Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

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. Pre-press, no. Pre-press, pp. 1-11, 2024

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. Pre-press, no. Pre-press, pp. 1-15, 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. Pre-press, no. Pre-press, pp. 1-11, 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. Pre-press, no. Pre-press, pp. 1-10, 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. Pre-press, no. Pre-press, pp. 1-14, 2024

Authors: Ryoo, Nayoung | Suh, Jeewon | Son, Eun Ji | Park, Young Ho | Kim, SangYun

Article Type: Short Communication

Abstract: Background: Subjective cognitive decline (SCD) refers to self-reported cognitive decline in individuals with normal performance on standardized cognitive tests. Understanding the factors predicting progression from SCD to mild cognitive impairment (MCI) is crucial, as approximately 14% of SCD cases progress to dementia and about 27% develop MCI over four years. Objective: This study aims to identify neuropsychological predictors of progression from SCD to MCI, focusing on cognitive domains assessed through neuropsychological tests. Methods: This retrospective study at Seoul National University Bundang Hospital analyzed a cohort of 107 patients diagnosed with SCD through comprehensive assessment. Patients underwent …annual neuropsychological testing, including the Digit Span Test, Boston Naming Test, Rey Complex Figure Test, Seoul Verbal Learning Test, and Stroop Test. Results: Annually, these patients underwent neuropsychological tests over a 5-year period; 24 progressed to MCI per NIA-AA criteria. Key predictors of MCI progression included age, ischemic heart disease, and scores from the forward digit span, delayed recall, and Boston naming tests. Lower scores in delayed recall and Boston naming tests significantly correlated with a higher risk of MCI (p  < 0.001). Conclusions: These findings suggest a need for targeted management of memory and language functions to monitor disease progression effectively. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, neuropsychological tests, preclinical Alzheimer’s disease, progressive subjective cognitive decline, subjective cognitive decline

DOI: 10.3233/JAD-231042

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 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. Pre-press, no. Pre-press, pp. 1-11, 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. Pre-press, no. Pre-press, pp. 1-21, 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. Pre-press, no. Pre-press, pp. 1-12, 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. Pre-press, no. Pre-press, pp. 1-12, 2024