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

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