Journal of Alzheimer's Disease - Volume 101, issue 2

Authors: Wei, Wenyan | Jiang, Ying | Hu, Guizhen | He, Yanfang | Chen, Huiyi

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders and is characterized by a decrease in learning capacity, memory loss and behavioral changes. In addition to the well-recognized amyloid-β cascade hypothesis and hyperphosphorylated Tau hypothesis, accumulating evidence has led to the proposal of the mitochondrial dysfunction hypothesis as the primary etiology of AD. However, the predominant molecular mechanisms underlying the development and progression of AD have not been fully elucidated. Mitochondrial dysfunction is not only considered an early event in AD pathogenesis but is also involved in the whole course of the disease, with numerous pathophysiological processes, including …disordered energy metabolism, Ca2+ homeostasis dysfunction and hyperactive oxidative stress. In the current review, we have integrated emerging evidence to summarize the main mitochondrial alterations— bioenergetic metabolism, mitochondrial inheritance, mitobiogenesis, fission– fusion dynamics, mitochondrial degradation, and mitochondrial movement— underlying AD pathogenesis; precisely identified the mitochondrial regulators; discussed the potential mechanisms and primary processes; highlighted the leading players; and noted additional incidental signaling pathway changes. This review may help to stimulate research exploring mitochondrial metabolically-oriented neuroprotection strategies in AD therapies, leading to a better understanding of the link between the mitochondrial dysfunction hypothesis and AD pathogenesis. Show more

Keywords: Alzheimer’s disease, aging, mitochondria, molecular therapy

DOI: 10.3233/JAD-240092

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 379-396, 2024

Authors: Giudicessi, Averi | McDowell, Celina Pluim | Martinez, Jairo E. | Baena, Ana | Vila-Castelar, Clara | Norton, Daniel | Aguirre-Acevedo, Daniel C. | Tirado, Victoria | Bocanegra, Yamile | Guzman-Velez, Edmarie | Lopera, Francisco | Cronin-Golomb, Alice | Quiroz, Yakeel T.

Article Type: Review Article

Abstract: Background: The largest identified kindred worldwide with a single mutation causing autosomal-dominant Alzheimer’s disease (ADAD) is a family from Antioquia, Colombia, carrying the Presenilin-1 (PSEN1 ) E280A (Paisa) mutation. The majority of mutation carriers develop dementia, typically commencing in their late 30 s, with a median onset age of 49 years. Cognitive decline is a hallmark feature. Objective: This review synthesizes the existing literature on neuropsychological assessments in PSEN1 E280A mutation carriers throughout their lifespan. We provide a comprehensive overview of cognitive outcomes in this unique population. Methods: We reviewed and integrated the published research, analyzing …studies on neuropsychological assessments in PSEN1 E280A carriers. Our focus was on measures of verbal, semantic, episodic, and spatial memory, and encompassed other cognitive domains such as language, attention, visuospatial memory, and executive functioning. Results: Verbal, semantic, episodic, and spatial memory emerged as the most sensitive indicators of preclinical changes in PSEN1 E280A carriers. Inconsistencies were noted in findings from tests assessing language, attention, visuospatial memory, and executive functioning, suggesting potential limitations in detecting early cognitive changes in PSEN1 mutation carriers. Specific cognitive tasks developed for this population proved effective but underutilized. Conclusions: The review underscores the importance of continued test development tailored to detect early cognitive changes in PSEN1 E280A carriers, potentially enhancing ADAD screening. Furthermore, investigating ADAD mutations in children may identify early changes in AD and enhance our understanding of neuropsychological functioning across the lifespan. This synthesis provides valuable insights for researchers, clinicians, and policymakers engaged in the study and management of ADAD. Show more

Keywords: Alzheimer’s disease, autosomal dominant Alzheimer’s disease, cognitive measures, cognitive outcomes, dementia, early detection, familial AD, preclinical AD

DOI: 10.3233/JAD-240360

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 397-415, 2024

Authors: Yao, Yirou | Zhu, Shun | Ni, Jingnian | Wei, Mingqing | Li, Ting | Long, Siwei | Shi, Jing | Tian, Jinzhou

Article Type: Systematic Review

Abstract: Background: As a natural antioxidant, uric acid has neuroprotective effects. The association between uric acid levels and dementia risk was reported by previous studies. However, recently published studies showed that the relationship between uric acid and dementia risk might be heterogeneous in dementia subtypes. Objective: This study aimed to clarify the relationship between hyperuricemia (or gout) and dementia. Methods: The PubMed and Web of Science databases were systematically searched up to April 2024 to identify relevant studies. A meta-analysis was conducted using hazard ratios (HR) or odds ratios (OR) and 95% confidence interval (CI) as pooled …indicators. Heterogeneity between the studies was examined using Cochran’s Q statistic and I2 statistic. Subgroup analyses were conducted for gender and age. Stratification analysis, sensitivity analyses and meta-regression were conducted to explore possible explanations for heterogeneity. Publication bias was assessed by funnel plot and Egger’s test. Results: A total of 11 studies met the inclusion criteria including 2,928,152 participants were abstracted. Hyperuricemia (or gout) did not reduce the overall risk of dementia (OR/HR = 0.92, 95% CI: 0.81–1.05) and vascular dementia (OR/HR = 0.74, 95% CI: 0.53–1.05), but may have a protective effect against Alzheimer’s disease (OR/HR = 0.82, 95% CI: 0.70–0.96). Subgroup analysis showed that a lower risk of dementia was observed in men (OR/HR = 0.83, 95% CI: 0.77–0.90) and patients whose age under 65 (OR/HR = 0.83, 95% CI: 0.72–0.95). Conclusions: Patients with gout or hyperuricemia have a low risk of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, dementia, gout, hyperuricemia, meta-analysis, uric acid

DOI: 10.3233/JAD-240076

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 417-427, 2024

Authors: Jann, Kay | Cen, Steven | Santos, Mariella | Aksman, Leon | Wijesinghe, Dilmini | Zhang, Ru | Lynch, Kirsten | Ringman, John M. | Wang, Danny J.

Article Type: Short Communication

Abstract: Reduced functional magnetic resonance imaging (fMRI)-complexity in Alzheimer’s disease (AD) progression has been demonstrated and found to be associated with tauopathy and cognition. However, association of fMRI-complexity with amyloid and influence of genetic risk (APOE ɛ 4) remain unknown. Here we investigate the association between fMRI-complexity, tau-PET, and amyloid-PET as well as influence of APOE genotype using multivariate generalized linear models. We show that fMRI-complexity has a strong association with tau but not amyloid deposition and that the presence of an APOE ɛ 4 allele enhances this effect. Thus fMRI-complexity provides a surrogate marker of impaired brain …functionality in AD progression. Show more

Keywords: Alzheimer’s disease, amyloid, APOE, fMRI-complexity, tau

DOI: 10.3233/JAD-240459

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 429-435, 2024

Authors: Silva-Rudberg, Jason A. | Mecca, Adam P.

Article Type: Article Commentary

Abstract:  Magnetic resonance imaging (MRI)-based diffusion methods can quantify water molecule diffusion within tissues and are used to measure microstructural changes due to neurodegeneration. In a recent issue of the Journal of Alzheimer ’s Disease , Nakaya et al. report on the “Assessment of Gray Matter Microstructural Alterations in Alzheimer’s Disease by Free Water Imaging”. This study and others indicate that MRI diffusion methods, including free water imaging and diffusion tensor imaging, can reveal gray matter microstructural changes present in many AD-affected brain regions. These techniques are a valuable tool for multi-modal and longitudinal imaging studies that can offer insights into …AD neurobiology. Show more

Keywords: Alzheimer’s disease, diffusion imaging, diffusion tensor imaging, free water imaging

DOI: 10.3233/JAD-240673

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 437-439, 2024

Authors: Oliveira, Fabricio Ferreira de

Article Type: Article Commentary

Abstract: Knowledge of performance in activities of daily living and quality of life is important for management decisions and research endpoints. The use of harmonized scales is essential for objective assessment of both caregivers and patients with dementia with Lewy bodies. Functionality and quality of life are more impaired in dementia with Lewy bodies than in Alzheimer’s disease, mostly due to higher prevalence of behavioral symptoms and motor manifestations in dementia with Lewy bodies. More longitudinal studies are required to assess if causality mediates the associations of clinical features with functional independence and worsened quality of life in these patients.

Keywords: Activities of daily living, Alzheimer’s disease, behavioral symptoms, cognitive disorders, dementia, Lewy body dementia, neurodegenerative diseases, neuropsychiatry, quality of life

DOI: 10.3233/JAD-240676

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 441-443, 2024

Authors: Uh, Kyungjun | Monarch, Kaylynn | Reese, Emily D. | Rodriguez, Katherine | Yoon, Junchul | Spate, Lee D. | Samuel, Melissa S. | Koh, Sehwon | Chen, Paula R. | Jarome, Timothy J. | Allen, Timothy A. | Prather, Randall S. | Lee, Kiho

Article Type: Research Article

Abstract: Background: Presenilin 1 (PSEN1 ) is one of the genes linked to the prevalence of early onset Alzheimer’s disease. In mice, inactivation of Psen1 leads to developmental defects, including vertebral malformation and neural development. However, little is known about the role of PSEN1 during the development in other species. Objective: To investigate the role of PSEN1 in vertebral development and the pathogenic mechanism of neurodegeneration using a pig model. Methods: CRISPR/Cas9 system was used to generate pigs with different mutations flanking exon 9 of PSEN1 , including those with a deleted exon 9 …(Δexon9). Vertebral malformations in PSEN1 mutant pigs were examined by X-ray, micro-CT and micro-MRI. Neuronal cells from the brains of PSEN1 mutant pigs were analyzed by immunoflourescence, followed by image analysis including morphometric evaluation via image J and 3D reconstruction. Results: Pigs with a PSEN1 null mutation (Δexon9-12) died shortly after birth and had significant axial skeletal defects, whereas pigs carrying at least one Δexon9 allele developed normally and remained healthy. Effects of the null mutation on abnormal skeletal development were also observed in fetuses at day 40 of gestation. Abnormal distribution of astrocytes and microglia in the brain was detected in two PSEN1 mutant pigs examined compared to age-matched control pigs. The founder pigs were bred to establish and age PSEN1 ΔE9/+ pigs to study their relevance to clinical Alzheimer’s diseases. Conclusions: PSEN1 has a critical role for normal vertebral development and PSEN1 mutant pigs serves as novel resources to study Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, CRISPR/Cas9, Pig, Presenilin-1

DOI: 10.3233/JAD-231297

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 445-461, 2024

Authors: Nianogo, Roch A. | Hays, Ron D. | Gong, Yufan | Yu, Yu | Ritz, Beate | Duru, O. Kenrik

Article Type: Research Article

Abstract: Background: The mechanisms through which acculturation influences the onset of cognitive impairment and dementia are not well understood, especially among older Hispanics. Objective: To investigate whether inflammation and psycho-behavioral factors mediate the relationship between acculturation and incident dementia among older Mexican Americans. Methods: We analyzed the Sacramento Area Latino Study on Aging (1998–2007, SALSA), a longitudinal study (N  = 1,194) with 10 years of follow-up, and used g-computation for mediation analysis with pooled logistic regression to evaluate whether acculturation (assessed by the Revised Acculturation Rating Scale for Mexican Americans [ARSMA-II]) affected dementia or cognitive impairment but not …dementia (CIND) through inflammation (i.e., interleukin 6 [IL-6], tumor necrosis factor-α (TNF-α ), high-sensitivity C-reactive protein [hs-CRP]), smoking, alcohol consumption, and depressive symptoms. The potential mediators were assessed at baseline. Results: The 10-year average adjusted risk ratio (aRR) for the effect of high U.S. acculturation and dementia/CIND was 0.66, 95% CI (0.36, 1.30). The indirect effects were: IL-6 (aRR = 0.98, 95% CI (0.88, 1.05)); TNF-α (aRR:0.99, 95% CI (0.93, 1.05)); hs-CRP: (aRR = 1.21, 95% CI (0.84, 1.95)); current smoking: aRR = 0.97, 95% CI (0.84, 1.16); daily/weekly alcohol consumption (aRR = 1.00, 95% CI (0.96, 1.05)); and depressive symptom score (aRR = 1.03, 95% CI (0.95, 1.26)). Hs-CRP yielded a proportion mediated of -26%, suggesting that hs-CRP could suppress the potential effect of high U.S. acculturation. The other factors explored resulted in little to no mediation. Conclusions: The effect of acculturation on time to incident dementia/CIND varied over time. Our study suggests that inflammation could suppress the effect between high U.S. acculturation and dementia risk. Show more

Keywords: Acculturation, Alzheimer’s disease, causal inference, dementia, disparities, inflammation, mediation, Mexican, stress

DOI: 10.3233/JAD-231341

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 463-473, 2024

Authors: Kreshpa, Wendy | Raffa, Stefano | Girtler, Nicola | Brugnolo, Andrea | Mattioli, Pietro | Orso, Beatrice | Calizzano, Francesco | Arnaldi, Dario | Peira, Enrico | Chincarini, Andrea | Tagliafico, Luca | Monacelli, Fiammetta | Calcagno, Pietro | Serafini, Gianluca | Gotta, Fabio | Mandich, Paola | Pretta, Stefano | Del Sette, Massimo | Sofia, Luca | Sambuceti, Gianmario | Morbelli, Silvia | Schenone, Angelo | Massa, Federico | Pardini, Matteo | Argenti, Lucia | Biffa, Gabriella | Bosinelli, Francesca | Bozzo, Giulia | Castellan, Lucio | Castellini, Paola | Colombo, Barbara | Gandoglia, Ilaria | Giacomini, Gabriele | Lombardo, Lorenzo | Losa, Mattia | Mancini, Raffaele | Murialdo, Alessandra | Nencioni, Alessio | Nozza, Paolo | Origone, Paola | Pelagotti, Virginia | Roccatagliata, Luca

Article Type: Research Article

Abstract: Background: Discrepancy between caregiver and patient assessments of apathy in mild cognitive impairment (MCI) is considered an index of apathy unawareness, independently predicting progression to AD dementia. However, its neural underpinning are uninvestigated. Objective: To explore the [18 F]FDG PET-based metabolic correlates of apathy unawareness measured through the discrepancy between caregiver and patient self-report, in patients diagnosed with MCI. Methods: We retrospectively studied 28 patients with an intermediate or high likelihood of MCI-AD, progressed to dementia over an average of two years, whose degree of apathy was evaluated by means of the Apathy Evaluation Scale (AES) …for both patients (PT-AES) and caregivers (CG-AES). Voxel-based analysis at baseline was used to obtain distinct volumes of interest (VOIs) correlated with PT-AES, CG-AES, or their absolute difference (DISCR-AES). The resulting DISCR-AES VOI count densities were used as covariates in an inter-regional correlation analysis (IRCA) in MCI-AD patients and a group of matched healthy controls (HC). Results: DISCR-AES negatively correlated with metabolism in bilateral parahippocampal gyrus, posterior cingulate cortex, and thalamus, PT-AES score with frontal and anterior cingulate areas, while there was no significant correlation between CG-AES and brain metabolism. IRCA revealed that MCI-AD patients exhibited reduced metabolic/functional correlations of the DISCR-AES VOI with the right cingulate gyrus and its anterior projections compared to HC. Conclusions: Apathy unawareness entails early disruption of the limbic circuitry rather than the classical frontal-subcortical pathways typically associated with apathy. This reaffirms apathy unawareness as an early and independent measure in MCI-AD, marked by distinct pathophysiological alterations. Show more

Keywords: Alzheimer’s disease, apathy, awareness, dementia, [18F]FDG PET, mild cognitive impairment

DOI: 10.3233/JAD-240430

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 475-485, 2024

Authors: Zhang, Qinghua | Zhao, Shicheng | Feng, Jianli | Wang, Shanshan | Song, Lin | Han, Qi | Cong, Lin | Wang, Yongxiang | Du, Yifeng | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Little is known about the associations of hearing loss, hippocampal volume, and motoric cognitive risk syndrome (MCR) in older adults. Objective: We aimed to investigate the associations of hearing loss with MCR and hippocampal volume; and the interaction of hearing loss with hippocampal volume on MCR. Methods: This population-based cross-sectional study included 2,540 dementia-free participants (age≥60 years; 56.5% women) in the baseline examination of the Multimodal Interventions to Delay Dementia and Disability in rural China. Data were collected through face-to-face interviews, clinical examination, and laboratory tests. Hearing function was assessed using pure tone audiometry test. …In the subsample (n  = 661), hippocampal volume was assessed on structural magnetic resonance images. Data were analyzed with logistic regression models. Results: In the total sample, MCR was diagnosed in 246 persons (9.7%). High-frequency hearing loss was significantly associated with an increased likelihood of MCR and slow gait. In the subsample, the restricted cubic spline plots indicated an inverted U-shaped nonlinear relationship between high-frequency hearing performance and hippocampal volume. Moreover, greater hippocampal volume was significantly associated with a deduced likelihood of MCR and subjective cognitive decline (SCD). In addition, there were statistical interactions of high-frequency hearing loss with hippocampal volume on MCR and slow gait (p for interaction < 0.05), such that the associations were statistically significant only among participants free of high-frequency hearing loss. Conclusions: High-frequency hearing loss was associated with an increased likelihood of MCR in older adults. The hippocampus might play a part in the relationship of high-frequency hearing loss and MCR. Show more

Keywords: Aging, Alzheimer’s disease, hearing loss, hippocampal volume, motoric cognitive risk syndrome

DOI: 10.3233/JAD-240522

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 487-498, 2024

Authors: Hosoya, Megumi | Toi, Sono | Yoshizawa, Hiroshi | Kitagawa, Kazuo

Article Type: Research Article

Abstract: Background: Gait impairment is observed in patients with small vessel disease (SVD); however, the association between gait function and long-term outcome remains unclear. Objectives: This study aimed to clarify the predictive value of gait function on incident dementia, survival and functional outcome. Methods: Data were derived from a Japanese cohort of patients with SVD. This study included 522 participants who underwent 3-m timed up and go test (TUG), and gait speed, TUG time, was divided into tertiles. Magnetic resonance imaging was used to evaluate severity of white matter hyperintensities, lacunes, and medial temporal atrophy. Primary outcome …was dementia. All-cause death and functional outcome by modified Rankin scale at the last visit was also evaluated. Results: The median age was 71 years, and median TUG time was 9.91 s. During follow-up period of 4.8 years, 32 cases of dementia occurred. Cox proportional hazard analysis revealed that slow gait speed (TUG time >  10.88 s) was associated with a significantly higher risk of incident dementia than fast (TUG time <  9.03) and middle (TUG time, 9.04–10.87 s) speeds after adjusting risk factors, Mini-Mental State Examination, SVD severity and brain atrophy (adjusted hazard ratio, 2.73; 95% confidence interval, 1.16–6.42, p  = 0.022). Slow speed was also associated with mortality and poor functional outcome compared with other speeds (adjusted odds ratio, 4.19; 95% confidence interval 1.92–9.18, p  <  0.001). Conclusions: Gait function was associated with incident dementia, mortality and poor functional outcome independently of cognitive function, brain atrophy, and SVD severity. Show more

Keywords: Alzheimer’s disease, dementia, functional outcome, gait speed, small vessel disease

DOI: 10.3233/JAD-240304

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 499-508, 2024

Authors: Giaquinto, Francesco | Lorenzini, Patrizia | Salvi, Emanuela | Carnevale, Giulia | Vaccaro, Roberta | Matascioli, Fabio | Corbo, Massimo | Locuratolo, Nicoletta | Vanacore, Nicola | Bacigalupo, Ilaria | Arabia, Gennarina | Amorosi, Alessandro | Bacigalupo, Ilaria | Bargagli, Anna Maria | Bartorelli, Luisa | Basso, Cristina | Berardinelli, Manuela | Bernardi, Maria Pompea | Bianchi, Caterina B.N.A | Blandi, Lorenzo | Boschi, Federica | Bruni, Amalia Cecilia | Caci, Alessandra | Caffarra, Paolo | Canevelli, Marco | Capasso, Andrea | Cipollari, Susanna | Cozzari, Mariapia | Di Costanzo, Alfonso | Di Fiandra, Teresa | Di Palma, Annalisa | Fabbo, Andrea | Francescone, Federica | Gabelli, Carlo | Gainotti, Sabina | Galeotti, Francesca | Gambina, Giuseppe | Gasparini, Marina | Giannini, Maria Assunta | Gilli, Micaela | Giordano, Marcello | Greco, Annarita | Guaita, Antonio | Izzicupo, Fabio | Landoni, Fiammetta | Lidonnici, Elisa | Locuratolo, Nicoletta | Logroscino, Giancarlo | Lombardi, Alessandra | Losito, Gilda | Lubian, Francesca | Lupinetti, Maria Cristina | Madrigali, Sara | Marra, Camillo | Masera, Filippo | Massaia, Massimiliano | Mastromattei, Antonio | Matera, Antonio | Matera, Manlio | Mazzoleni, Francesco | Melani, Carla | Meloni, Serena | Memeo, Elena | Musso, Marco | Notarelli, Antonella | Onofrj, Marco | Palummeri, Ernesto | Panetta, Valeria | Petrini, Carlo | Piccoli, Tommaso | Pirani, Alessandro | Piras, Stefano | Porro, Gabriella | Possenti, Mario | Rendina, Elena | Riolo, Antonino | Riva, Luciana | Salvi, Emanuela | Santini, Sara | Scalmana, Silvia | Scarpelli, Nando | Secreto, Piero | Seganfreddo, Monica | Sensi, Stefano | Severino, Carla | Spadin, Patrizia | Spallino, Patrizia | Spinelli, Anna Laura | Stracciari, Andrea | Trabucchi, Marco | Vanacore, Nicola | Zaccardi, Antonio | Accardo, Egidio | Ahmad, Omar | Ajena, Domenico | Alba, Giovanni | Albanese, Alberto | Albergati, Andrea | Alessandria, Maria | Alfieri, Pasquale | Alimenti, Mario | Aliprandi, Angelo | Altavilla, Roberto | Amarù, Salvatore | Ambrosino, Immacolata | Amideo, Felice | Ammendola, Stefania | Amoruso, Francesco | Andreati, Candida | Andreone, Vincenzo | Angeloni, Rossano | Annunziata, Francesco | Antenucci, Sara | Appollonio, Ildebrando | Arabia, Gennarina | Arcudi, Luciano | Ardillo, Marianna | Arena, Maria Carmela Gabriella | Arighi, Andrea | Arpino, Gennaro | Bagalà, Anna | Baiano, Antonio | Balestrino, Antonio | Barbagallo, Mario | Barbuto, Marianna | Bargnani, Cesare | Barone, Paolo | Bartoli, Antonella | Bauco, Claudia | Bellelli, Giuseppe | Bellini, Marco Antonio | Bellora, Aldo | Benati, Giuseppe | Beretta, Sandro | Bergamini, Lucia | Bergonzini, Eleonora | Bessi, Valentina | Bianchetti, Angelo | Bisio, Erika | Boiardi, Roberta | Bollani, Elisabetta | Bologna, Laura | Bolzetta, Francesco | Boni, Stefano | Borgogni, Tiziano | Bottini, Gabriella | Bottone, Ida | Bove, Angela | Bruno Bossio, Roberto | Bruno, Giuseppe | Bruno, Patrizia | Bucca, Carmela | Buganza, Manuela | Buzzi, Graziano | Buzzi, Paolo | Cacchio’, Gabriella | Cafarelli, Arturo | Cafazzo, Viviana | Caggiula, Marcella | Cagnin, Annachiara | Calabrese, Gianluigi | Calabrese, Giusi Alessandro | Calandra, Maria | Caleri, Veronica | Calvani, Donatella | Camerlingo, Massimo | Cantello, Roberto | Capasso, Andrea | Capellari, Sabina | Capobianco, Giovanni | Capoluongo, Maria Carmela | Cappelletti, Rossana | Capra, Claudio | Caravona, Natalia | Stucchi, Carlo Maria | Carluccio, Maria Alessandra | Carteri, Severina | Casanova, Anna | Caserta, Francescosaverio | Caso, Paolo | Cassaniti, Gaetana | Cassetta, Emanuele | Casson, Silvia | Castiello, Vincenzo | Cattaruzza, Tatiana | Ceccon, Anna | Ceci, Moira | Cella, Sabatino | Cenciarelli, Silvia | Censori, Bruno | Cerqua, Giuliano | Cerrone, Paolo | Cervera, Pasquale | Chemotti, Silvia | Chiari, Annalisa | Chiloiro, Roberta | Cirilli, Luisa | Clerici, Raffaella | Coin, Alessandra | Colacino, Gianfranco | Colacioppo, Francesco Paolo | Colao, Rosanna | Colin, Antonio | Coluccia, Brigida | Conti, Giancarlo Maria | Coppola, Filomena | Coppola, Francesca | Corbo, Massimo | Cossu, Antonello | Costa, Alfredo | Costa, Gabriella | Costa, Manuela | Cotelli, Maria Sofia | Cottone, Salvatore | Cozzolino, Maria Immacolata | Crucitti, Andrea | Cumbo, Eduardo | Currà, Antonio | Dallocchio, Carlo | D’amico, Ferdinando | D’Amore, Anna | De Carolis, Stefano | De Donato, Maurizio | De Feo, Paola | De La Pierre, Franz | De Laurentiis, Maria | De Lauretis, Ida | De Luca Gian, Placido | De Palma, Alessandro | De Togni, Laura | Demontis, Antonio | D’Epiro, Dora | Desideri, Giovambattista | Desiderio, Miranda | Di Donato, Marco | Di Emidio, Gabriella | Di Giacopo, Raffaella | Di Lazzaro, Vincenzo | Di Leo, Rita | Di Marco, Salvatore | Di Quarto, Gaetano | Dijk, Babette | Dikova, Natasa | Dioguardi, Maria Stefania | Dominici, Federica | Dotta, Michele | Dotti, Carla | Esposito, Domenica | Esposito, Sabrina | Esposito, Zaira | Ettorre, Evaristo | Fabbo, Andrea | Faccenda, Giovanna | Falanga, Angelamaria | Falorni, Michela | Falvo, Fraia | Fappani, Agostina | Farina, Elisabetta Ismilde Mariagiovanna | Fascendini, Sara | Fattapposta, Francesco | Favatella, Irene | Femminella, Grazia Daniela | Ferrara, Salvatore | Ferrari, Patrizia | Ferraris, Alessandra | Ferraro, Franco | Ferri, Raffaele | Ferrigno, Salvatore | Filastro, Francesco | Filippi, Massimo | Finelli, Antonio | Finelli, Chiara | Fiori, Maria Rita | Fiorillo, Francesco | Floris, Gianluca | Fontanella, Anna | Forgione, Luigi | Foti, Andrea | Foti, Francesca Fulvia | Frediani, Fabio | Frontera, Giovanni | Fulgido, Maria Luigia | Fundarò, Cira | Fuschillo, Carmine | Gabbani, Luciano | Gabelli, Carlo | Galati, Franco | Galli, Renato | Gallo, Angelo | Gallo, Livia | Gallucci, Maurizio | Galluccio, Gabriella | Gareri, Pietro | Gasperi, Lorenzo | Gelmini, Giovanni | Gennuso, Michele | Gerace, Carmela | Ghersetti, Daria | Giambattistelli, Federica | Giantin, Valter | Giordano, Bernardo | Giorelli, Maurizio | Giorgianni, Agata | Giubilei, Franco | Godi, Laura | Gorelli, Luciano | Gragnaniello, Daniela | Granziera, Serena | Greco, Giuseppe | Grella, Rodolfo | Grieco, Michele | Grimaldi, Luigi | Guarino, Maria | Guarnerio, Chiara | Guidi, Giovanni | Guidi, Leonello | Iallonardo, Lucia | Iavarone, Alessandro | Ingegni, Tiziana | Insardà, Pasqualina | Ivaldi, Claudio | Izzicupo, Fabio | Labate, Carmelo Roberto | Lacava, Roberto | Lalli, Francesco | Lammardo, Anna Maria | Laurienzo, Paolo Massimo | Leonardi, Alessandro | Leotta, Maria Rosa | Leuzzi, Rosario | Linarello, Simona | Litterio, Pasqualino | Lo Coco, Daniele | Lo Storto, Mario Rosario | Logi, Chiara | Logullo, Francesco Ottavio | Lombardi, Alessandra | Lombardi, Fortunato | Lorido, Antonio | Losavio, Francesco Antonio | Lubian, Francesca | Luca, Antonina | Ludovico, Livia | Lunardelli, Maria | Lupo, Mariarosaria | Luzzi, Simona | Maddestra, Maurizio | Maio, Gennaro | Maiotti, Mariangela | Malagnino, Anna Maria | Mancini, Giovanni | Manica, Angela | Maniscalco, Michele | Manni, Barbara | Manucra, Antonio | Manzoni, Laura | Marabotto, Marco | Marchesiello, Giuseppe | Marcon, Michela | Marcone, Alessandra | Marconi, Roberto | Margiotta, Alessandro | Marianantoni, Angela | Mariani, Donatella | Marino, Gemma | Marino, Saverio | Marinoni, Vito | Marra, Angela | Marra, Camillo | Marrari, Maria | Martelli, Mabel | Marti, Alessandro | Martorana, Alessandro | Marvardi, Martina | Mascolo, Saverio | Massimiliano, Massaia Mario Bo | Massimo, Lenzi Lucio | Mastronuzzi, Vita Maria Alba | Mazzi, Maria Letizia | Mazzone, Andrea | Mecacci, Rossella | Mecocci, Patrizia | Medici, Deidania | Mei, Daniele | Melandri, Gian Giuseppe | Melis, Maurizio | Meneghello, Francesca | Menon, Vanda | Menza, Carmen | Merlo, Paola | Milan, Graziella | Milia, Antonio | Millia, Calogero Claudio | Minervini, Sergio | Mobilia, Carolina Anna | Moleri, Massimo | Molteni, Elena | Moniello, Giovanni | Montanari, Stefano | Mormile, Maria Teresa | Moro, Giuseppe | Moscato, Gianluca | Mossello, Enrico | Mundo, Angela Domenica | Mura, Giuseppe | Musca, Fabio | Musso, Anna Maria | Nardelli, Anna | Neviani, Francesca | Nicosia, Viviana | Nociti, Vincenzo | Novelli, Alessio | Nuccetelli, Francesco | Onofrj, Marco | Orefice, Lorenza | Orsucci, Daniele | Pace, Alfonso | Paci, Cristina | Padoan, Roberta | Padovani, Alessandro | Palleschi, Lorenzo | Palmisani, Maria Teresa | Palmucci, Marco | Palumbo, Pasquale | Panico, Nadia Rita | Pansini, Antonella | Pantieri, Roberta | Paolello, Paolo | Pardini, Matteo | Parnetti, Lucilla | Parrotta, Emma | Passamonte, Michela | Pastore, Agostino | Pastorello, Ebe | Pelini, Luca | Pellati, Morena | Pellegrino, Mario | Pellicano, Clelia | Pelliccioni, Giuseppe | Pennisi, Maria Giovanna | Perini, Michele | Perotta, Daniele | Persico, Diego | Petrella, Virginia | Petri, Fabia | Piccininni, Maristella | Pierguidi, Laura | Pietrella, Alessio | Pilotto, Alberto | Pinto, Patrizia | Pirani, Alessandro | Pizza, Vincenzo | Plantone, Domenico | Plastino, Massimiliano | Poddighe, Patrizia | Pomati, Simone | Pompilio, Angela | Pontecorvo, Marialuisa | Prelle, Alessandro | Previderè, Giorgio | Pucci, Ennio | Puoti, Gianfrano | Putzu, Valeria | Rabasca, Annaflavia | Raffaele, Massimo | Rainero, Innocenzo | Rais, Claudia | Rana, Michele | Ranzenigo, Alberto | Rea, Giovanni | Righetti, Enrico | Rinaldi, Giuseppe | Rini, Augusto | Rizzo, Maria Rosaria | Rizzo, Massimo | Rocca, Paola | Roffredo, Laura | Roglia, Daniela | Romagnoni, Franco | Romano, Carlo | Romasco, Annalisa | Romeo, Leonardo | Ronzoni, Stefano | Rosci, Chiara Emilia | Rosso, Mara | Rozzini, Renzo | Ruberto, Eleonora | Ruberto, Stefania | Rungger, Gregorio | Ruotolo, Giovanni | Russo, Francesco | Russo, Giuseppe | Sabina, Roncacci | Sacco, Simona | Sacilotto, Giorgio | Salemi, Giuseppe | Salotti, Paolo | Salvatore, Elena | Sambati, Luisa | Sanges, Giuseppe | Santamaria, Francesco | Santilli, Ignazio Michele | Santoro, Mariangela | Saponara, Riccardo | Scarmagnan, Monica | Scataglini, Fabrizio | Seccia, Loredana | Selmo, Vladimir | Sensi, Stefano | Sicurella, Luigi | Silvestri, Antonello | Simone, Massimo | Sirca, Antonella | Sleiman, Intissar | Solla, Paolo | Sperber, Sarah Anna | Spinelli, Laura | Spoegler, Franz | Sucapane, Patrizia | Suraci, Domenico | Tagliabue, Benedetta | Tagliente, Stefania | Tamietti, Elena | Tedeschi, Gianluca | Tetto, Antonio | Tiezzi, Alessandro | Tiraboschi, Pietro | Tognoni, Gloria | Tomasetti, Carmine | Torchia, Francesco | Toriello, Giuseppe | Trevisi, Giovanna | Tripi, Gabriele | Trombetta, Giuseppe | Tulliani, Alessandro | Vaccina, Antonella Rita | Valentinis, Luca | Varricchio, Gina | Vasquez, Giuliano Antonella | Vella, Filomena | Verde, Federico | Verlato, Chiara | Vezzadini, Giuliana | Vidale, Simone | Vignoli, Assunta | Villani, Daniele | Vitelli, Alfredo | Volpentesta, Luigina | Volpi, Gino | Vozza, Domenico | Wanderlingh, Patrizia | Wenter, Christian | Zaccherini, Davide | Zanardo, Massimo | Zanette, Giampietro | Zanetti, Michela | Zanetti, Orazio | Zanferrari, Carla | Zuffi, Marta | Zupo, Vincenzo

Article Type: Research Article

Abstract: Background: The wait for the upcoming disease-modifying therapies (DMT) for Alzheimer’s disease in Europe is raising questions about the preparedness of national healthcare systems to conduct accurate diagnoses and effective prescriptions. In this article, we focus on the current situation in Italy. Objective: The primary goal is to propose a profile of the Italian Centers for Cognitive Disorders and Dementias (CCDDs) that could be taken into consideration by regional and autonomous provincial authorities when deciding on the prescribing centers for DMT. Methods: Based on responses to a national survey on CCDDs in Italy, we identified the …CCDDs that meet the requirements for effective prescription: 1) Multidisciplinary team; 2) Minimum Core Test for the neuropsychological assessment; 3) PET, CSF, and Brain MRI assessments. Univariate and multivariate comparisons were conducted between CCDDs that met the criteria and the others. Results: Only 10.4% of CCDDs met the requirements for effective DMT prescription, mainly located in Northern Italy. They are also characterized by longer opening hours, a higher number of professionals, a university location, and a higher frequency of conducting genetic tests, and could potentially result in prescribing centers. Conclusions: The findings suggest that the Italian national healthcare system may benefit from further enhancements to facilitate the effective prescription of DMTs. This could involve initiatives to reduce fragmentation, ensure adequate resources and equipment, and secure sufficient funding to support this aspect of healthcare delivery. Show more

Keywords: Alzheimer’s disease, Centers for Cognitive Disorders and Dementias, cognitive assessment, disease-modifying therapy, memory clinic, public health

DOI: 10.3233/JAD-240594

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 509-524, 2024

Authors: Yang, Jing | Ran, Kathleen | Ma, Wenzhe | Chen, Yanshi | Chen, Yanxin | Zhang, Can | Ye, Hui | Lu, Ying | Ran, Chongzhao

Article Type: Research Article

Abstract: Background: Reduction of the production of amyloid-β (Aβ) species has been intensively investigated as potential therapeutic approaches for Alzheimer’s disease (AD). However, the degradation of Aβ species, another potential beneficial approach, has been far less explored. Objective: To investigate the potential of multi-copper oxidases (MCOs) in degrading Aβ peptides and their potential benefits for AD treatment. Methods: We investigated the degradation efficiency of MCOs by using electrophoresis and validated the ceruloplasmin (CP)-Aβ interaction using total internal reflection fluorescence microscopy, fluorescence photometer, and fluorescence polarization measurement. We also investigated the therapeutic effect of ascorbate oxidase (AO) by …using induced pluripotent stem (iPS) neuron cells and electrophysiological analysis with brain slices. Results: We discovered that CP, an important MCO in human blood, could degrade Aβ peptides. We also found that other MCOs could induce Aβ degradation as well. Remarkably, we revealed that AO had the strongest degrading effect among the tested MCOs. Using iPS neuron cells, we observed that AO could rescue neuron toxicity which induced by Aβ oligomers. In addition, our electrophysiological analysis with brain slices suggested that AO could prevent an Aβ-induced deficit in synaptic transmission in the hippocampus. Conclusions: To the best of our knowledge, our report is the first to demonstrate that MCOs have a degrading function for peptides/proteins. Further investigations are warranted to explore the possible benefits of MCOs for future AD treatment. Show more

Keywords: Alzheimer’s disease, amyloid-β degradation, ascorbate oxidase, ceruloplasmin

DOI: 10.3233/JAD-240625

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 525-539, 2024

Authors: Saternos, Hannah | Hamlett, Eric D. | Guzman, Samuel | Head, Elizabeth | Granholm, Ann-Charlotte | Ledreux, Aurélie

Article Type: Research Article

Abstract: Background: Down syndrome (DS) is one of the most commonly occurring chromosomal conditions. Most individuals with DS develop Alzheimer’s disease (AD) by 50 years of age. Recent evidence suggests that AD pathology in the locus coeruleus (LC) is an early event in sporadic AD. It is likely that the widespread axonal network of LC neurons contributes to the spread of tau pathology in the AD brain, although this has not been investigated in DS-AD. Objective: The main purpose of this study was to profile AD pathology and neuroinflammation in the LC, comparing AD and DS-AD in postmortem human …tissues. Methods: We utilized immunofluorescence and semi-quantitative analyses of pTau (4 different forms), amyloid-β (Aβ), glial, and neuronal markers in the LC across 36 cases (control, DS-AD, and AD) to compare the different pathological profiles. Results: Oligomeric tau was highly elevated in DS-AD cases compared to LOAD or EOAD cases. The distribution of staining for pT231 was elevated in DS-AD and EOAD compared to the LOAD group. The DS-AD group exhibited increased Aβ immunostaining compared to AD cases. The number of tau-bearing neurons was also significantly different between the EOAD and DS-AD cases compared to the LOAD cases. Conclusions: While inflammation, pTau, and Aβ are all involved in AD pathology, their contribution to disease progression may differ depending on the diagnosis. Our results suggest that DS-AD and EOAD may be more similar in pathology than LOAD. Our study highlights unique avenues to further our understanding of the mechanisms governing AD neuropathology. Show more

Keywords: Alzheimer’s disease, amyloid-beta, astrocyte, Down syndrome, locus coeruleus, microglia, tau

DOI: 10.3233/JAD-240043

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 541-561, 2024

Authors: Gutierrez, Johnny | Kurz, Carolin | Sandoval, Cosme | Edmonds, Rose | Bittner, Tobias | Perneczky, Robert | Biever, Anne

Article Type: Research Article

Abstract: Background: Studies comparing cerebrospinal fluid (CSF) and plasma complement proteins in Alzheimer’s disease (AD) patients versus healthy controls (HC) have yielded inconsistent results. Discrepancies in the preanalytical sample handling could contribute to the heterogeneity in the reported findings. Objective: Using qualified immunoassays, we aimed at assessing the impact of preanalytical procedures on complement proteins in blood and CSF from AD patients and HCs. Methods: We supplemented HC and AD CSF/plasma with complement stabilizers and measured the complement proteins C4a, C4, C3a, C3, Factor Bb and Factor B by immunoassay. We tested the impact of freeze-thaw (FT) …cycles on fluid complement proteins. Results: Most complement proteins were mildly impacted by FT cycles in plasma but not CSF, except for C3a which displayed greater sensitivity to FTs in CSF than in plasma. In CSF, the effect of FTs on C3a was reduced but not prevented by the supplementation with EDTA (±Futhan). Conclusions: Our findings provide recommendations for CSF/plasma sample handling to ensure robust and reproducible complement biomarker analyses in AD. Show more

Keywords: Alzheimer’s disease, complement, neuroinflammation biomarkers, preanalytical handling

DOI: 10.3233/JAD-240287

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 563-576, 2024

Authors: Zhang, Xuemei | You, Jie | Qao, Qun | Qi, Xinyang | Shi, Jingping | Li, Junrong

Article Type: Research Article

Abstract: Background: The fractional amplitude of low-frequency fluctuations (fALFFs) can detect spontaneous brain activity. However, the association between abnormal brain activity and cognitive function, amyloid protein (Aβ), and emotion in Alzheimer’s disease (AD) patients remains unclear. Objective: This study aimed to survey alterations in fALFF in different frequency bands and the relationship between abnormal brain activity, depressive mood, and cognitive function to determine the potential mechanism of AD. Methods: We enrolled 34 AD patients and 32 healthy controls (HC). All the participants underwent resting-state magnetic resonance imaging, and slow-4 and slow-5 fALFF values were measured. Subsequently, the …study determined the correlation of abnormal brain activity with mood and cognitive function scores. Results: AD patients revealed altered mfALFF values in the slow-5 and slow-4 bands. In the slow-4 band, the altered mfALFF regions were the right cerebellar crus I, right inferior frontal orbital gyrus (IFOG), right supramarginal gyrus, right precuneus, angular gyrus, and left middle cingulate gyrus. Elevated mfALFF values in the right IFOG were negatively associated with Montreal Cognitive Assessment scores, Boston Naming Test, and Aβ1–42 levels. The mfALFF value of the AD group was lower than the HC group in the slow-5 band, primarily within the right inferior parietal lobule and right precuneus. Conclusions: Altered mfALFF values in AD patients are linked with cognitive dysfunction. Compared with HCs, Aβ1–42 levels in AD patients are related to abnormal IFOG activity. Therefore, mfALFF could be a potential biomarker of AD. Show more

Keywords: Alzheimer’s disease, cerebellum, cognitive function, resting-state functional MRI

DOI: 10.3233/JAD-231040

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 577-587, 2024

Authors: Li, Xuan-Yu | Yuan, Li-Xia | Ding, Chang-Chang | Guo, Teng-Fei | Du, Wen-Ying | Jiang, Jie-Hui | Jessen, Frank | Zang, Yu-Feng | Han, Ying

Article Type: Research Article

Abstract: Background: A range of imaging modalities have reported Alzheimer’s disease-related abnormalities in individuals experiencing subjective cognitive decline (SCD). However, there has been no consistent local abnormality identified across multiple neuroimaging modalities for SCD. Objective: We aimed to investigate the convergent local alterations in amyloid-β (Aβ) deposition, glucose metabolism, and resting-state functional MRI (RS-fMRI) metrics in SCD. Methods: Fifty SCD patients (66.4±5.7 years old, 19 men [38%]) and 15 normal controls (NC) (66.3±4.4 years old, 5 men [33.3%]) were scanned with both [18 F]-florbetapir PET and [18 F]-fluorodeoxyglucose PET, as well as simultaneous RS-fMRI from February 2018 …to November 2018. Voxel-wise metrics were retrospectively analyzed, including Aβ deposition, glucose metabolism, amplitude of low frequency fluctuation (ALFF), regional homogeneity (ReHo), and degree centrality(DC). Results: The SCD group showed increased Aβ deposition and glucose metabolism (p  < 0.05, corrected), as well as decreased ALFF, ReHo, and DC (p  < 0.05, uncorrected) in the left dorsal precuneus (dPCu). Furthermore, the dPCu illustrated negative resting-state functional connectivity with the default mode network. Regarding global Aβ deposition positivity, the Aβ deposition in the left dPCu showed a gradient change, i.e., Aβ positive SCD > Aβ negative SCD > Aβ negative NC. Additionally, both Aβ positive SCD and Aβ negative SCD showed increased glucose metabolism and decreased RS-fMRI metrics in the dPCu. Conclusions: The dorsal precuneus, an area implicated in early AD, shows convergent neuroimaging alterations in SCD, and might be more related to other cognitive functions (e.g., unfocused attention) than episodic memory. Show more

Keywords: Alzheimer’s disease, functional magnetic resonance imaging, positron emission tomography, precuneus, subjective cognitive decline

DOI: 10.3233/JAD-231360

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 589-601, 2024

Authors: Hung, Shih-Han | Chang, Alison H. | Cheng, Yen-Fu | Lin, Herng-Ching | Chen, Chin-Shyan

Article Type: Research Article

Abstract: Background: The relationship between young-onset dementia and peripheral vestibular disorders remained largely unknown although this association was observed in the older population. Objective: This case-control study aims to investigate the association of young-onset dementia with a pre-existing diagnosis of peripheral vestibular disorders using a population-based data from Taiwan’s Longitudinal Health Insurance Database 2010. Methods: This study included 989 patients with young-onset dementia and 2967 propensity-score-matching controls. Differences in baseline characteristic between patients with young-onset dementia and controls were investigated using chi-square tests or t-tests. Multiple logistic regression models were employed to assess the association of young-onset …dementia (outcome) with pre-existing peripheral vestibular disorders (predictor). Results: Compared to patients without young-onset dementia, those affected by this condition exhibited a statistically significantly higher rate of peripheral vestibular disorders (18.3% versus 8.2%, p  < 0.001). Furthermore, our analysis found notable between-group disparities in the rates of Meniere’s Disease (3.5% versus 2.0%, p = 0.015), benign paroxysmal positional vertigo (2.4% versus 1.1%, p = 0.006), and vestibular neuritis (2.4% versus 1.1%, p = 0.003). Multiple logistic regression analysis showed that the presence of prior peripheral vestibular disorders increased the odds of young-onset dementia [2.603 (95% CI = 2.105∼3.220)] after adjusting for age, sex, monthly income, geographic location, urbanization level, hyperlipidemia, diabetes, coronary heart disease, hearing loss, and hypertension. Conclusions: The study findings demonstrate a notable association between young-onset dementia and pre-existing peripheral vestibular disorders, suggesting that vestibular malfunction could play a role in the development of young-onset dementia. Show more

Keywords: Alzheimer’s disease, dementia, peripheral vestibular disorders, young-onset dementia

DOI: 10.3233/JAD-240309

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 603-610, 2024

Authors: Chen, Yixin | Ji, Xueying | Bao, Zhijun

Article Type: Research Article

Abstract: Background: The connection between diabetes-associated cognitive dysfunction (DACD) and Alzheimer’s disease (AD) has been shown in several observational studies. However, it remains controversial as to how the two related. Objective: To explore shared genes and pathways between DACD and AD using bioinformatics analysis combined with biological experiment. Methods: We analyzed GEO microarray data to identify DEGs in AD and type 2 diabetes mellitus (T2DM) induced-DACD datasets. Weighted gene co-expression network analysis was used to find modules, while R packages identified overlapping genes. A robust protein-protein interaction network was constructed, and hub genes were identified with Gene …ontology enrichment and Kyoto Encyclopedia of Genome and Genome pathway analyses. HT22 cells were cultured under high glucose and amyloid-β 25–35 (Aβ25-35 ) conditions to establish DACD and AD models. Quantitative polymerase chain reaction with reverse transcription verification analysis was then performed on intersection genes. Results: Three modules each in AD and T2DM induced-DACD were identified as the most relevant and 10 hub genes were screened, with analysis revealing enrichment in pathways such as synaptic vesicle cycle and GABAergic synapse. Through biological experimentation verification, 6 key genes were identified. Conclusions: This study is the first to use bioinformatics tools to uncover the genetic link between AD and DACD. GAD1, UCHL1, GAP43, CARNS1, TAGLN3, and SH3GL2 were identified as key genes connecting AD and DACD. These findings offer new insights into the diseases’ pathogenesis and potential diagnostic and therapeutic targets. Show more

Keywords: Alzheimer’s disease, diabetes-associated cognitive dysfunction, diabetes mellitus, hub genes, protein-protein interaction network, weighted gene co-expression network analysis

DOI: 10.3233/JAD-240353

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 611-625, 2024

Authors: Kinjo, Yoshino | Saji, Naoki | Murotani, Kenta | Sakima, Hirokuni | Takeda, Akinori | Sakurai, Takashi | Ohya, Yusuke | Kusunose, Kenya

Article Type: Research Article

Abstract: Background: Recent studies have demonstrated an association between pulse wave velocity (PWV), cerebral small vessel disease (SVD), and cognitive impairment such as Alzheimer’s disease. However, the association between brachial-ankle PWV and enlarged perivascular spaces (EPVS), one component of cerebral SVD remains controversial. Objective: To investigate the relationship between brachial-ankle PWV and EPVS severity in participants without dementia. Methods: We performed a cross-sectional study of data of 74 participants from sub-analysis of ongoing research. We assessed cognitive function, brachial-ankle PWV, and brain magnetic resonance imaging (MRI) features. Using brain MRI, EPVS were separately assessed as basal ganglia …(BG)-EPVS or centrum semiovale (CSO)-EPVS on the basis of their location. The relationship between EPVS severity and brachial-ankle PWV was evaluated using multivariable ordinal logistic regression analyses. Results: We analyzed 74 participants (women: 47%, mean age: 73 years, mild cognitive impairment [MCI]: 74%). Compared with participants with normal cognition, those with MCI were more likely to have both severe BG-EPVS and severe CSO-EPVS. In multivariable analyses, high brachial-ankle PWV and age were independently associated with BG-EPVS severity (odds ratio [95% confidence interval]: 1.19 [1.02–1.38], 1.09 [1.01–1.17], respectively), whereas only age was independently associated with CSO-EPVS severity. A causal mediation analysis under a counterfactual approach revealed a significant pure natural indirect effect of brachial-ankle PWV on MCI that was mediated by BG-EPVS (estimate: 1.04, 95% CI: 1.01–1.12, p  = 0.006). Conclusions: Brachial-ankle PWV was associated with BG-EPVS severity. High PWV may cause cerebrovascular pulsatility, which accelerates BG-EPVS and may worsen cognitive impairment. Show more

Keywords: Alzheimer’s disease, cerebral small vessel disease, cognitive decline, enlarged perivascular spaces, pulsatility, pulse wave velocity

DOI: 10.3233/JAD-240589

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 627-636, 2024

Authors: Sun, Wenxian | Chen, Yufei | Yang, Yuting | Wang, Pin | Gong, Jin | Han, Xiaodong | Xu, Chang | Luan, Heya | Li, Shaoqi | Li, Ruina | Wen, Boye | Lv, Sirong | Wei, Cuibai

Article Type: Research Article

Abstract: Background: The cholinergic hypothesis is one of the main theories that describe the pathogenesis of Alzheimer’s disease (AD). Cholinergic neurons degenerate early and are severely damaged in AD. Despite extensive research, the causes of cholinergic neuron damage and the underlying molecular changes remain unclear. Objective: This study aimed to explore the characteristics and transcriptomic changes in cholinergic neurons derived from human induced pluripotent stem cells (iPSCs) with APP mutation. Methods: Peripheral blood mononuclear cells from patients with AD and healthy individuals were reprogrammed into iPSCs. The iPSCs were differentiated into cholinergic neurons. Cholinergic neurons were …stained, neurotoxically tested, and electrophysiologically and transcriptomically analyzed. Results: The iPSCs-derived cholinergic neurons from a patient with AD carrying a mutation in APP displayed enhanced susceptibility to Aβ1-42 -induced neurotoxicity, characterized by severe neurotoxic effects, such as cell body coagulation and neurite fragmentation. Cholinergic neurons exhibited electrophysiological impairments and neuronal death after 21 days of culture in the AD group. Transcriptome analysis disclosed 883 differentially expressed genes (DEGs, 420 upregulated and 463 downregulated) participating in several signaling pathways implicated in AD pathogenesis. To assess the reliability of RNA sequencing, the expression of 16 target DEGs was validated using qPCR. Finally, the expression of the 8 core genes in different cell types of brain was analyzed by the AlzData database. Conclusions: In this study, iPSCs-derived cholinergic neurons from AD patients with APP mutations exhibit characteristics reminiscent of neurodegenerative disease. Transcriptome analysis revealed the corresponding DEGs and pathways, providing potential biomarkers and therapeutic targets for advancing AD research. Show more

Keywords: Alzheimer’s disease, cholinergic neurons, induced pluripotent stem cells, transcriptomics

DOI: 10.3233/JAD-240299

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 637-649, 2024

Authors: Hanyu, Haruo | Koyama, Yumi | Umekida, Kazuki | Watanabe, Sadayoshi | Matsuda, Hiroshi | Koike, Riki | Takashima, Akihiko

Article Type: Research Article

Abstract: Background: The entorhinal cortex is the very earliest involvement of Alzheimer’s disease (AD). Grid cells in the medial entorhinal cortex form part of the spatial navigation system. Objective: We aimed to determine whether path integration performance can be used to detect patients with mild cognitive impairment (MCI) at high risk of developing AD, and whether it can predict cognitive decline. Methods: Path integration performance was assessed in 71 patients with early MCI (EMCI) and late MCI (LMCI) using a recently developed 3D virtual reality navigation task. Patients with LMCI were further divided into those displaying characteristic …brain imaging features of AD, including medial temporal lobe atrophy on magnetic resonance imaging and posterior hypoperfusion on single-photon emission tomography (LMCI+), and those not displaying such features (LMCI–). Results: Path integration performance was significantly lower in patients with LMCI+than in those with EMCI and LMCI–. A significantly lower performance was observed in patients who showed progression of MCI during 12 months, than in those with stable MCI. Path integration performance distinguished patients with progressive MCI from those with stable MCI, with a high classification accuracy (a sensitivity of 0.88 and a specificity of 0.70). Conclusions: Our results suggest that the 3D virtual reality navigation task detects prodromal AD patients and predicts cognitive decline after 12 months. Our navigation task, which is simple, short (12–15 minutes), noninvasive, and inexpensive, may be a screening tool for therapeutic choice of disease-modifiers in individuals with prodromal AD. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, path integration, prodromal Alzheimer’s disease, progression, virtual reality

DOI: 10.3233/JAD-240347

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 651-660, 2024

Authors: Nagata, Tomoyuki | Nakajima, Shinichiro | Kito, Shinsuke | Shinagawa, Shunichiro

Article Type: Research Article

Abstract: Background: Delusional ideations, one of neuropsychiatric symptoms (NPSs), are frequently shown in the long-term progression of Alzheimer’s disease (AD), and comorbid with other NPSs including depression or agitation. Despite various types of delusional ideations, the comorbidity between each delusional ideation and depressive symptoms has not been discussed. Objective: The present cross-sectional study is aimed at testing the hypothetical mechanism of comorbid pattern in AD. Methods: Among 421 patients with AD, we analyzed the dataset of the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer’s Disease to compare age, sex, racial type, Mini-Mental State Examination (MMSE) scores, and Neuropsychiatric …Inventory (NPI) depression score of between the presence and absence of each delusional ideation (delusion of persecution, theft, jealousy, abandonment, phantom boarder, Capgras syndrome, misidentification of place, or television sign). Next, with the stratification based on MMSE score of < or > = 15 points, we further explored association between delusional ideation and depressive symptom that was found significances in the primary analysis Results: Among eight subtypes of delusional ideations, depression score was higher in those with persecution delusion or Capgras syndrome. Moreover, the Capgras syndrome was associated with presence of depression in severer global cognitive impairment status. Conclusions: As comorbid NPSs of delusional ideation in AD, depressive severity is associated with specific delusional subtype: persecution delusion and Capgras syndrome. Capgras syndrome may be attributable to severe cognitive impairment in addition to depressive symptom. The consideration of pathogenetic differences in the distinct delusional ideations may be helpful for clinicians to select the treatment strategy. Show more

Keywords: Alzheimer’s disease, delusion, depression, misidentification, paranoid

DOI: 10.3233/JAD-240702

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 661-670, 2024

Authors: Souza, Natalie Aparecida Pereira de | Simões Neto, José Pedro | Dourado, Marcia Cristina Nascimento

Article Type: Research Article

Abstract: Background: Young-onset AD (YOAD) typically occurs before the age of 65 and affects less than 6% of all people diagnosed with AD. There is a lack of research on differences between decision-making capacity and awareness according to age at onset of dementia. Objective: We investigated the relationship between decision-making capacity and awareness domains in people with young- (YOAD) and late-onset Alzheimer’s disease (LOAD). Methods: A cross-sectional study included 169 consecutively selected people with AD and their caregivers (124 people with LOAD and 45 people with YOAD). Results: People with YOAD were more cognitively impaired, …but more aware of their cognitive deficits and health condition, with moderate effect sizes. All people with AD presented deficits in the domains of decision-making capacity, with more impairment in understanding. There was a relationship between understanding and awareness domains, such that awareness was particularly important for decision-making capacity in the YOAD group. Conclusions: Better awareness involved better understanding in the YOAD group. Clinically, our findings shed light on the need to consider the differences in the domains of awareness and their relationship with other clinical aspects such as decision-making capacity according to age at onset of AD. Furthermore, our data can suggest hypotheses for larger and more robust prospective studies. Show more

Keywords: Alzheimer’s disease, awareness, decision-making capacity, domains of decision-making capacity, late onset, young onset

DOI: 10.3233/JAD-231324

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 671-680, 2024

Authors: Perreira, Krista M. | Hotz, V. Joseph | Duke, Naomi N. | Aiello, Allison E. | Belsky, Daniel W. | Brown, Tyson | Jensen, Todd | Harris, Kathleen Mullan

Article Type: Research Article

Abstract: Background: Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) have increased in prevalence. Objective: This article describes the Add Health Parent Study (AHPS) Phase 2, a study of social, behavioral, and biological factors influencing healthy aging and risk for AD/ADRD, in a national sample of adults aged 58–90. Methods: Sample members are parents of the National Longitudinal Study of Adolescent to Adult Health (Add Health) cohort, initially interviewed in Add Health in midlife (1994-95). AHPS Phase 1 (2015–17) collected longitudinal data on a random subsample of parents and their spouse/partners, who were mostly Non-Hispanic (NH) White. …AHPS Phase 2 will collect the same longitudinal socio-behavioral, and health survey data on all remaining NH Black and Hispanic parents (Black and Hispanic Supplement, BHS). Additionally, Phase 2 will collect cognitive and DNA data from AHPS Phase 1 and BHS sample parents and their current spouse/partners. Results: Funded by the National Institute on Aging, recruitment will occur between June 2025 and May 2026, producing an expected total AHPS sample of 5506 parents and their spouse/partners. Conclusions: The AHPS will be the first longitudinal cohort study powered to address multigenerational racial/ethnic disparities in AD/ADRD risk and protective factors across race/ethnic groups and socioeconomic strata. Show more

Keywords: Add health, Alzheimer’s disease, Black or African American, DNA, Hispanic or Latino, intergenerational, parents

DOI: 10.3233/JAD-240201

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 681-691, 2024

Authors: Guo, Fan | Tan, Meng-Shan | Hu, Hao | Ou, Ya-Nan | Zhang, Ming-Zhan | Sheng, Ze-Hu | Chi, Hao-Chen | Tan, Lan

Article Type: Research Article

Abstract: Background: Bridging integrator 1 (BIN1 ) gene polymorphism has been reported to play a role in the pathological processes of Alzheimer’s disease (AD). Objective: To explore the association of BIN1 loci with neuroinflammation and AD pathology. Methods: Alzheimer’s Disease Neuroimaging Initiative (ADNI, N  = 495) was the discovery cohort, and Chinese Alzheimer’s Biomarker and LifestylE (CABLE, N  = 619) study was used to replicate the results. Two BIN1 gene polymorphism (rs7561528 and rs744373) were included in the analysis. Multiple linear regression model and causal mediation analysis conducted through 10,000 bootstrapped iterations were used to examine the …BIN1 loci relationship with cerebrospinal fluid (CSF) AD biomarkers and alternative biomarker of microglial activation microglia-soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Results: In ADNI database, we found a significant association between BIN1 loci (rs7561528 and rs744373) and levels of CSF phosphorylated-tau (P-tau) (pc  = 0.017; 0.010, respectively) and total-tau (T-tau) (pc  = 0.011; 0.013, respectively). The BIN1 loci were also correlated with CSF sTREM2 levels (pc  = 0.010; 0.008, respectively). Mediation analysis demonstrated that CSF sTREM2 partially mediated the association of BIN1 loci with P-tau (Proportion of rs7561528 : 20.8%; Proportion of rs744373 : 24.8%) and T-tau (Proportion of rs7561528 : 36.5%; Proportion of rs744373 : 43.9%). The analysis in CABLE study replicated the mediation role of rs7561528. Conclusions: This study demonstrated the correlation between BIN1 loci and CSF AD biomarkers as well as microglia biomarkers. Additionally, the link between BIN1 loci and tau pathology was partially mediated by CSF sTREM2. Show more

Keywords: Alzheimer’s disease, BIN1, microglia, polymorphism, sTREM2, tau pathology

DOI: 10.3233/JAD-240372

Citation: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 693-704, 2024