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

Authors: Perry, George

Article Type: Introduction

DOI: 10.3233/JAD-249015

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S1-S1, 2024

Authors: Merrick, Richard | Brayne, Carol

Article Type: Research Article

Abstract: Background: There is renewed interest in whether sex differences in dementia risk exist, and what influence social and biological factors have. Objective: To review evidence from the Cognitive Function and Ageing Studies (CFAS), a multi-center population-representative cohort study in the UK; focusing on dementia and cognition, incorporating findings on participants’ health and social circumstances. Methods: After identifying all CFAS publications, the results of all sex-stratified primary analyses of CFAS data were narratively reviewed. Results: Of 337 publications, 94 report results by sex (including null findings), which are summarized by theme: dementia epidemiology, cognition, mental …health, health expectancy, social context and biological resource (including neuropathology). Conclusions: Where differences are found they most commonly favor men; however, greater mortality in men may confound associations with age-related outcomes. This ‘survival bias’ may explain findings of greater risk of dementia and faster cognitive decline in women. Age-specific dementia incidence was similar between sexes, although reduced incidence across study generations was more pronounced in men. Mood disorders were more prevalent in women, but adjusting for disability and deprivation attenuated the association. Prominent findings from other cohorts that women have more Alzheimer’s disease pathology and greater risk of dementia from the Apolipoprotein E ɛ 4 allele were not observed, warranting further investigation. The ‘male-female health-survival paradox’ is demonstrated whereby women live longer but with more comorbidity and disability. Examining why health expectancies changed differently over two decades for each sex (interacting with deprivation) may inform population interventions to improve cognitive, mental and physical health in later life. Show more

Keywords: Aging, Alzheimer’s disease, cognitive decline, dementia, epidemiology, gender, healthy life expectancy, mental health, sex differences

DOI: 10.3233/JAD-240358

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S3-S12, 2024

Authors: Sittig, Johannes | Pickert, Lena | Weigert, Hannah | Deelen, Joris | Polidori, M. Cristina | Nelles, Gereon

Article Type: Research Article

Abstract: Background: With advancing age, cognitive decline is frequently associated with endothelial dysfunction, but data on vascular performance prior to the onset of mild cognitive impairment (MCI) is scarce. Objective: To investigate the relationship between endothelial function, vital parameters and cognitive performance in older adults with subjective cognitive decline (SCD). Methods: Forty-five volunteers aged 65 years and older with SCD underwent comprehensive geriatric assessment-based prognosis evaluation by means of the Multidimensional Prognostic Index (MPI), full neuropsychological examination and peripheral arterial tonometry measurement by means of EndoPAT™ 2000 to evaluate endothelial flexibility and vital parameters. Six months after …initial evaluation, participants were contacted by phone and a telephone-administered version of the MPI (TELE-MPI) was conducted. Results: Fifteen study participants scored below the cutoff score of 26 on the Montreal Cognitive Assessment, suggesting MCI (26.56±2.23). Nominal significant correlations were found between heart rate (HR) and trail making test (TMT) A (β= –0.49, p  = 0.03), between heart rate variability (HRV) and TMT B (β= 0.78, p  = 0.041), between power of low-frequency band (LF) HRV and Mini Nutritional Assessment-Short Form (β= 0.007, p  = 0.037) as well as between augmentation index (AI) and CogState Detection Test (β= 0.002, p  = 0.034). Conclusions: HR, HRV, and AI, but not endothelial flexibility are associated with cognitive performance in SCD and suspected MCI patients and may serve as clinical biomarkers in the early diagnosis of neurodegenerative disorders with advancing age. Show more

Keywords: Alzheimer’s disease, augmentation index, dementia, endothelial function, heart-brain syndrome, heart rate, heart rate variability, mild cognitive impairment, Multidimensional Prognostic Index, subjective cognitive decline

DOI: 10.3233/JAD-240661

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S13-S24, 2024

Authors: Kaltsa, Maria | Tsolaki, Anthoula | Lazarou, Ioulietta | Mittas, Ilias | Papageorgiou, Mairi | Papadopoulou, Despina | Tsimpli, Ianthi Maria | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: The assessment of language deficits can be valuable in the early clinical diagnosis of neurodegenerative disorders, including Alzheimer’s disease (AD). Objective: The present study aims to explore whether language markers at the macrostructural level could assist with the placement of an individual across the dementia continuum employing production data from structured narratives. Methods: We administered a Picture Sequence Narrative Discourse Task to 170 speakers of Greek: young healthy controls (yHC), cognitively intact healthy elders (eHC), elder participants with subjective cognitive impairment (SCI), with mild cognitive impairment (MCI), and with AD dementia at the mild/moderate stages. …Structural MRIs, medical history, neurological examination, and neuropsychological/cognitive screening determined the status of each speaker to appropriately groupthem. Results: The data analysis revealed that the Macrostructure Index, Irrelevant Info, and Narration Density markers can track cognitive decline and AD (p  < 0.001; Macrostructural Index: eHC versus AD Sensitivity 93.8%, Specificity 74.4%, MCI versus AD Sensitivity 93.8%, Specificity 66.7%; Narration Density: eHC versus AD Sensitivity 90.6%, Specificity 71.8%, MCI versus AD Sensitivity 93.8%, Specificity 66.7%). Moreover, Narrative Complexity was significantly affected for subjects with AD, Irrelevant Info increased in the narrations of speakers with MCI and AD, while Narration Length did not appear to indubitably differentiate between the cognitively intact groups and the clinical ones. Conclusions: Narrative Macrostructure Indices provide valuable information on the language profile of speakers with(out) intact cognition revealing subtle early signs of cognitive decline and AD suggesting that the inclusion of language-based assessment tools would facilitate the clinical process. Show more

Keywords: Alzheimer’s disease, Greek, healthy aging, macrostructure skills, mild cognitive impairment, narratives, picture sequence discourse tasks, subjective cognitive impairment

DOI: 10.3233/JAD-240496

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S25-S43, 2024

Authors: Amaral-Carvalho, Viviane | Bento Lima-Silva, Thais | Inácio Mariano, Luciano | Cruz de Souza, Leonardo | Cerqueira Guimarães, Henrique | Santoro Bahia, Valéria | Nitrini, Ricardo | Tonidandel Barbosa, Maira | Sanches Yassuda, Mônica | Caramelli, Paulo

Article Type: Research Article

Abstract: Background: The Addenbrooke’s Cognitive Examination-Revised (ACE-R) is an accessible cognitive tool that supports the early detection of mild cognitive impairment (MCI), Alzheimer’s disease (AD), and behavioral variant frontotemporal dementia (bvFTD). Objective: To investigate the diagnostic efficacy of the ACE-R in MCI, AD, and bvFTD through the identification of novel coefficients for differentiation between these diseases. Methods: We assessed 387 individuals: 102 mild AD, 37 mild bvFTD, 87 with amnestic MCI patients, and 161 cognitively unimpaired controls. The Mokken scaling technique facilitated the extraction out of the 26 ACE-R items that exhibited a common latent trait, thereby …generating the Mokken scales for the AD group and the MCI group. Subsequently, we performed logistic regression, integrating each Mokken scales with sociodemographic factors, to differentiate between AD and bvFTD, as well as between AD or MCI and control groups. Ultimately, the Receiver Operating Characteristic curve analysis was employed to assess the efficacy of the coefficient’s discrimination. Results: The AD-specific Mokken scale (AD-MokACE-R) versus bvFTD exhibited an Area Under the Curve (AUC) of 0.922 (88% sensitivity and specificity). The AD-MokACE-R versus controls achieved an AUC of 0.968 (93% sensitivity, 94% specificity). The MCI-specific scale (MCI-MokACE-R) versus controls demonstrated an AUC of 0.859 (78% sensitivity, 79% specificity). Conclusions: The ACE-R’s capacity is enhanced through statistical methods and demographic integration, allowing for accurate differentiation between AD and bvFTD, as well as between MCI and controls. This new method not only reinforces its clinical value in early diagnosis but also surpasses traditional approaches noted in prior studies. Show more

Keywords: Aging, Alzheimer’s disease, cognition, dementia, frontotemporal dementia, mild cognitive impairment, neuropsychological tests

DOI: 10.3233/JAD-240554

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S45-S55, 2024

Authors: Lozupone, Madia | Dibello, Vittorio | Sardone, Rodolfo | Altamura, Mario | Bellomo, Antonello | Daniele, Antonio | Solfrizzi, Vincenzo | Resta, Emanuela | Panza, Francesco

Article Type: Editorial

Abstract: Social dysfunction is a maladaptive process of coping, problem solving, and achieving one’s goals. A new definition of apathy was cross-linked to social dysfunction, with a reduced goal-directed behavior and social interaction as a separate dimension. We hypothesized that these two neuropsychiatric symptoms may be included in the mild behavioral impairment diagnostic framework, operationalizing and standardizing late-life neuropsychiatric symptom assessment, to improve risk determination of dementia. Social dysfunction and apathy were transdiagnostic and prodromic for late-life cognitive disorders. A transdiagnostic approach could provide a useful mean for a better understanding of apathy and related conditions such as social behavior.

Keywords: Alzheimer’s disease, apathy, biopsychosocial frailty, dementia, depression, late-life cognitive disorders, mild behavioral impairment, mild cognitive impairment, social dysfunction, social withdrawal

DOI: 10.3233/JAD-240556

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S57-S61, 2024

Authors: Petersen, Melissa E. | Zhang, Fan | Hall, James R. | Julovich, David | Rissman, Robert A. | Meeker, Karin L. | Phillips, Nicole | Large, Stephanie | Ances, Beau M. | O’Bryant, Sid E.

Article Type: Research Article

Abstract: Background: Examination of Alzheimer’s disease (AD) related biomarkers among diverse communities has remained limited. Objective: The aim of this study was to expand on prior work to provide a characterization of ptau181 among a diverse community sample. Consideration was taken regarding the impact of comorbidities on ptau181 levels including medical. Methods: 3,228 (n  = 770 African American [AA], n  = 1,231 Hispanic, and n  = 1,227 non-Hispanic white [NHW]) Health and Aging Brain Study- Health Disparities (HABS-HD) participants were included in this study. ANCOVAs were conducted to examine differences in ptau181 levels across race and ethnic groups. Violin plots …were also generated stratified by APOE ɛ 4 carrier status, Amyloid PET positivity status, medical comorbidity (hypertension, dyslipidemia, chronic kidney disease [CKD], and diabetes) and by cognitive diagnosis. Results: Ptau181 levels were found to differ between Hispanics and NHW after covarying for age, sex, and APOE ɛ 4 status. Amyloid PET positivity was associated with higher ptau181 levels across all groups. APOE ɛ 4 positivity status was only significantly associated with ptau181 levels among AAs. Across all race and ethnic groups, those with a diagnosis of CKD had higher levels of ptau181. When stratified by cognitive diagnosis, cognitively unimpaired Hispanics had higher ptau181 if they also had a diagnosis of CKD or diabetes. p -values ≤0.01. Conclusions: Differences in ptau181 levels were shown in a diverse community sample. Medical comorbidities had a differing effect on ptau181 levels particularly among Hispanics even without cognitive impairment. Findings support the need for future work to consider comorbid conditions when examining the utility of ptau181. Show more

Keywords: Alzheimer’s disease, biomarkers, diverse, plasma, ptau181

DOI: 10.3233/JAD-240633

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S63-S73, 2024

Authors: Gogola, Alexandra | Cohen, Ann D. | Snitz, Beth | Minhas, Davneet | Tudorascu, Dana | Ikonomovic, Milos D. | Shaaban, C. Elizabeth | Doré, Vincent | Matan, Cristy | Bourgeat, Pierrick | Mason, N. Scott | Leuzy, Antoine | Aizenstein, Howard | Mathis, Chester A. | Lopez, Oscar L. | Lopresti, Brian J. | Villemagne, Victor L.

Article Type: Research Article

Abstract: Background: Tau accumulation in Alzheimer’s disease is associated with short term clinical progression and faster rates of cognitive decline in individuals with high amyloid-β deposition. Defining an optimal threshold of tau accumulation predictive of cognitive decline remains a challenge. Objective: We tested the ability of regional tau PET sensitivity and specificity thresholds to predict longitudinal cognitive decline. We also tested the predictive performance of thresholds in the proposed new NIA-AA biological staging for Alzheimer’s disease where multiple levels of tau positivity are used to stage participants. Methods: 18 F-flortaucipir scans from 301 non-demented participants were processed …and sampled. Four cognitive measures were assessed longitudinally. Regional standardized uptake value ratios were split into infra- and suprathreshold groups at baseline using previously derived thresholds. Survival analysis, log rank testing, and Generalized Estimation Equations assessed the relationship between the application of regional sensitivity/specificity thresholds and change in cognitive measures as well as tau threshold performance in predicting cognitive decline within the new NIA-AA biological staging. Results: The meta temporal region was best for predicting risk of short-term cognitive decline in suprathreshold, as compared to infrathreshold participants. When applying multiple levels of tau positivity, each subsequent level of tau identified cognitive decline at earlier timepoints. Conclusions: When using 18 F-flortaucipir, meta temporal suprathreshold classification was associated with increased risk of cognitive decline, suggesting that abnormal tau deposition in the cortex predicts decline. Likewise, the application of multiple levels of tau clearly predicts the distinctive cognitive trajectories in the new NIA-AA biological staging framework. Show more

Keywords: Alzheimer’s disease, 18F-flortaucipir, PET, tau

DOI: 10.3233/JAD-240543

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S75-S92, 2024

Authors: Egebäck Arulf, Sofia | Ziyue Zhou, Robin | Kirsebom, Bjørn-Eivind | Jejcic, Alenka | Fladby, Tormod | Winblad, Bengt | Tjernberg, Lars | Schedin-Weiss, Sophia

Article Type: Research Article

Abstract: Background: The N-glycan structure bisecting N-acetylglucosamine (bisecting GlcNAc) is present on several N-glycans that are elevated in Alzheimer’s disease (AD), and previous studies have shown that bisecting GlcNAc levels correlate with total tau and phospho-tau181 in cerebrospinal fluid at early stages of AD. A recent population-based study showed that bisecting GlcNAc correlates with total tau also in blood and that this correlation could predict conversion to dementia. Objective: In this study, we have further investigated how bisecting GlcNAc relates to total tau and phospho-tau 181 in cerebrospinal fluid samples from controls and cases with early cognitive deficits, stratified …by amyloid/tau status and gender. Methods: Relative levels of bisecting GlcNAc in cerebrospinal fluid were measured by an enzyme-linked lectin assay in individuals with subjective cognitive decline, mild cognitive impairment and controls from the Norwegian Dementia Disease Initiation cohort. Results: As in our previous study, the correlation between bisecting GlcNAc and total tau or phospho-tau181 was particularly strong in the subjective cognitive decline group. The correlation was observed in amyloid negative and tau negative as well as amyloid positive and tau positive individuals, both in females and in males. Interestingly, among the amyloid negative and tau negative individuals, the correlation was observed in individuals with subjective cognitive decline but not in the controls. Conclusions: Thus, bisecting GlcNAc could be a biomarker for early cognitive decline. Show more

Keywords: Alzheimer’s disease, bisecting N-acetylglucosamine, dementia, mild cognitive impairment, N-glycosylation, phospho-tau, subjective cognitive decline, total tau

DOI: 10.3233/JAD-240628

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S93-S101, 2024

Authors: Duits, Flora H. | Nilsson, Johanna | Zetterberg, Henrik | Blennow, Kaj | van der Flier, Wiesje M. | Teunissen, Charlotte E. | Brinkmalm, Ann

Article Type: Research Article

Abstract: Background: Synaptic dysfunction is closely associated with cognitive function in Alzheimer’s disease (AD), and is present already in an early stage of the disease. Objective: Using serial cerebrospinal fluid (CSF) sampling, we aimed to investigate slopes of CSF synaptic proteins, and their relation with cognition along the AD continuum. Methods: We included subjects with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) (n  = 50 amyloid-β+ [A  +], n  = 50 A–) and 50 patients with AD dementia from the Amsterdam dementia cohort, with CSF at two time points (median[IQR] 2.1[1.4–2.7] years). We analyzed 17 synaptic proteins …and neurofilament light (NfL). Using linear mixed models we assessed trajectories of protein levels, and associations with cognitive decline (repeated Mini-Mental State Examination). We used Cox regression models to assess predictive value of protein levels for progression to AD dementia. Results: At baseline most proteins showed increased levels in AD dementia compared to the other groups. In contrast NPTX2 levels were lower in AD dementia. Higher baseline levels of SNAP25, β-syn, and 14-3-3 proteins were associated with faster cognitive decline (St.B[SE] –0.27[0.12] to –0.61[0.12]). Longitudinal analyses showed that SYT1 and NPTX levels decreased over time in AD dementia (st.B[SE] –0.10[0.04] to –0.15[0.05]) and SCD/MCI-A+ (St.B[SE] –0.07[0.03] to –0.12[0.03]), but not in SCD/MCI-A- (pinteraction  < 0.05). Increase over time in NfL levels was associated with faster cognitive decline in AD dementia (St.B[SE] –1.75[0.58]), but not in the other groups (pinteraction  < 0.05). Conclusions: CSF synaptic proteins showed different slopes over time, suggesting complex synaptic dynamics. High levels of especially SNAP-25 may have value for prediction of cognitive decline in early AD stages, while increase in NfL over time correlates better with cognitive decline in later stages. Show more

Keywords: Alzheimer’s disease, biomarkers, cognitive decline, mass spectrometry, synapses

DOI: 10.3233/JAD-240610

Citation: Journal of Alzheimer's Disease, vol. 100, no. s1, pp. S103-S114, 2024

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