Journal of Alzheimer's Disease - Volume 94, issue 3

Authors: Araujo-Menendez, Carlos E.E. | Saelzler, Ursula G. | Stickel, Ariana M. | Sundermann, Erin E. | Banks, Sarah J. | Paipilla, Andrea | Barnes, McKinna L. | Panizzon, Matthew S.

Article Type: Research Article

Abstract: Background: Race/ethnicity is associated with differences in reproductive history and cognition individually, yet it remains an understudied factor in the relationship between parity and later-life cognition. Objective: To evaluate if the association between parity and cognition differs between racial/ethnic groups. Methods: Participants included 778 older, postmenopausal women from the Health and Nutrition Examination Survey (Latina: n  = 178, Non-Latino Black [NLB]: n  = 169, Non-Latino White [NLW]: n  = 431) who self-reported at least one birth. Cognitive outcomes included working memory, learning memory, and verbal fluency. Covariates included age, education, cardiovascular and other reproductive health factors, adult socioeconomic status …(SES) and depressive symptoms. We fit a series of linear models to examine a) whether parity was associated with cognitive functioning, b) if this association varied by race/ethnicity through parity by race/ethnicity interactions, and c) individual parity with cognition associations stratified by race/ethnicity. Results: In the full sample, parity was significantly negatively associated with Digit Symbol Substitution Test (DSST) performance (b  = –0.70, p  = 0.024) but not Animal Fluency or word-list learning and memory. Tests of race/ethnicity-by-parity interactions were not statistically significant (ps > 0.05). However, stratified analyses by race/ethnicity showed a differential effect of parity on DSST performance, such that parity was significantly negatively associated with DSST performance (b  = –1.66, p  = 0.007) among Latinas but not in NLWs (b  = –0.16, p  = 0.74) or NLBs (b  = –0.81, p  = 0.191). Conclusion: Among Latina, but not NLB or NLW women, greater parity was associated with worse processing speed/executive functioning later in life. Further research is needed to understand the mechanisms driving racial/ethnic differences. Show more

Keywords: Alzheimer’s disease, cognition, cross-cultural research, pregnancy, reproductive health

DOI: 10.3233/JAD-221210

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1157-1168, 2023

Authors: Audronyte, Egle | Pakulaite-Kazliene, Gyte | Sutnikiene, Vaiva | Kaubrys, Gintaras

Article Type: Research Article

Abstract: Background: Olfactory dysfunction is an early symptom of Alzheimer’s disease (AD). However, olfactory tests are rarely performed in clinical practice because their diagnostic efficacy in detecting early AD is unclear. Objective: To investigate odor discrimination in patients with early AD and the efficacy of olfactory discrimination tests in differentiating these patients from subjects with normal cognition (CN). Methods: Thirty patients each with mild dementia due to AD (MD-AD) and mild cognitive impairment due to AD (MCI-AD) and 30 older subjects with CN were enrolled. All participants underwent cognitive examinations (CDR, MMSE, ADAS-Cog 13, and verbal fluency) …and odor discrimination tests (Sniffin’ Sticks test, Burghart®, Germany). Results: The MD-AD group achieved significantly worse scores on the olfactory discrimination test than the MCI-AD group, and the MCI-AD group achieved significantly worse results than the CN group (p  < 0.05). A cut-off score of≤10 had a diagnostic accuracy of 94.44% (95% CI, 87.51–98.17%) in differentiating patients with MCI-AD/MD-AD from subjects with CN and of 91.67% (95% CI, 81.61–97.24%) in differentiating those with MCI-AD from subjects with CN. Our multinomial logistic regression model with demographic data and ADAS-Cog 13 scores as predictor variables correctly classified 82.2% of the cases (CN, 93.3%; MC-AD, 70%; MD-AD, 83.3%); on adding the olfactory discrimination score to the model, the percentage increased to 92.2% (CN, 96.7%; MCI-AD, 86.7%; MD-AD, 93.3%). Conclusion: Odor discrimination is impaired in cases of early AD and continues to deteriorate as the disease progresses. The olfactory discrimination test showed good diagnostic efficacy in detecting early AD. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, olfaction, olfactory impairment

DOI: 10.3233/JAD-230077

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1169-1178, 2023

Authors: Alves, Suélen Santos | de Oliveira, José Antônio Cortes | Lazarini-Lopes, Willian | Servilha-Menezes, Gabriel | Grigório-de-Sant’Ana, Mariana | Del Vecchio, Flavio | Mazzei, Rodrigo Focosi | Sousa Almeida, Sebastião | da Silva Junior, Rui Milton Patrício | Garcia-Cairasco, Norberto

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative and progressive disorder with no cure and constant failures in clinical trials. The main AD hallmarks are amyloid-β (Aβ) plaques, neurofibrillary tangles, and neurodegeneration. However, many other events have been implicated in AD pathogenesis. Epilepsy is a common comorbidity of AD and there is important evidence indicating a bidirectional link between these two disorders. Some studies suggest that disturbed insulin signaling might play an important role in this connection. Objective: To understand the effects of neuronal insulin resistance in the AD-epilepsy link. Methods: We submitted the streptozotocin (STZ) induced …rat AD Model (icv-STZ AD) to an acute acoustic stimulus (AS), a known trigger of seizures. We also assessed animals’ performance in the memory test, the Morris water maze and the neuronal activity (c-Fos protein) induced by a single audiogenic seizure in regions that express high levels of insulin receptors. Results: We identified significant memory impairment and seizures in 71.43% of all icv-STZ/AS rats, in contrast to 22.22% of the vehicle group. After seizures, icv-STZ/AS rats presented higher number of c-Fos immunopositive cells in hippocampal, cortical, and hypothalamic regions. Conclusion: STZ may facilitate seizure generation and propagation by impairment of neuronal function, especially in regions that express high levels of insulin receptors. The data presented here indicate that the icv-STZ AD model might have implications not only for AD, but also for epilepsy. Finally, impaired insulin signaling might be one of the mechanisms by which AD presents a bidirectional connection to epilepsy. Show more

Keywords: Acoustic stimulus, Alzheimer’s disease, epilepsy, insulin resistance, memory, seizures, streptozotocin

DOI: 10.3233/JAD-230153

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1179-1196, 2023

Authors: Castelblanco-Toro, Sandra Milena | Jurado-Delgado, Janeth | Meneses-Bernal, Juan Felipe | Santacruz-Escudero, José Manuel | Santamaria-García, Hernando

Article Type: Research Article

Abstract: Background: Fear of falling (FoF) is a condition associated with falls, multi-morbidity, and functional impairment. To date it remains unknow which clinical, somatic, socio-demographic, behavioral, and emotional factors are associated with FoF and how these factors interact in people with Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Objective: Identify the association of FoF with clinical, socio-demographic, and neuropsychiatric factors in patients with AD and bvFTD. Methods: We evaluated 98 participants, 58 with AD and 40 with bvFTD at mild or moderate stages and assess FoF using the Falls Efficacy Scale-International. Additionally, we analyzed cognitive, …physical performance variables, functional impairment, and affective and behavioral symptoms associated with FoF using standardized scales and a regression model analysis. Results: The prevalence of FoF in AD and bvFTD was 51% and 40%, respectively. In the AD group, physical performance [F (3, 53) = 4.318, p  = 0.009], the behavioral symptoms model [F (19, 38) = 3.314, p  = 0.001], and the anxiety model [F (1, 56) = 13.4, p ≤0.01] showed statistically significant values. In addition, the presence of hallucinations assessed with the Neuropsychiatric Inventory and social behavior assessed with the Mild Behavioral Impairment Checklist were significant. In contrast, in the bvFTD group, a homologous group of models was evaluated but we did not find any significant results. Conclusion: FoF in people with AD was related to physical performance, neuropsychiatric symptoms such as apathy and hallucinations, and affective symptoms such as anxiety. However, this pattern was not seen in the bvFTD group, and therefore further studies are required. Show more

Keywords: Alzheimer’s disease, behavioral symptoms, fear of falling, frontotemporal dementia, physical performance

DOI: 10.3233/JAD-230266

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1197-1207, 2023

Authors: Zhang, Jie | Gao, Shang | Liu, Wei

Article Type: Research Article

Abstract: Background: There is a close association between Alzheimer’s disease (AD) and circadian rhythms, and neuroinflammatory-related pathways are associated with both interactions. Objective: To reveal the relationship between circadian rhythm (CR) and AD at the level of genes, pathways, and molecular functions through bioinformatics. Methods: We analyzed the differential genes between AD and control groups in GSE122063 and found the important gene modules; obtained CR-related genes from GeenCard database; used Venn 2.1 database to obtain the intersection of genes of AD important modules with CR-related genes; and used STRING database and Cytoscape 3.7.1 to construct the gene …protein-protein interaction network. The MCODE plugin was used to screen pivotal genes and analyze their differential expression. We trranslated with www.DeepL.com/Translator (free version) to obtain transcriptional regulatory relationships from the TRRUST database and construct a hub gene-transcription factor relationship network. Results: A total of 42 common genes were screened from AD and CR genes, mainly involving signaling pathways such as neuroactive ligand-receptor interactions. A total of 10 pivotal genes were screened from the common genes of CR and AD, which were statistically significant in the comparison of AD and control groups (p  < 0.001), and ROC analysis showed that all these pivotal genes had good diagnostic significance. A total of 36 TFs of pivotal genes were obtained. Conclusion: We identified AD- and CR-related signaling pathways and 10 hub genes and found strong associations between these related genes and biological processes such as inflammation. Show more

Keywords: Alzheimer’s disease, bioinformatics, circadian rhythm, hub genes

DOI: 10.3233/JAD-230177

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1209-1224, 2023

Authors: Sorrentino, Federica | Fenoglio, Chiara | Sacchi, Luca | Serpente, Maria | Arighi, Andrea | Carandini, Tiziana | Arosio, Beatrice | Ferri, Evelyn | Arcaro, Marina | Visconte, Caterina | Rotondo, Emanuela | Scarpini, Elio | Galimberti, Daniela

Article Type: Research Article

Abstract: Background: The longevity gene Klotho (KL ) was recently associated with neurodegenerative diseases including Alzheimer’s disease (AD). Its role in the brain has not been completely elucidated, although evidence suggests that KL-VS heterozygosity is associated with a reduced risk of AD in Apolipoprotein E ɛ 4 carriers. Conversely, no data about genetic association with frontotemporal dementia (FTD) are available so far. Objective: To investigate the involvement of KL in AD and FTD by the determination of the genetic frequency of KL-VS variant and the expression analysis of KL gene. Methods: A population consisting …of 438 patients and 240 age-matched controls was enrolled for the study. KL-VS and APOE genotypes were assessed by allelic discrimination through a QuantStudio 12K system. KL gene expression analysis was performed in a restricted cohort of patients consisting of 43 AD patients, 41 FTD patients and 19 controls. KL gene expression was assessed in peripheral blood mononuclear cells with specific TaqMan assay. Statistical analysis was performed using GraphPad 9 Prims software. Results: KL-VS frequency was comparable to the ones found in literature and no differences were found in both allelic and genotypic frequencies between patients and controls were found. Conversely, KL expression levels were significantly lower in AD and FTD patients compared with controls (mean fold regulation – 4.286 and – 6.561 versus controls in AD and FTD, respectively, p  = 0.0037). Conclusion: This is the first study investigating KL in FTD. We showed a decreased expression of the gene in AD and FTD, independent of the genotype, suggesting a role of Klotho in common steps during neurodegeneration. Show more

Keywords: Alzheimer’s disease, expression, frontotemporal dementia, Klotho, neurodegeneration

DOI: 10.3233/JAD-230322

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1225-1231, 2023

Authors: Kang, Jae Myeong | Shin, Jeong-Hyeon | Kim, Woo-Ram | Seo, Seongho | Seo, Haeun | Lee, Sang-Yoon | Park, Kee Hyung | Na, Duk L. | Okamura, Nobuyuki | Seong, Joon-Kyoung | Noh, Young

Article Type: Research Article

Abstract: Background: Little is known regarding the differential effects of the apolipoprotein E (APOE ) ɛ 4 on the regional topography of amyloid and tau in patients with both early-onset (EOAD) and late-onset Alzheimer’s disease (LOAD). Objective: To compare the distribution and association of tau, amyloid, and cortical thickness among groups classified by the presence of APOE ɛ 4 allele and onset age. Methods: A total of 165 participants including 54 EOAD patients (29 ɛ 4-; 25 ɛ 4+), 45 LOAD patients (21 ɛ 4-; 24 ɛ 4+), and 66 age-matched controls underwent 3T MRI, 18 …F-THK5351 (THK) and 18 F-flutemetamol (FLUTE) PET scans, APOE genotyping, and neuropsychological tests. Data for voxel-wise and standardized uptake values from PET scans were analyzed in the context of APOE and age at onset. Results: EOAD ɛ 4- patients showed greater THK retention in the association cortices, whereas their EOAD ɛ 4+ counterparts had more retention in medial temporal areas. THK topography of LOAD ɛ 4+ was similar to EOAD ɛ 4 + . THK correlated positively with FLUTE and conversely with mean cortical thickness, being lowest in EOAD ɛ 4-, highest in LOAD ɛ 4-, and modest in ɛ 4+ groups. Even in the APOE ɛ 4+ groups, THK tended to correlate with FLUTE and mean cortical thickness in the inferior parietal region in EOAD and in the medial temporal region in LOAD. LOAD ɛ 4- manifested with prevalent small vessel disease markers and the lowest correlation between THK retention and cognition. Conclusion: Our observations suggest the differential effects of the APOE ɛ 4 on the relationship between tau and amyloid in EOAD and LOAD. Show more

Keywords: Alzheimer’s disease, amyloid, APOE, early-onset Alzheimer’s disease, tau

DOI: 10.3233/JAD-230339

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1233-1246, 2023

Authors: D’Cunha, Nathan M. | Holloway, Helen | Gibson, Diane | Thompson, Jane | Bail, Kasia | Kurrle, Susan | Day, Sally | Olson, James | Smith, Nicole | Clarke, Heather | Buckley, Charise | Isbel, Stephen

Article Type: Research Article

Abstract: Background: Small-scale models of dementia care are a potential solution to deinstitutionalize residential aged care and have been associated with improved resident outcomes, including quality of life and reduced hospitalizations for people living with dementia. Objective: This study aimed to generate strategies and ideas on how homes for people living with dementia in a village setting within a suburban community, could be designed and function without external boundaries. In particular, how could residents of the village and members of the surrounding community access and engage safely and equitably so that interpersonal connections might be fostered? Methods: …Twenty-one participants provided an idea for discussion at three Nominal Group Technique workshops, including people living with dementia, carers or former carers, academics, researchers, and clinicians. Discussion and ranking of ideas were facilitated in each workshop, and qualitative data were analyzed thematically. Results: All three workshops highlighted the importance of a surrounding community invested in the village; education and dementia awareness training for staff, families, services, and the community; and the necessity for adequately and appropriately trained staff. An appropriate mission, vision, and values of the organization providing care were deemed essential to facilitate an inclusive culture that promotes dignity of risk and meaningful activities. Conclusion: These principles can be used to develop an improved model of residential aged care for people living with dementia. In particular, inclusivity, enablement, and dignity of risk are essential principles for residents to live meaningful lives free from stigma in a village without external boundaries. Show more

Keywords: Alzheimer’s disease, aged care, co-design, dementia, dementia care, dementia village, geriatrics, group homes, nursing, nursing homes

DOI: 10.3233/JAD-230368

Citation: Journal of Alzheimer's Disease, vol. 94, no. 3, pp. 1247-1263, 2023