Journal of Alzheimer's Disease - Volume 101, issue 4

Authors: Veronelli, Laura | Daini, Roberta | Mannino, Alice | Rossetti, Alessia | Gilardone, Giulia | Corbo, Massimo | Primativo, Silvia

Article Type: Research Article

Abstract: Background: Visuo-perceptual and visuo-attentional disorders, such as global processing deficit and simultanagnosia, are not routinely investigated in prodromal forms of typical Alzheimer’s disease, as amnestic mild cognitive impairment (MCI). Objective: This study evaluated global processing abilities through Navon’s classical paradigm in individuals with amnestic MCI and investigated the related visuo-perceptual and attentional components involved in simultanagnosia. Methods: Sixteen consecutive patients with amnestic MCI (6 single-domain, 10 multiple-domain) and 16 matched controls were requested to identify global and local elements of hierarchical Navon letters, and to name large and small solid letters. Results: While correctly …identifying solid letters, patients with multiple-domain amnestic MCI were less accurate in processing the global level of hierarchical stimuli compared to controls. Single-case analyses suggested that global processing may also be impaired in single-domain amnestic MCI. In addition, patients with pathological performance in the Navon task showed perceptual and/or visual focal attention deficits. Conclusions: Early dysfunction of holistic processing can be detected in amnestic MCI. Visuo-perceptual and/or visual focal attention mechanisms, which have been shown to be damaged in Posterior Cortical Atrophy patients with simultanagnosia, may be impaired in individuals with amnestic MCI. Investigation and identification of global processing deficits in MCI could contribute to early diagnosis and longitudinal monitoring of the disease. Show more

Keywords: Alzheimer’s disease, focal attention, global processing deficits, mild cognitive impairment, Navon, simultanagnosia, visuo-perceptual processing

DOI: 10.3233/JAD-240375

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1151-1165, 2024

Authors: Chan, Carol K. | Lane, Kathleen A. | Gao, Sujuan | Adeoye-Olatunde, Omolola A. | Biber, Sarah | Glover, Crystal M. | Johnson, David K. | Risacher, Shannon L. | Saykin, Andrew J. | Wang, Sophia

Article Type: Research Article

Abstract: Background: Despite the need to increase engagement of underrepresented groups (URG) in Alzheimer’s disease and related dementias (ADRD) studies, enrollment remains low. Objective: Compare referral sources across racial and ethnic groups among participants enrolled in ADRC studies. Methods: Data for this cross-sectional secondary analysis were extracted from the National Alzheimer’s Coordinating Center Uniform Data Set. We performed mixed effects logistic regression models using generalized estimating equations for professional referral versus non-professional referral by racial and ethnic group, adjusted for age, gender, education, visit year, and Clinical Dementia Rating scale (CDR) with a random effect for study …site. Results: Included in the analysis were 48,330 participants across 46 ADRCs (mean [SD] age, 71.3 [10.5] years; 20,767 female [57%]; 4,138 Hispanic [8.6%]; 1,392 non-Hispanic Asian [2.9%]; 6,766 non-Hispanic Black [14%] individuals; and 676 individuals [1.4%] of other races. Non-Hispanic Black and Asian participants had lower odds of being referred by a professional contact compared to non-Hispanic White participants (Black: adjusted OR = 0.61, 95% CI = 0.44–0.86, p  = 0.005; Asian: adjusted OR = 0.65, 95% CI, p  = 0.004). In participants who had completed an MRI, there was no significant difference in referral source across ethnic and racial groups. Conclusions: Further studies are needed to better understand the systemic and structural factors that contribute to differences in referral sources and disparities in recruitment of URG into ADRD studies. Show more

Keywords: Alzheimer’s disease, diversity, language, race and ethnicity, recruitment

DOI: 10.3233/JAD-240485

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1167-1176, 2024

Authors: Abi-Ghanem, Charly | Salinero, Abigail E. | Smith, Rachel M. | Kelly, Richard D. | Belanger, Kasey M. | Richard, Riane N. | Paul, Aaron S. | Herzog, Ava A. | Thrasher, Christina A. | Rybka, Krystyna A. | Riccio, David | Gannon, Olivia J. | Kordit, David | Kyaw, Nyi-Rein | Mansour, Febronia M. | Groom, Emily | Brooks, Heddwen L. | Robison, Lisa S. | Pumiglia, Kevin | Zuloaga, Damian G. | Zuloaga, Kristen L.

Article Type: Research Article

Abstract: Background: About two-thirds of those with Alzheimer’s disease (AD) are women, most of whom are post-menopausal. Menopause accelerates dementia risk by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid-life metabolic disease (obesity, diabetes/prediabetes) is a well-known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents. Objective: Our goal was to determine the effects of a high fat diet on metabolic outcomes in the AppNL-F knock-in mouse model of AD and assess the effects of menopause. Methods: First, 3-month-old AppNL-F and WT female …mice were placed on either a control or a high fat diet until 10 months of age then assessed for metabolic outcomes. Next, we did a more extensive assessment in AppNL-F mice that were administered VCD (4-vinylcyclohexene diepoxide) or vehicle (oil) and placed on a control or high fat diet for 7 months. VCD was used to model menopause by causing accelerated ovarian failure. Results: Compared to WT controls, AD female mice had worse glucose intolerance. Menopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. There were interactions between diet and menopause on some metabolic health serum biomarkers and the expression of hypothalamic markers related to energy balance. Conclusions: This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further understanding the interaction between menopause and metabolic health in the context of AD. Show more

Keywords: Alzheimer’s disease, glucose metabolism, hypothalamus, menopause, metabolic disease, obesity

DOI: 10.3233/JAD-231332

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1177-1194, 2024

Authors: Curiel Cid, Rosie E. | Ortega, Alexandra | Vaillancourt, David | Asken, Breton | Crocco, Elizabeth A. | Armstrong, Melissa J. | Duara, Ranjan | Crenshaw, Kirsten | Adjouadi, Malek | Rosselli, Monica | Wang, Wei-en | Loewenstein, David A.

Article Type: Research Article

Abstract: Background: Semantic intrusion errors (SIEs) are both sensitive and specific to PET amyloid-β (Aβ) burden in older adults with amnestic mild cognitive impairment (aMCI). Objective: Plasma Aβ biomarkers including the Aβ42/40 ratio using mass spectrometry are expected to become increasingly valuable in clinical settings. Plasma biomarkers are more clinically informative if linked to cognitive deficits that are salient to Alzheimer’s disease (AD). Methods: This study included 119 older adults enrolled in the 1Florida Alzheimer’s Disease Research Center (ADRC), 45 aMCI participants scored below the established Aβ42/40 ratio cut-off of 0.160 using the Quest AD-Detect™ …assay indicating Aβ positivity (Aβ+), while 50 aMCI participants scored above this cut-off indicating Aβ negative status (Aβ–). Additionally, 24 cognitively unimpaired (CU) persons scored above the cut-off of 0.160 (Aβ–). Results: The aMCI plasma Aβ+ group evidenced the greatest percentage of SIEs, followed by the aMCI Aβ–. The CU Aβ– group exhibited the lowest percentage of SIEs. After adjustment for global cognitive impairment, aMCI plasma Aβ+ continued to demonstrate greater SIEs on tests tapping the failure to recover from proactive semantic interference (frPSI) as compared to the aMCI Aβ–group. Using pre-established cut-offs for frPSI impairment, 8.3% of CU Aβ– participants evidenced deficits, compared to 37.8% of aMCI Aβ–, and 74.0% of aMCI Aβ+. Conclusions: SIEs reflecting frPSI were associated with aMCI Aβ+ status based on the Aβ42/40 ratio. Results suggest the importance of SIEs as salient cognitive markers that map onto underlying AD pathology in the blood. Show more

Keywords: Alzheimer’s disease, amyloid-β, Aβ42/40, LASSI-L, mild cognitive impairment, plasma biomarkers, semantic intrusion errors

DOI: 10.3233/JAD-240164

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1195-1204, 2024

Authors: Lingenberg, Alma | Herrmann, François R. | Armand, Stéphane | Péron, Julie | Assal, Frédéric | Allali, Gilles

Article Type: Research Article

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) can present with both episodic amnestic syndrome and biomarkers of Alzheimer’s disease (AD) pathology. Objective: To examine the associations between amnestic syndrome and cerebrospinal fluid (CSF) AD biomarkers in iNPH and the CSF tap test response in iNPH patients with amnestic syndrome. Methods: We used the Free and Cued Selective Reminding Test to divide iNPH into amnestic and non-amnestic patients. We compared their clinical, biological, and radiological characteristics and examined the reversibility of gait spatiotemporal parameters and neuropsychological performances after a CSF tap test. Univariate and multiple linear regression models …examined the association between memory performance and clinical-biological characteristics. Results: Sixty-two non-amnestic patients (mean age 77.0±7.0 years, 38.7% female) and thirty-eight amnestic patients (mean age 77.0±5.9 years, 36.8% female) presented similar levels of AD biomarkers and clinical-radiological profiles. Global cognition and education levels were lower in the amnestic iNPH group. We found no association between AD biomarkers and memory performances (total tau: β= –4.50; 95% CI [–11.96;2.96]; p  = 0.236; amyloid-β (1–42): β= 8.60, 95% CI [–6.30;23.50]; p  = 0.240). At baseline, amnestic iNPH patients performed worse on executive functions, attention, and gait speed but improved similarly to the non-amnestic iNPH patients after the tap test. Conclusions: In our clinical sample of iNPH patients, we confirm the lack of specificity of the amnestic profile for predicting AD pathology. Clinicians should not preclude amnestic iNPH patients from undergoing an invasive procedure of CSF derivation. Show more

Keywords: Alzheimer’s disease, amyloid protein, cerebrospinal fluid biomarkers, diagnosis, episodic memory, idiopathic normal pressure hydrocephalus, memory deficits, neuropsychology, normal pressure hydrocephalus, tau protein

DOI: 10.3233/JAD-240439

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1205-1216, 2024

Authors: Zhang, Tan | Wang, Xin | Jester, Hannah M. | Zhou, Xueyan | Ma, Tao

Article Type: Research Article

Abstract: Background: Apathy is a state of decreased interest, lack of initiative, reduced goal-directed activity and blunted emotional responses. Apathy is one of the most common neuropsychiatric symptoms (NPS) in patients with Alzheimer’s disease (AD) and is also relatively omnipresent in individuals with Down syndrome (DS). Little is known about the apathy-like behaviors in rodent models of AD and DS. Objective: This study aimed to characterize apathy-like behaviors with aging in two established DS mouse models: Ts65Dn and Dp16. Methods: A battery of behavioral tests including nestlet shredding, marble burying, nest building, and burrowing were performed to …examine apathy-like behaviors. Individual z-scores for each mouse for each test, and a composite z-score of apathy-like behavior were analyzed for all mice from these behavioral tests. Results: Analysis of individual test results and composite z-score revealed significant apathy-like behaviors in Ts65Dn mice compared to WT controls. In contrast, Dp16 mice did not exhibit significant apathy-like behaviors. Conclusions: Our study is the first to characterize apathy-like behaviors in mouse models of DS with aging and highlights the difference between Ts65Dn and Dp16 DS model mice regarding apathy-like manifestations with aging. Show more

Keywords: Alzheimer’s disease, apathy-like behavior, Down syndrome, Dp16, mouse model, Ts65Dn

DOI: 10.3233/JAD-240675

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1217-1226, 2024

Authors: Ottaviani, Silvia | Tagliafico, Luca | Muzyka, Mariya | Page, Elena | Ottaviani, Ennio | Ponzano, Marta | Signori, Alessio | Nencioni, Alessio | Monacelli, Fiammetta

Article Type: Research Article

Abstract: Background: As the population ages, the concept of frailty becomes increasingly relevant and may be considered a precursor between aging and the development of dementia in later life. Similarly, the construct of cognitive reserve (CR) is an accepted model of cognitive resilience that may account for individual differences in trajectories of brain aging, mitigating the clinical expression of dementia. Objective: We aim to estimate the role of CR and frailty in moderating the prediction of dementia in the population aged over 80 who are attending an Italian outpatient memory clinic. Methods: Comprehensive Geriatric Assessment, Clinical Frailty …Scale (CFS) to screen for frailty, and Cognitive Reserve Index questionnaire (CRIq) to evaluate CR, were used to assess patients systematically. We performed multivariate logistic regression to assess associations with dementia. Model performance and interaction between frailty and cognitive reserve were then evaluated. Results: 166 patients were consecutively enrolled (mean age was 85.7 years old, females composed 68%); 25% had a diagnosis of amnestic mild cognitive impairment, and 75% had a diagnosis of dementia. Multivariate regression analysis showed that CRIq and CFS were the main clinical assessment tools associated with the presence of dementia, even after collinearity adjustment. No significant interaction of CFS*CRIq was found. Conclusions: To our knowledge, this is the first study to investigate the association between CR, frailty, dementia, and their related interacting terms in a real-world population of very old patients. Our findings may suggest that both CR and frailty shape an individual’s resilience throughout their lifetime. This may potentially counteract the effects of brain neuropathology, in line with the hypothesis that meaningful associations exist between CR, frailty, and cognition in later life. Show more

Keywords: Alzheimer’s disease, cognitive reserve, dementia, frailty, older adults

DOI: 10.3233/JAD-231121

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1227-1235, 2024

Authors: Rosenau, Colin | Köhler, Sebastian | van Boxtel, Martin | Tange, Huibert | Deckers, Kay

Article Type: Research Article

Abstract: Background: The “LIfestyle for BRAin health” (LIBRA) index was recently updated with three new modifiable factors: hearing impairment, social contact, and sleep (LIBRA2), but has not yet been validated. Objective: Comparison of the performance of both LIBRA versions in predicting dementia risk. Methods: Longitudinal data from the English Longitudinal Study of Ageing (ELSA) and the Maastricht Aging Study (MAAS) were used. The weighted LIBRA (11/12 factors available) and LIBRA2 (14/15 factors available) scores were calculated, with higher scores representing an unhealthier lifestyle. Dementia diagnoses were based on self- or informant reported physician diagnosis, an informant-based cognitive …screening tool, registry data or test data. Cox-proportional hazards regression was used to investigate the association between LIBRA(2) scores and dementia risk. Model fit and predictive accuracy were determined using the Akaike information criterion and Harrell’s C index. Results: Over an average follow-up of 8.3 years in ELSA and 17.9 years in MAAS, 346 (4.6%) and 120 (8.5%) individuals developed dementia, respectively. In ELSA, a one-point increase in LIBRA2 was associated with an 8% (1.06–1.11) higher dementia risk (LIBRA: 13%, 1.09–1.16). In MAAS, a one-point increase in LIBRA2 was associated with a 6% (1.01–1.12) higher dementia risk (LIBRA: 8%, 0.99–1.16). In ELSA, LIBRA (Harrell’s C = 0.68) and LIBRA2 (Harrell’s C = 0.67) performed similarly. In MAAS, LIBRA2 (Harrell’s C = 0.62) performed better compared to LIBRA (Harrell’s C = 0.52) Conclusions: LIBRA2 is a better model for identifying individuals at increased dementia risk and for public health initiatives aimed at dementia risk reduction. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, healthy lifestyle, primary prevention, protective factors, risk factors, risk reduction behavior

DOI: 10.3233/JAD-240666

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1237-1248, 2024

Authors: Mattke, Soeren | Tang, Yu | Hanson, Mark | von Arnim, Christine A.F. | Frölich, Lutz | Grimmer, Timo | Onur, Oezguer A. | Perneczky, Robert | Teipel, Stefan | Thyrian, Jochen René

Article Type: Research Article

Abstract: Background: Amyloid-targeting therapies for Alzheimer’s disease (AD) might become available in Germany soon. The combination of a large pool of prevalent cases and a complex diagnostic process to determine eligibility for these treatments is likely to challenge health systems’ capacity. Objective: To analyze Germany’s healthcare system capacity to identify treatment-eligible patients in a timely and equitable manner. Methods: We modeled patients’ diagnostic journey and projects wait times due to capacity constraints for AD specialist visits and PET scans from 2024 to 2043. Model parameters were derived from published data and expert input. Results: Wait …times would be ∼50 months over the model horizon, if patients were referred to specialists based on a brief cognitive assessment in primary care. Wait times for patients with social health insurance are projected to be 1.9 times those of patients with private insurance, with peak wait times of around 76 and 40 months, respectively. Adding a blood test for the AD pathology as additional triage step would reduce wait times to below 24 months. Conclusions: In spite of having a well-resourced health system, Germany is projected to be unable to cope with the demand for biomarker-based AD diagnosis, if a disease-modifying AD treatment were introduced. As these treatments might become available by the end of 2024, decisive action, in particular dissemination of high-performing AD blood tests for triage in primary care, will be needed to prevent delays in access and potentially avoidable and inequitable disease progression. Show more

Keywords: Alzheimer’s disease, biomarker, disease-modifying treatment, health system preparedness, specialty care, diagnosis, wait times

DOI: 10.3233/JAD-240728

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1249-1259, 2024

Authors: Beckmann, Matthew N.

Article Type: Research Article

Abstract: Background: When Ronald Reagan revealed his Alzheimer’s diagnosis in 1994, it rekindled a lingering question: did dementia affect Reagan during his eight years as president? Amid countless countervailing anecdotes, Berisha et al. (2015) stepped in with an inventive systematic test. Scouring Ronald Reagan’s 46 formal press conferences for specific linguistic markers, the study discovered “significant differences in variables known to be associated with the onset of dementia” (962). Objective: Here I test whether Reagan’s unique word usage rate decline is spurious, a function of reporters’ increasing penchant for asking “follow-up” questions. Methods: Focusing on the …President’s specific responses to distinct questions, I reanalyze Reagan’s unique word usage rate while holding constant the number and type of reporter questions. Results: I find Reagan’s unique word usage rate held form throughout his eight years in the White House. Conclusions: I conclude by considering the implications for Reagan’s legacy and Alzheimer’s research. Show more

Keywords: Alzheimer’s disease, early diagnosis, natural language processing, research methodology

DOI: 10.3233/JAD-240294

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1261-1266, 2024

Authors: Liu, Xin Lian | Yeerlan, Jianishaya | Liu, Zhirong | Bai, Yang | Wang, Qin | Yan, YiRui | Xu, LuKe | Jia, Cui | Zhang, LuShun

Article Type: Research Article

Abstract: Background: No effective drugs currently exist to cure Alzheimer’s disease (AD) due to its complexity and the lack of understanding of the involved molecular signaling and pathways. The relationship between liver health and AD is now widely recognized. Still, molecular links and shared pathways between the liver and brain remain unclear, making the liver-brain axis in AD therapies a new area for exploration. However, bibliometric studies on this topic are lacking. Objective: This study aims to review the liver-brain axis in AD and identify future research hotspots and trends through bibliometric analysis. Methods: Articles and reviews …related to AD and liver and its related diseases were searched in the Web of Science Core Collection (WoSCC) database up to 2024. Data were processed and visually analyzed using VOSviewer, CiteSpace, and Pajek. Results: We collected 1,777 articles on AD and liver and its related diseases from 2,517 institutions across 80 countries. Keyword cluster analysis identified 11 clusters, with ‘insulin resistance,’ ‘amyloid-beta,’ ‘apolipoprotein-E,’ ‘oxidative stress,’ and ‘inflammation’ appearing most frequently, and exhibiting strong total link strength. These results indicate that these topics have been the primary focus of research on the liver-brain axis in AD. Conclusions: This study is the first to comprehensively analyze the liver-brain axis in AD using bibliometric methods. The research results identify recent research frontiers and hotspots, aiding scholars in gaining a deeper understanding of the correlation between AD and the liver. Show more

Keywords: Alzheimer’s disease, bibliometric analysis, liver, liver-brain axis, review

DOI: 10.3233/JAD-240688

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1267-1280, 2024

Authors: Park, Jiae | Oh, Jung-Pyo | Ku, Kyojin | Jin, Yeonsun | Kim, Eun Jung | Lee, Ji-Hyun

Article Type: Research Article

Abstract: Background: Drug-induced adverse symptoms affect patients’ quality of life (QoL) during treatment. Understanding the underlying mechanisms of drug-induced adverse effects could help prevent them. As current drugs have limited effects in halting the progress of Alzheimer’s disease (AD), patients are required to take these drugs over a long period. The main obstacles to long-term compliance are drug-elicited side effects that deteriorate patient QoL. Objective: Donepezil, the most popular acetylcholinesterase inhibitor (AChEI) drug for AD, induces various side effects, especially at high doses. This study aimed to identify a drug that can attenuate the side effects of donepezil and …investigate the underlying mechanisms. Methods: Five-week-old Sprague-Dawley rats received daily oral donepezil and N-acetylcysteine (NAC) for four weeks. General symptoms following administration were monitored daily to address drug-related adverse effects. Cytosolic calcium influx and generation of reactive oxygen species (ROS) after drug treatment were measured in vitro using C2C12 myotubes. Results: High-dose donepezil induced numerous adverse symptoms in male and female rats, which were markedly attenuated by co-treatment with NAC. NAC significantly reduced both acute and chronic muscle-related symptoms caused by donepezil. Additionally, in vitro studies showed that high-dose donepezil increased ROS and intracellular calcium ([Ca2+ ]i) levels in muscle cells, contributing to these adverse effects. NAC co-treatment dramatically reduced ROS and [Ca2+ ]i levels in muscle cells. Conclusions: Combined treatment with NAC effectively diminishes the adverse effects elicited by donepezil by regulating ROS and [Ca2+ ]i levels in the skeletal muscle, which could contribute to improving donepezil treatment in patients. Show more

Keywords: Acetylcysteine, adverse effects, Alzheimer’s disease, donepezil

DOI: 10.3233/JAD-240709

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1281-1292, 2024

Authors: Pereira, Helena Rico | Diogo, Vasco Sá | Prata, Diana | Ferreira, Hugo Alexandre

Article Type: Research Article

Abstract: Background: Early detection of amyloid-β (Aβ) positivity is essential for an accurate diagnosis and treatment of Alzheimer’s disease (AD), but it is currently costly and/or invasive. Objective: We aimed to classify Aβ positivity (Aβ+) using morphometric features from magnetic resonance imaging (MRI), a more accessible and non-invasive technique, in two clinical population scenarios: one containing AD, mild cognitive impairment (MCI) and cognitively normal (CN) subjects, and another only cognitively impaired subjects (AD and MCI). Methods: Demographic, cognitive (Mini-Mental State Examination [MMSE] scores), regional morphometry MRI (volumes, areas, and thicknesses), and derived morphometric graph theory (GT) features …from all subjects (302 Aβ+, age: 73.3±7.2, 150 male; 246 Aβ–, age: 71.1±7.1, 131 male) were combined in different feature sets. We implemented a machine learning workflow to find the best Aβ+ classification model. Results: In an AD+MCI+CN population scenario, the best-performing model selected 120 features (107 GT features, 12 regional morphometric features and the MMSE total score) and achieved a negative predictive value (NPVadj ) of 68.4%, and a balanced accuracy (BAC) of 66.9%. In a AD+MCI scenario, the best model obtained NPVadj of 71.6%, and BAC of 70.7%, using 180 regional morphometric features (98 volumes, 52 areas and 29 thicknesses from temporal, parietal, and frontal brain regions). Conclusions: Although with currently limited clinical applicability, regional MRI morphometric features have clinical usefulness potential for detecting Aβ status, which may be augmented by a combination with cognitive data when cognitively normal subjects make up a substantial part of the population presenting for diagnosis. Show more

Keywords: Alzheimer’s disease, amyloid-β, dementia, diagnostic imaging, machine learning

DOI: 10.3233/JAD-240366

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1293-1305, 2024

Authors: Babulal, Ganesh M. | Zha, Wenqing | Trani, Jean-Francois | Guerra, Jorge Llibre | Tee, Boon Lead | Zhu, Yiqi | Chen, Yaohua | Chen, Ling | Bubu, Michael | Josephy-Hernandez, Sylvia | Wandera, Stephen | Karanja, Wambūi | Ellajosyula, Ratnavalli | Caramelli, Paulo

Article Type: Research Article

Abstract: Background: The significant increase in Alzheimer’s disease and related dementia prevalence is a global health crisis, acutely impacting low- and lower-middle and upper-middle-income countries (LLMICs/UMICs). Objective: The objective of this study is to identify key barriers and gaps in dementia care and research in LLMICs and UMICs. Methods: We conducted an international, cross-sectional survey among clinicians and healthcare professionals (n  = 249 in 34 countries) across LLMICs and UMICs, exploring patient demographics, use of clinical diagnosis, dementia evaluation, screening/evaluation tools, and care and treatment. Results: Significant disparities were found in diagnostic practices, access to assessments, …and access to care. On average, clinicians in LLMICs saw more patients, had less time for evaluations, lower use of formal screening and tools, and less access to biomarkers. They were also under-resourced compared to UMICs. Conclusions: The findings provide insights for policymakers, healthcare organizations, and researchers to address the complex challenges associated with dementia care in diverse settings. Addressing these challenges requires a multipronged approach involving local, national, and international stakeholders. Show more

Keywords: Alzheimer’s disease, dementia, disparity, low and middle-income countries, resources, underserved

DOI: 10.3233/JAD-240650

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1307-1320, 2024

Authors: Wu, Yanjuan | Liu, Yixuan | Liu, Yuyang | Chen, Yuntao | Lobanov-Rostovsky, Sophia | Zhang, Yuting | Liu, Yuanli | Brunner, Eric J. | French, Eric | Liao, Jing

Article Type: Research Article

Abstract: Background: Previous estimates on future socioeconomic costs of dementia in China are inconsistent, and the main drivers of these costs are unclear. Objective: This study projected future socioeconomic costs (healthcare, formal social care, and informal care costs) and value of quality adjusted life years (QALYs) lost to dementia in China and assessed drivers of socioeconomic costs. Methods: Based on our prior projection on dementia cases to 2050 by a Markov model, we forecasted future socioeconomic costs and the value of QALYs from a societal perspective, utilizing the China Health and Retirement Longitudinal Study and the Chinese …Longitudinal Healthy Longevity Survey. In our main analysis, dementia incidence increased by 2.9% annually, while sensitivity analyses considered a flat or 1.0% annual decrease in the temporal trend of dementia incidence. Furthermore, we decomposed socioeconomic costs changes (2018 US$) into population growth, population aging, dementia prevalence and average socioeconomic costs per case. Results: The annual socioeconomic costs and value of QALYs lost to dementia will reach $1,233 billion and $702 billion by 2050. If dementia incidence stays constant or decreases by 1.0% annually, the costs and QALYs would respectively decrease by 34% or 43% in 2050. Informal care is currently, and projected to remain, the largest share of socioeconomic costs. Population aging and rising dementia prevalence will mainly drive the growth in socioeconomic costs through 2050. Conclusions: Dementia casts an increasingly large economic burden on Chinese society, mainly driven by fast aging population and growing dementia prevalence. Show more

Keywords: Alzheimer’s disease, China, costs of quality of life lost, dementia, modeling studies, socioeconomic costs

DOI: 10.3233/JAD-240583

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1321-1331, 2024

Authors: Del Tredici, Kelly | Schön, Michael | Feldengut, Simone | Ghebremedhin, Estifanos | Kaufman, Sarah K. | Wiesner, Diana | Roselli, Francesco | Mayer, Benjamin | Amunts, Katrin | Braak, Heiko

Article Type: Research Article

Abstract: Background: Neuropathologic studies of brains from autopsy series show tau inclusions (pretangles, neuropils threads, neurofibrillary tangles) are detectable more than a decade before amyloid-β (Aβ) deposition in Alzheimer’s disease (AD) and develop in a characteristic manner that forms the basis for AD staging. An alternative position views pathological tau without Aβ deposition as a ‘primary age-related tauopathy’ (PART) rather than prodromal AD. Recently, an early focus of tau inclusions in the Ammon’s horn second sector (CA2) with relative sparing of CA1 that occurs before tau inclusions develop in the entorhinal cortex (EC) was proposed as an additional feature of PART. …Objective: To test the ‘definite PART’ hypothesis. Methods: We used AT8-immunohistochemistry in 100μ m sections to examine the EC, transentorhinal cortex (TRE), and Ammon’s horn in 325 brains with tau inclusions lacking Aβ deposits (average age at death 66.7 years for females, 66.4 years for males). Results: 100% of cases displayed tau inclusions in the TRE. In 89% of cases, the CA1 tau rating was greater than or equal to that in CA2. In 25%, CA2 was devoid of tau inclusions. Only 4% displayed a higher tau score in CA2 than in the TRE, EC, and CA1. The perforant path also displayed early tau changes. APOE genotyping was available for 199/325 individuals. Of these, 44% had an ɛ 4 allele that placed them at greater risk for developing later NFT stages and, therefore, clinical AD. Conclusions: Our new findings call into question the PART hypothesis and are consistent with the idea that our cases represent prodromal AD. Show more

Keywords: Alzheimer’s disease, Ammon’s horn, APOE, CA2, entorhinal cortex, neurofibrillary tangles, PART hypothesis, pretangles, tau seeding, tractus perforans

DOI: 10.3233/JAD-240483

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1333-1353, 2024

Authors: Wang, Qiuchen | Fu, Mengjie | Gao, Lihui | Yuan, Xin | Wang, Ju

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder that is the most common form of dementia in the elderly. The drugs currently used to treat AD only have limited effects and are not able to cure the disease. Drug repositioning has increasingly become a promising approach to find potential drugs for diseases like AD. Objective: To screen potential drug candidates for AD based on the relationship between risk genes of AD and drugs. Methods: We collected the risk genes of AD and retrieved the information of known drugs from DrugBank. Then, the AD-related genes and the …targets of each drug were mapped to the human protein-protein interaction network (PPIN) to represent AD and the drugs on the network. The network distances between each drug and AD were calculated to screen the drugs proximal to AD-related genes on PPIN, and the screened drug candidates were further analyzed by molecular docking and molecular dynamics simulations. Results: We compiled a list of 714 genes associated with AD. From 5,833 drugs used for human diseases, we identified 1,044 drugs that could be potentially used to treat AD. Then, amyloid-β (Aβ) protein, the key molecule involved in the pathogenesis of AD was selected as the target to further screen drugs that may inhibit Aβ aggregation by molecular docking. We found that ergotamine and RAF-265 could bind stably with Aβ. In further analysis by molecular dynamics simulations, both drugs exhibited reasonable stability. Conclusions: Our work indicated that ergotamine and RAF-265 may be potential candidates for treating AD. Show more

Keywords: Alzheimer’s disease, drug repositioning, ergotamine, molecular docking, risk genes

DOI: 10.3233/JAD-240235

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1355-1366, 2024

Authors: Ansah, John P. | Zacharia, Hannah | Chiu, Chi-Tsun

Article Type: Research Article

Abstract: Background: The association between COVID-19 infection and the onset of dementia among adults 65 years and older has the potential to increase the burden of dementia worldwide significantly. Our research, which focuses on understanding the likely increase in the burden of dementia due to COVID-19 infection in the USA, has crucial public policy implications. By providing these insights, we aim to empower policymakers, healthcare professionals, researchers, and public health officials to make informed decisions and plan for the future. Objective: Project the prevalence of dementia in the United States while accounting for the impact of COVID-19 infection on …the onset of dementia. Methods: A dynamic multi-state population model was developed. The model was initialized with USA demographic data and estimates of age, gender, and race-specific transition rates from the Health and Retirement Study (HRS). Results: The projected increase in the burden of dementia among Americans 65 years and older is a staggering 14.838 million by 2050. However, due to the COVID-19 pandemic, we anticipate an additional 265,000 to 677,000 older adults 65 years and older will be affected by dementia. This will escalate the burden of dementia to a potential 15.103 million to 15.515 million by 2050, a significant human toll that we must be prepared for. Conclusions: The projected dementia numbers underscore the urgent need for policy and intervention in social care services and healthcare needs planning. This includes providing robust support systems for caregivers and ensuring the healthcare staff is adequately trained to meet the healthcare needs of dementia patients and their families. Show more

Keywords: Alzheimer’s diseases, dementia, multi-state population model, race and ethnicity, system dynamics

DOI: 10.3233/JAD-240177

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1367-1377, 2024

Authors: Verdelho, Ana | Correia, Manuel | Gonçalves-Pereira, Manuel | Madureira, Sofia | Vilela, Pedro | Santos, Ana Catarina | Rodrigues, Mário | Borges, Mariana | Ferro, José M. | Santa-Clara, Helena

Article Type: Research Article

Abstract: Background: Vascular cognitive impairment is frequent, in mild (mVCI) or severe forms (vascular dementia). Objective: To do a randomized controlled-trial to evaluate the impact of physical activity on cognition (primary outcome), neurocognitive measures, quality of life, functional status, and physical function (secondary outcomes), in patients with mVCI. Methods: A hundred and four patients with mVCI (mean age 71.2 years; 53 women) were randomized for a six-month intervention of moderate physical activity (60-minute sessions, 3 times/week) (n  = 53) or best-practice “usual care” (n  = 51). Comprehensive evaluations of primary and secondary outcomes included an objective measure of physical …activity through accelerometry at baseline and after intervention. Results: Mean session attendance was 58%. Adverse events were negligible. After 6 months, no significant primary outcome change was observed, either in the intervention or ‘usual care’ group. The intervention group improved significantly in some secondary outcomes in physical function - aerobic capacity (U = 403; p  = 0.000) and agility (U = 453; p  = 0.005) after 6 months. Regardless of randomization arm, a post-hoc analysis based on fulfilling at least 21.5 minutes/day of moderate or 10.7 minutes/day of vigorous physical activity (World Health Organization-WHO standards) revealed improvements. These were not only in motor capacity but also on the global measure of cognition, executive functions and memory. Conclusions: Physical activity was safe and beneficial regarding domains of physical function. No significant cognitive decline was registered over 6-months, regardless of intervention allocation. Larger samples, longer follow-ups and focus on intervention adherence are needed to fully analyze the impact of WHO recommendations for physical activity in mVCI populations. Show more

Keywords: Alzheimer’s disease, intervention, non-Alzheimer’s disease neurocognitive disorder, physical activity, prevention, vascular cognitive impairment

DOI: 10.3233/JAD-240246

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1379-1392, 2024

Authors: Rajamaki, Blair | Braithwaite, Billy | Hartikainen, Sirpa | Tolppanen, Anna-Maija

Article Type: Research Article

Abstract: Background: Multimorbidity is common in older adults and complicates diagnosing and care for this population. Objective: We investigated co-occurrence patterns (clustering) of medical conditions in persons with Alzheimer’s disease (AD) and their matched controls. Methods: The register-based Medication use and Alzheimer’s disease study (MEDALZ) includes 70,718 community-dwelling persons with incident AD diagnosed during 2005-2011 in Finland and a matched comparison cohort. Latent Dirichlet Allocation was used to cluster the comorbidities (ICD-10 diagnosis codes). Modeling was performed separately for AD and control cohorts. We experimented with different numbers of clusters (also known as topics in the field …of Natural Language Processing) ranging from five to 20. Results: In both cohorts, 17 of the 20 most frequent diagnoses were the same. Based on a qualitative assessment by medical experts, the cluster patterns were not affected by the number of clusters, but the best interpretability was observed in the 10-cluster model. Quantitative assessment of the optimal number of clusters by log-likelihood estimate did not imply a specific optimal number of clusters. Multidimensional scaling visualized the variability in cluster size and (dis)similarity between the clusters with more overlapping of clusters and variation in group size seen in the AD cohort. Conclusions: Early signs and symptoms of AD were more commonly clustered together in the AD cohort than in the comparison cohort. This study experimented with using natural language processing techniques for clustering patterns from an epidemiological study. From the computed clusters, it was possible to qualitatively identify multimorbidity that differentiates AD cases and controls. Show more

Keywords: Alzheimer’s disease, ICD-10 codes, latent Dirichlet allocation, natural language processing, register-based studies, topic modeling

DOI: 10.3233/JAD-240490

Citation: Journal of Alzheimer's Disease, vol. 101, no. 4, pp. 1393-1403, 2024