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

Authors: Liu, Yanchao | He, Benrong | Du, Kai | Zheng, Jie | Ke, Dan | Mo, Wen | Li, Yanni | Jiang, Tao | Xiong, Rui | Sun, Fei | Zhao, Shi | Wei, Wei | Xu, Zhipeng | Zhang, Shujuan | Li, Shihong | Wang, Xin | Zhou, Qiuzhi | Ye, Jinwang | Liang, Yi | Lin, Hao | Liu, Yong | Chen, Liangkai | Zhang, Huaqiu | Zhang, Yao | Gao, Yang | Wang, Jian-Zhi

Article Type: Research Article

Abstract: Background: The prevalence of Alzheimer’s disease (AD) is increasing, therefore, identifying biomarkers to predict those vulnerable to AD is imperative. Type 2 diabetes (T2D) serves as an independent risk factor for AD. Early prediction of T2D patients who may be more susceptible to AD, so as to achieve early intervention, is of great significance to reduce the prevalence of AD. Objective: To establish periphery biomarkers that could predict conversion of T2D into pre-AD-like cognitive decline. Methods: A follow-up study was carried out from 159 T2D patients at baseline. The correlations of cognitive states (by MMSE score) …with multi-periphery biomarkers, including APOE genotype, plasma amyloid-β level, platelet GSK-3β activity, and olfactory score were analyzed by logistic regression. ROC curve was used for establishing the prediction model. Additionally, MRI acquired from 38 T2D patients for analyzing the correlation among cognitive function, biomarkers and brain structure. Results: Compared with the patients who maintained normal cognitive functions during the follow-up period, the patients who developed MCI showed worse olfactory function, higher platelet GSK-3β activity, and higher plasma Aβ42 /Aβ40 ratio. We conducted a predictive model which T2D patients had more chance of suffering from pre-AD-like cognitive decline. The MRI data revealed MMSE scores were positively correlated with brain structures. However, platelet GSK-3β activity was negatively correlated with brain structures. Conclusions: Elevated platelet GSK-3β activity and plasma Aβ42 /Aβ40 ratio with reduced olfactory function are correlated with pre-AD-like cognitive decline in T2D patients, which used for predicting which T2D patients will convert into pre-AD-like cognitive decline in very early stage. Show more

Keywords: Alzheimer’s disease, biomarker, brain structure, mild cognitive impairment, prediction model, type 2 diabetes

DOI: 10.3233/JAD-240455

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S115-S129, 2024

Authors: Poudel, Purna | Frost, Shaun M. | Eslick, Shaun | Sohrabi, Hamid R. | Taddei, Kevin | Martins, Ralph N. | Hone, Eugene

Article Type: Research Article

Abstract: Background: As an extension of the central nervous system (CNS), the retina shares many similarities with the brain and can manifest signs of various neurological diseases, including Alzheimer’s disease (AD). Objective: To investigate the retinal spectral features and develop a classification model to differentiate individuals with different brain amyloid levels. Methods: Sixty-six participants with varying brain amyloid-β protein levels were non-invasively imaged using a hyperspectral retinal camera in the wavelength range of 450–900 nm in 5 nm steps. Multiple retina features from the central and superior views were selected and analyzed to identify their variability among individuals with …different brain amyloid loads. Results: The retinal reflectance spectra in the 450–585 nm wavelengths exhibited a significant difference in individuals with increasing brain amyloid. The retinal features in the superior view showed higher inter-subject variability. A classification model was trained to differentiate individuals with varying amyloid levels using the spectra of extracted retinal features. The performance of the spectral classification model was dependent upon retinal features and showed 0.758–0.879 accuracy, 0.718–0.909 sensitivity, 0.764–0.912 specificity, and 0.745–0.891 area under curve for the right eye. Conclusions: This study highlights the spectral variation of retinal features associated with brain amyloid loads. It also demonstrates the feasibility of the retinal hyperspectral imaging technique as a potential method to identify individuals in the preclinical phase of AD as an inexpensive alternative to brain imaging. Show more

Keywords: Alzheimer’s disease, amyloid, brain, hyperspectral imaging, machine learning, retina

DOI: 10.3233/JAD-240631

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S131-S152, 2024

Authors: Ferrer, Isidro

Article Type: Review Article

Abstract: Senile plaques, mainly diffuse, and cerebral amyloid-β (Aβ) angiopathy are prevalent in the aging brain of non-human primates, from lemurs to non-human Hominidae. Aβ but not hyper-phosphorylated tau (HPtau) pathology is the common nominator proteinopathy of non-human primate brain aging. The abundance of Aβ in the aging primate brain is well tolerated, and the impact on cognitive functions is usually limited to particular tasks. In contrast, human brain aging is characterized by the early appearance of HPtau pathology, mainly forming neurofibrillary tangles, dystrophic neurites of neuritic plaques, and neuropil threads, preceding Aβ deposits by several decades and by its severity …progressing from selected nuclei of the brain stem, entorhinal cortex, and hippocampus to the limbic system, neocortex, and other brain regions. Neurofibrillary tangles correlate with cognitive impairment and dementia in advanced cases. Aβ pathology is linked in humans to altered membrane protein and lipid composition, particularly involving lipid rafts. Although similar membrane alterations are unknown in non-human primates, membrane senescence is postulated to cause the activated β-amyloidogenic pathway, and Aβ pathology is the prevailing signature of non-human and human primate brain aging. Show more

Keywords: Alzheimer’s disease, amyloid-β , brain aging, primates, tau

DOI: 10.3233/JAD-240389

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S153-S164, 2024

Authors: Grant, William B.

Article Type: Review Article

Abstract: The two major determining factors for Alzheimer’s disease (AD) are genetics and lifestyle. Alleles of the apolipoprotein E (APOE) gene play important roles in the development of late-onset AD, with APOE ɛ 4 increasing risk, APOE ɛ 3 being neutral, and APOE ɛ 2 reducing risk. Several modifiable lifestyle factors have been studied in terms of how they can modify the risk of AD. Among these factors are dietary pattern, nutritional supplements such as omega-3 fatty acids, and B vitamins, physical exercise, and obesity, and vitamin D. The Western diet increases risk of AD, while dietary …patterns such as the Mediterranean and vegetarian/vegan diets reduce risk. Foods associated with reduced risk include coffee, fruits and vegetables, whole grains and legumes, and fish, while meat and ultraprocessed foods are associated with increased risk, especially when they lead to obesity. In multi-country ecological studies, the amount of meat in the national diet has the highest correlation with risk of AD. The history of research regarding dietary patterns on risk of AD is emphasized in this review. The risk of AD can be modified starting at least by mid-life. People with greater genetic risk for AD would benefit more by choosing lifestyle factors to reduce and/or delay incidence of AD. Show more

Keywords: Alzheimer’s disease, APOE, dietary pattern, ecological study, genetic risk, lifestyle, meat, obesity, ultraprocessed foods, Western diet

DOI: 10.3233/JAD-240658

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S165-S178, 2024

Authors: Oriá, Reinaldo B. | Smith, Carr J. | Ashford, J. Wesson | Vitek, Michael P. | Guerrant, Richard L.

Article Type: Review Article

Abstract: Fortea et al.’s. (2024) recent data analysis elegantly calls attention to familial late-onset Alzheimer’s disease (AD) with APOE4 homozygosity. The article by Grant (2024) reviews the factors associated with AD, particularly the APOE genotype and lifestyle, and the broad implications for prevention, both for individuals with the lifestyles associated with living in resource-rich countries and for those enduring environmental adversity in poverty settings, including high exposure to enteric pathogens and precarious access to healthcare. Grant discusses the issue of APOE genotype and its implications for the benefits of lifestyle modifications. This review highlights that bearing APOE4 …could constitute an evolutionary benefit in coping with heavy enteric infections and malnutrition early in life in the critical formative first two years of brain development. However, the critical issue may be that this genotype could be a health concern under shifts in lifestyle and unhealthy diets during aging, leading to severe cognitive impairments and increased risk of AD. This commentary supports the discussions of Grant and the benefits of improving lifestyle for decreasing the risks for AD while providing further understanding and modelling of the early life benefits of APOE4 amidst adversity. This attention to the pathophysiology of AD should help further elucidate these critical, newly appreciated pathogenic pathways for developing approaches to the prevention and management in the context of the APOE genetic variations associated with AD. Show more

Keywords: Alzheimer’s disease, APOE, Apolipoprotein E, malnutrition, neuroplasticity, prevention

DOI: 10.3233/JAD-240888

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S179-S185, 2024

Authors: Serpente, Maria | Fenoglio, Chiara | Arcaro, Marina | Carandini, Tiziana | Sacchi, Luca | Pintus, Manuela | Rotondo, Emanuela | Borracci, Vittoria | Ghezzi, Laura | Bouzigues, Arabella | Russell, Lucy L. | Foster, Phoebe H. | Ferry-Bolder, Eve | van Swieten, John C. | Jiskoot, Lize C. | Seelaar, Harro | Sánchez Valle, Raquel | Laforce, Robert | Graff, Caroline | Vandenberghe, Rik | de Mendonça, Alexandre | Tiraboschi, Pietro | Santana, Isabel | Gerhard, Alexander | Levin, Johannes | Sorbi, Sandro | Otto, Markus | Pasquier, Florence | Ducharme, Simon | Butler, Chris R. | Le Ber, Isabelle | Finger, Elizabeth | Tartaglia, Maria Carmela | Masellis, Mario | Rowe, James B. | Synofzik, Matthis | Moreno, Fermin | Borroni, Barbara | Rohrer, Jonathan D. | Arighi, Andrea | Galimberti, Daniela | Alberici, Antonella | Afonso, Sónia | Alves, Patricia | Anderl-Straub, Sarah | Antonell, Anna | Balasa, Mircea | Barandiaran, Myriam | Bargalló, Nuria | Bartha, Robert | Bender, Benjamin | Bernhardt, Alexander Maximilian | Bertoux, Maxime | Bertrand, Anne | Bessi, Valentina | Black, Sandra | Bocca, Giorgio | Bocchetta, Martina | Borrego-Ecija, Sergi | Brice, Alexis | Bruffaerts, Rose | Buccellato, Francesca R | Buratti, Emanuele | Cantoni, Valentina | Caroppo, Paola | Cash, David | Castelo-Branco, Miguel | Colliot, Olivier | Convery, Rhian | Cope, Thomas | Costa-Coelho, Tiago | Croitoru, Ioana | Camuzat, Agnès | D’Anca, Marianna | de Boer, Liset | de Houwer, Julie | Deramecourt, Vincent | Durães, João | Di Fede, Giuseppe | Ferrari, Camilla | Florio, Graziana | Frascotti, Marta | Freedman, Morris | Funkiewiez, Aurélie | Gabilondo, Alazne | Gasparotti, Roberto | Giaccone, Giorgio | Giannini, Lucia | Goldsmith, Sophie | Graf, Lisa | Jelic, Vesna | Keren, Ron | Krüger, Johanna | Kuchcinski, Gregory | Langheinrich, Tobias | Lebouvier, Thibaud | Leitão, Maria João | Lemos, João | Lima, Marisa | Lladó, Albert | Lombardi, Gemma | Lombardi, Jolina | Malpetti, Maura | Maruta, Carolina | Mengel, David | Miltenberger, Gabriel | Mitchell, Sara | Montembault, Maxime | Nacmias, Benedetta | Nilsson, Mattias | Öijerstedt, Linn | Olives, Jaume | Papma, Janne M. | Pijnenburg, Yolande | Poesen, Koen | Polito, Cristina | Poos, Jackie | Premi, Enrico | Prioni, Sara | Prix, Catharina | Redaelli, Veronica | Rittman, Timothy | Rademakers, Rosa | Rinaldi, Daisy | Rogaeva, Ekaterina | Rollin, Adeline | Rosa-Neto, Pedro | Almeida, Maria Rosario | Rossi, Giacomina | Samra, Kiran | Saracino, Dario | Sayah, Sabrina | Scarpini, Elio | Schönecker, Sonja | Shoesmith, Christen | Simões do Couto, Frederico | Stockbauer, Anna | Tábuas-Pereira, Miguel | Tang-Wai, David | Taheri Rydell, Melissa | Tainta, Mikel | Thomas, David L | Vandenbulcke, Mathieu | Van Damme, Philip | van Minkelen, Rick | Verdelho, Ana | Viklund, Henrik | Vimercati, Roberto | Vogels, Annick | Wagemann, Olivia | Wlasich, Elisabeth

Article Type: Research Article

Abstract: Background: Long non-coding RNAs (lncRNAs) play crucial roles in gene regulation and are implicated in neurodegenerative diseases, including frontotemporal dementia (FTD). However, their expression patterns and potential as biomarkers in genetic FTD involving Chromosome 9 Open Reading Frame (C9ORF72 ), Microtubule Associated Protein Tau (MAPT ), and Progranulin (GRN ) genes are not well understood. Objective: This study aimed to profile the expression levels of lncRNAs in peripheral blood mononuclear cells collected within the GENetic Frontotemporal dementia Initiative (GENFI). Methods: Fifty-three lncRNAs were analyzed with the OpenArray Custom panel, in 131 patients with mutations in C9ORF72 …, MAPT , and GRN , including 68 symptomatic mutation carriers (SMC) and 63 presymptomatic mutation carriers (PMC), compared with 40 non-carrier controls (NC). Results: Thirty-eight lncRNAs were detectable; the relative expression of NEAT1 and NORAD was significantly higher in C9ORF72 SMC as compared with NC. GAS5 expression was instead significantly lower in the GRN group versus NC. MAPT carriers showed no significant deregulations. No significant differences were observed in PMC. Disease duration did not correlate with lncRNA expression. Conclusions: NEAT1 and NORAD are upregulated in C9ORF72 SMC and GAS5 levels are downregulated in GRN SMC, underlining lncRNAs’ relevance in FTD and their potential for biomarker development. Further validation and mechanistic studies are crucial for clinical implications. Show more

Keywords: Alzheimer’s disease, chromosome 9 open reading frame 72, frontotemporal dementia, long non-coding RNA, microtubule associated protein tau, progranulin

DOI: 10.3233/JAD-240557

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S187-S196, 2024

Authors: Buchman, Aron S. | Yu, Lei | Oveisgharan, Shahram | Zammit, Andrea R. | Wang, Tianhao | Shulman, Joshua M. | VanderHorst, Veronique | Nag, Sukrit | Bennett, David A.

Article Type: Research Article

Abstract: Background: The interrelationship of parkinsonism, Parkinson’s disease (PD) and other Alzheimer’s disease (AD) and Alzheimer’s disease and related dementias (ADRD) pathologies is unclear. Objective: We examined the progression of parkinsonian signs in adults with and without parkinsonism, and their underlying brain pathologies. Methods: Annual parkinsonian signs were based on a modified Unified Parkinson’s Disease Rating Scale. We used linear mixed effects models to compare the progression of parkinsonian signs in 3 groups categorized based on all available clinical evaluations: Group1 (never parkinsonism or clinical PD), Group2 (ever parkinsonism, but never clinical PD), Group3 (ever clinical PD). …In decedents, we examined the progression of parkinsonian signs with PD and eight other AD/ADRD pathologies. Results: During average follow-up of 8 years, parkinsonian signs on average increased by 7.3% SD/year (N = 3,807). The progression of parkinsonian signs was slowest in Group1 (never parkinsonism or clinical PD), intermediate in Group2, and fastest in Group3. In decedents (n  = 1,717) pathologic PD and cerebrovascular (CVD) pathologies were associated with a faster rate of progressive parkinsonian signs (all p values <0.05). However, pathologic PD was rare in adults without clinical PD (Group1, 5%; Group2, 7% versus Group3, 55%). Yet, 70% of adults in Group2 without pathologic PD showed one or more CVD pathologies. In Group2, adults with pathologic PD showed faster progression of parkinsonian signs compared with those without evidence of pathologic PD and their rate of progression was indistinguishable from adults with clinical PD. Conclusions: Parkinsonism in old age is more commonly related to cerebrovascular pathologies relative to pathologic PD and only a minority manifest prodromal PD. Show more

Keywords: Alzheimer’s disease, Parkinson’s disease, parkinsonism, pathology

DOI: 10.3233/JAD-240593

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S197-S209, 2024

Authors: Leinenga, Gerhard | Padmanabhan, Pranesh | Götz, Jürgen

Article Type: Review Article

Abstract: Alzheimer’s disease is characterized by progressive impairment of neuronal functions culminating in neuronal loss and dementia. A universal feature of dementia is protein aggregation, a process by which a monomer forms intermediate oligomeric assembly states and filaments that develop into end-stage hallmark lesions. In Alzheimer’s disease, this is exemplified by extracellular amyloid-β (Aβ) plaques which have been placed upstream of tau, found in intracellular neurofibrillary tangles and dystrophic neurites. This implies causality that can be modeled as a linear activation cascade. When Aβ load is reduced, for example, in response to an anti-Aβ immunotherapy, cognitive functions improve in plaque-forming mice. …They also deteriorate less in clinical trial cohorts although real-world clinical benefits remain to be demonstrated. Given the existence of aged humans with unimpaired cognition despite a high plaque load, the central role of Aβ has been challenged. A counter argument has been that clinical symptoms would eventually develop if these aged individuals were to live long enough. Alternatively, intrinsic mechanisms that protect the brain in the presence of pathology may exist. In fact, Aβ toxicity can be abolished by either reducing or manipulating tau (through which Aβ signals), at least in preclinical models. In addition to manipulating steps in this linear pathocascade model, mechanisms of restoring brain reserve can also counteract Aβ toxicity. Low-intensity ultrasound is a neuromodulatory modality that can improve cognitive functions in Aβ-depositing mice without the need for removing Aβ. Together, this highlights a dissociation of Aβ and cognition, with important implications for therapeutic interventions. Show more

Keywords: Alzheimer’s disease, amyloid-β, behavior, focused ultrasound, Fyn kinase, immunotherapy, neuromodulation, scanning ultrasound, tau

DOI: 10.3233/JAD-240616

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S211-S222, 2024

Authors: Arendash, Gary W. | Lin, Xiaoyang | Cao, Chuanhai

Article Type: Research Article

Abstract: Background: While drainage/removal of fluid and toxins from the brain by cerebrospinal fluid (CSF) directly into venous blood is well-known, a second drainage route has recently been (re)discovered—meningeal lymphatic vessels (mLVs)—which are responsible for up to half of total brain fluid/toxin drainage. The cytokine vascular endothelial growth factor (VEGF) increases mLV diameter and numbers to increase mLV drainage, resulting in increased mLV drainage. Alzheimer’s disease (AD) is characterized by low plasma and CSF levels of VEGF. Objective: To determine if non-invasive transcranial radiofrequency wave treatment (TRFT), through modulation of VEGF levels in blood and CSF, can affect removal …of toxins tau and amyloid-β (Aβ) from the brain. Methods: Eight mild/moderate AD subjects were given twice-daily 1-hour TRFT sessions at home by their caregivers. Blood and CSF samples were taken at baseline and following completion of 2 months of TRFT. Results: In plasma and/or CSF, strong baseline correlations between VEGF levels and AD markers (t-tau, p-tau, Aβ1-40 , Aβ1-42 ) were eliminated by TRFT. This effect was primarily due to TRFT-induced increases in VEGF levels in AD subjects with low or unmeasurable “baseline” VEGF levels. These increased VEGF levels were associated with increased clearance/drainage of tau and Aβ from the brain, likely through VEGF’s actions on mLVs. Conclusions: A new mechanism of TRFT is identified (facilitation of brain tau and Aβ clearance via VEGF) that is likely contributory to TRFT’s reversal of cognitive impairment in AD subjects. TRFT may be particularly effective for cognitive benefit in AD subjects who have low VEGF levels. Show more

Keywords: Alzheimer’s disease, amyloid-β, brain clearance, meningeal lymphatic vessels, radiofrequency waves, vascular endothelial growth factor, tau

DOI: 10.3233/JAD-240600

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S223-S241, 2024

Authors: Mandal, Pravat K. | Maroon, Joseph C. | Samkaria, Avantika | Arora, Yashika | Sharma, Shallu | Pandey, Ashutosh

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a major neurodegenerative disorder impacting millions of people with cognitive impairment and affecting activities of daily living. The deposition of neurofibrillary tangles of hyperphosphorylated tau proteins and accumulation of amyloid-β (Aβ) are the main pathological characteristics of AD. However, the actual causal process of AD is not yet identified. Oxidative stress occurs prior to amyloid Aβ plaque formation and tau phosphorylation in AD. The role of master antioxidant, glutathione, and metal ions (e.g., iron) in AD are the frontline area of AD research. Iron overload in specific brain regions in AD is associated with the rate …of cognitive decline. We have presented the outcome from various interventional trials involving iron chelators intended to minimize the iron overload in AD. To date, however, no significant positive outcomes have been reported using iron chelators in AD and warrant further research. Show more

Keywords: Alzheimer’s disease, clinical trials, iron-chelator, iron overload, oxidative stress, prooxidant

DOI: 10.3233/JAD-240605

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S243-S249, 2024

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