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