocampal microglia were found to express PCNA after 0.5 Gy Fe treatment, suggesting potential involvement of microglial dysfunction. Conclusions: Overall, our study provides new evidence of gender-specific and ion-dependent effects of space radiation on cognition and amyloid pathology in AD models. Show more

Keywords: Alzheimer’s disease, microglia, PCNA, senescence, space radiation

DOI: 10.3233/JAD-240570

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S327-S339, 2024

Authors: Alldred, Melissa J. | Pidikiti, Harshitha | Ibrahim, Kryillos W. | Lee, Sang Han | Heguy, Adriana | Hoffman, Gabriel E. | Mufson, Elliott J. | Stutzmann, Grace E. | Ginsberg, Stephen D.

Article Type: Research Article

Abstract: Background: Individuals with Down syndrome (DS) have intellectual disability and develop Alzheimer’s disease (AD) pathology during midlife, particularly in the hippocampal component of the medial temporal lobe memory circuit. However, molecular and cellular mechanisms underlying selective vulnerability of hippocampal CA1 neurons remains a major knowledge gap during DS/AD onset. This is compounded by evidence showing spatial (e.g., deep versus superficial) localization of pyramidal neurons (PNs) has profound effects on activity and innervation within the CA1 region. Objective: We investigated whether there is a spatial profiling difference in CA1 PNs in an aged female DS/AD mouse model. We posit …dysfunction may be dependent on spatial localization and innervation patterns within discrete CA1 subfields. Methods: Laser capture microdissection was performed on trisomic CA1 PNs in an established mouse model of DS/AD compared to disomic controls, isolating the entire CA1 pyramidal neuron layer and sublayer microisolations of deep and superficial PNs from the distal CA1 (CA1a) region. Results: RNA sequencing and bioinformatic inquiry revealed dysregulation of CA1 PNs based on spatial location and innervation patterns. The entire CA1 region displayed the most differentially expressed genes (DEGs) in trisomic mice reflecting innate DS vulnerability, while trisomic CA1a deep PNs exhibited fewer but more physiologically relevant DEGs, as evidenced by bioinformatic inquiry. Conclusions: CA1a deep neurons displayed numerous DEGs linked to cognitive functions whereas CA1a superficial neurons, with approximately equal numbers of DEGs, were not linked to pathways of dysregulation, suggesting the spatial location of vulnerable CA1 PNs plays an important role in circuit dissolution. Show more

Keywords: Alzheimer’s disease, bioinformatics, CA1, circuitry, Down syndrome, hippocampus, laser capture microdissection, RNA-seq, selective vulnerability, trisomy

DOI: 10.3233/JAD-240622

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S341-S362, 2024

Authors: Correia, Sónia C. | Perry, George | Moreira, Paula I.

Article Type: Review Article

Abstract: More than a century after the first description of Alzheimer’s disease (AD), the road to a cure for this complex and heterogeneous neurodegenerative disorder has been paved by countless descriptive hypotheses and successive clinical trial failures. Auspiciously, the era of genome-wide association studies revolutionized the classical “neurocentric” view of AD by providing clues that brain-resident immune cells (i.e., microglia and astrocytes) are also key players in the pathological and clinical trajectory of this neurodegenerative disorder. Considering that the intercommunication among neurons, astrocytes, and microglia is fundamental for the functional organization of the brain, it is evident that the disruption of …the proper functioning of this “triad” could contribute to the neuroinflammatory and neurodegenerative events that occur in the AD brain. Importantly, recent scientific progress in the burgeoning field of immunometabolism, a crossroad between metabolism and immune response, shed light on the importance of metabolic reprogramming of brain-resident immune cells in AD pathology. In this sense, the present review is aimed to summarize and discuss the current knowledge on the metabolic patterns of brain-resident immune cells during the AD continuum, putting a special focus on glucose, amino acids, and lipid metabolism. Changing the “old” picture of AD pathological basis by integrating the role of brain-resident immune cells it is imperative to establish new and feasible therapeutic interventions able to curb neuroinflammatory and neurodegenerative processes, and consequently cognitive deterioration. Show more

Keywords: Alzheimer’s disease, amino acids, astrocytes, glucose, lipids, metabolism, microglia

DOI: 10.3233/JAD-240787

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S363-S385, 2024