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Background: The approval of lecanemab, an anti-amyloid therapy for Alzheimer's disease (AD), necessitates addressing healthcare preparedness for disease-modifying treatment (DMT) to ensure appropriate, safe, and sustainable drug administration. Understanding public perceptions on this matter is crucial. We aimed to assess discrepancies and similarities in the perceptions of Japanese trial-ready cohort study ('J-TRC webstudy') participants and clinical specialists in the fields of dementia treatment and radiology, concerning affairs related to challenges in DMT preparedness. Methods: This was a cross-sectional prospective observational study conducted in November–December 2023. The J-TRC webstudy participants were invited to participate in an online survey using Google Forms, and clinical specialists were invited to complete a mail-based survey. Main questionnaire items had been designed to be common in both surveys, and their responses were analyzed for participant attributes, interests, attitudes, expectations, and concerns about DMTs without specifying lecanemab. Results: Responses were obtained from n = 2,050 J-TRC webstudy participants and n = 1,518 clinical specialists. Compared to specialists, more J-TRC respondents perceived the eligible proportion for DMT as smaller (59.1% versus 30.7%), perceived the eligible severity for DMT as more limited (58.0% versus 24.5%), and perceived the efficacy of DMT as slightly more encouraging (29.3% versus 34.8%). In terms of treatment prioritization, both J-TRC respondents and specialist respondents exhibited similar levels of acceptance for prioritizing patients to treat: e.g., approximately two-thirds endorsed patient prioritization under hypothetical resource constraints or other reasons. A medical rationale emerged as the most compelling reason for acceptance of patient prioritization across the surveys. In contrast, the need to address vulnerable populations was the reason that led to the least acceptance of prioritization, followed by economic considerations. Conclusions: Our findings offer valuable insights into the discrepancies in knowledge and perception between patients and healthcare providers. This could enhance the delivery of patient information in clinical settings and inform the discussion surrounding patient prioritization strategies. [ABSTRACT FROM AUTHOR]

Highlights: Progressive Supranuclear Palsy (PSP) presents with various clinical phenotypes, making accurate diagnosis difficult. No biomarker systems, such as the AT(N) system for Alzheimer's Disease (AD), have been established yet. In PSP, core AD cerebrospinal fluid biomarkers show a unique pattern, where Aβ42, Aβ40, p-tau, and t-tau levels are decreased while NfL levels are remarkably increased. Progressive Supranuclear Palsy (PSP) is the most common four-repeat tauopathy. PSP cases are typically characterized by vertical gaze palsy and postural instability; however, various phenotypes have been reported, making antemortem diagnosis based on clinical symptoms challenging. The development of biomarkers reflecting brain pathology and the ability to diagnose patients based on these biomarkers are essential for developing future intervention strategies, including disease-modifying therapies. However, despite many dedicated efforts, no highly specific fluid biomarker for PSP has yet been established. Conversely, several cerebrospinal fluid (CSF) biomarkers of Alzheimer's Disease (AD) have been established, and an AT(N) classification system has been proposed. Typically, among patients with AD, CSF amyloid β42 (Aβ42), but not Aβ40, is decreased, resulting in a reduction in the Aβ42/Aβ40 ratio, while tau phosphorylated at threonine 181 (p-tau181) and total tau (t-tau) are increased. Interestingly, the core CSF AD biomarkers show unique patterns in patients with PSP. Furthermore, reports have indicated that the CSF levels of both Aβ42 and Aβ40 are decreased independently of Aβ accumulation in PSP. Therefore, the Aβ42/Aβ40 ratio could potentially be used to differentiate PSP from AD. Additionally, studies have reported that CSF p-tau and t-tau are reduced in PSP, and that the neurofilament light chain is remarkably increased compared to healthy controls and patients with AD, even though PSP is a neurodegenerative disease associated with tau accumulation. These PSP-specific changes in AD-related core biomarkers may reflect the pathology of PSP and contribute to its diagnosis. As such, elucidating the mechanisms underlying the observed decreases in Aβ and tau levels could facilitate a better understanding of the pathogenesis of PSP. [ABSTRACT FROM AUTHOR]

Background: Polygenic effects have been proposed to account for some disease phenotypes; these effects are calculated as a polygenic risk score (PRS). This score is correlated with Alzheimer's disease (AD)-related phenotypes, such as biomarker abnormalities and brain atrophy, and is associated with conversion from mild cognitive impairment (MCI) to AD. However, the AD PRS has been examined mainly in Europeans, and owing to differences in genetic structure and lifestyle, it is unclear whether the same relationships between the PRS and AD-related phenotypes exist in non-European populations. In this study, we calculated and evaluated the AD PRS in Japanese individuals using genome-wide association study (GWAS) statistics from Europeans. Methods: In this study, we calculated the AD PRS in 504 Japanese participants (145 cognitively unimpaired (CU) participants, 220 participants with late mild cognitive impairment (MCI), and 139 patients with mild AD dementia) enrolled in the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) project. In order to evaluate the clinical value of this score, we (1) determined the polygenic effects on AD in the J-ADNI and validated it using two independent cohorts (a Japanese neuropathology (NP) cohort (n = 565) and the North American ADNI (NA-ADNI) cohort (n = 617)), (2) examined the AD-related phenotypes associated with the PRS, and (3) tested whether the PRS helps predict the conversion of MCI to AD. Results: The PRS using 131 SNPs had an effect independent of APOE. The PRS differentiated between CU participants and AD patients with an area under the curve (AUC) of 0.755 when combined with the APOE variants. Similar AUC was obtained when PRS calculated by the NP and NA-ADNI cohorts was applied. In MCI patients, the PRS was associated with cerebrospinal fluid phosphorylated-tau levels (β estimate = 0.235, p value = 0.026). MCI with a high PRS showed a significantly increased conversion to AD in APOE ε4 noncarriers with a hazard rate of 2.22. In addition, we also developed a PRS model adjusted for LD and observed similar results. Conclusions: We showed that the AD PRS is useful in the Japanese population, whose genetic structure is different from that of the European population. These findings suggest that the polygenicity of AD is partially common across ethnic differences. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Polygenic effects on the risk of Alzheimer's disease in the Japanese population." The authors of the original article have identified an error in Figure 2 and have provided a corrected version. The article has been updated accordingly. The correction notice includes a list of authors involved in the study, indicating a collaborative effort involving a diverse group of individuals. The purpose of the document is not explicitly stated, but it likely serves to rectify the error and ensure the accuracy of the original article. [Extracted from the article]

This study aimed to clarify associations of clinical and neuropsychological features and change in regional cerebral blood flow (rCBF) on 123 I-IMP-SPECT in patients with Parkinson's disease (PD) who developed dementia. Sixty-one PD patients (mean age, 65.9 ± 8.6 years; mean disease duration, 11.0 ± 11.0 years) were recruited and followed-up for two years. Clinical and neuropsychological characteristics, and rCBF from SPECT were compared between PD patients who developed dementia (PDD+) and those who remained undemented (PDD-). Thirty-eight PD patients (62.3%) were diagnosed with PD-MCI at baseline. During follow-up, 22 PD patients (36%) developed dementia (PDD+). Univariate logistic regression models showed that Hoehn and Yahr scale 4 (odds ratio [OR] 5.85; 95% confidence interval [CI] 1.35-30.75]), visual hallucination (OR 5.95; 95%CI 1.67-25.4]), and PD-MCI (OR 6.47; 95%CI 1.57-39.63]) represented a significant risk factor for PDD+. Among neuropsychological parameters, WAIS (Wechsler Adult Intelligence Scale)-III block design (OR 6.55; 95%CI 1.66-29.84), letter number sequencing (OR 7.01; 95%CI 1.65-36.64), digit-symbol coding (OR 3.90; 95%CI 1.13-14.2), Wechsler Memory Scale, revised (WMS-R) visual paired associates II (delayed recall) (OR 4.68; 95%CI 1.36-17.36), Logical memory I (immediate recall) (OR 8.30; 95%CI 1.37-90.89), Logical memory II (delayed recall) (OR 6.61; 95%CI 1.35-44.33), Visual reproduction I (immediate recall) (OR 7.67; 95%CI 2.11-31.40), and Visual reproduction II (delayed recall) (OR 5.64; 95%CI 1.62-21.47) were significant risk factors. Decreased rCBF assessed using the general linear model (two-sample t-test) by SPM8 was observed in the left precuneus (0, -66, 16), right cuneus (6, -76, 30), and left angular gyrus (-46, -74, 32) in PDD+ compared with PDD- patients. Collectively, we have here shown that clinical and neuropsychological characteristics as well as changes to rCBF in PD patients who converted to PDD+. These features should be carefully monitored to detect the development of dementia in PD patients.

This study explored the role of the ubiquitin-proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining changes in cerebrospinal fluid (CSF) levels of UPS proteins along with disease progression, AD imaging biomarkers (PiB PET, tau PET), neurodegeneration imaging measures (MRI, FDG PET), and Clinical Dementia Rating ® (CDR ® ). Using the SOMAscan assay, we detected subtle increases in specific ubiquitin enzymes associated with proteostasis in mutation carriers (MCs) up to two decades before the estimated symptom onset. This was followed by more pronounced elevations of UPS-activating enzymes, including E2 and E3 proteins, and ubiquitin-related modifiers. Our findings also demonstrated consistent correlations between UPS proteins and CSF biomarkers such as Aβ42/40 ratio, total tau, various phosphorylated tau species to total tau ratios (ptau181/T181, ptauT205/T205, ptauS202/S202, ptauT217/T217), and MTBR-tau243, alongside Neurofilament light chain (NfL) and the CDR ® . Notably, a positive association was observed with imaging markers (PiB PET, tau PET) and a negative correlation with markers of neurodegeneration (FDG PET, MRI), highlighting a significant link between UPS dysregulation and neurodegenerative processes. The correlations suggest that the increase in multiple UPS proteins with rising tau levels and tau-tangle associated markers, indicating a potential role for the UPS in relation to misfolded tau/neurofibrillary tangles (NFTs) and symptom onset. These findings indicate that elevated CSF UPS proteins in DIAD MCs could serve as early indicators of disease progression and suggest a link between UPS dysregulation and amyloid plaque, tau tangles formation, implicating the UPS as a potential therapeutic target in AD pathogenesis., Competing Interests: RJB is the Director of the DIAN-TU and Principal Investigator of DIAN and the DIAN-TU-001 trial. Unrelated to this study, for the DIAN-TU, he receives research support from the NIA, Eli Lilly and Company, F. Hoffman-La Roche, Ltd., Eisai, Alzheimer’s Association, GHR Foundation, Anonymous Organization, DIAN-TU Pharma Consortium (Active Members: Biogen, Eisai, Eli Lilly and Company, Janssen, F. Hoffmann-La Roche, Ltd./Genentech). JH is a paid consultant/advisor for Parabon Nanolabs, Roche, Prothena, and AlzPath. GYRH reports no competing interests directly relevant to this work. He has received grants or contracts from CIHR, NIA/NIH, has been a clinical trials investigator supported by Biogen, Cassava, and Lilly, has participated in expert advisory committee supported by Biogen, Roche, and NovoNordisk, and is the current president of C5R (Consortium of Canadian Centres for Clinical Cognitive Research). EMM receives Grant Funding from NIA; Institutional funding from Eli Lilly, Hoffmann-La Roche, Eisai. He is a DSMB member (paid directly) for Alector; Eli Lilly; a Scientific Advisory Board Member (paid directly to me) for Alzamend, Fondation Alzheimer. He acts as a Consultant/Advisor for Sage Therapeutics, Eli Lilly, Sanofi, AstraZeneca,Hoffmann La-Roche. CC has received research support from GSK and EISAI. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. CC is a member of the advisory board of Circular Genomics and owns stocks in these companies. DP is an employee of GlaxoSmithKline (GSK) and holds stock in GSK. CX is supported by National Institute on Aging (NIA) grants R01 AG067505 and R01 AG053550. All other authors have nothing to disclose. JCM is the Friedman Distinguished Professor of Neurology, Associate Director, Knight ADRC; Associate Director of DIAN and Founding Principal Investigator of DIAN. He is funded by NIH grants # P30 AG066444; P01AG003991; P01AG026276; and U19 AG024904. Neither he nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. TLSB has investigator-initiated research funding from the NIH, the Alzheimer’s Association, the Barnes-Jewish Hospital Foundation and Avid Radiopharmaceuticals. Dr. Benzinger participates as a site investigator in clinical trials sponsored by Avid Radiopharmaceuticals, Eli Lilly and Company, Biogen, Eisai, Jaansen, and F. Hoffmann-La Roche, Ltd. She also serves as an unpaid consultant to Eisai and Siemensand is on the Speaker’s Bureau for Biogen. AER reports no competing interests. He receives research support for this work from the National Institute on Aging (R01AG053267, U19AG032438) TI reports no competing interests. He received research support for this work from AMED (JP23dk0207066 and JP23dk0207049). GSD reports no competing interests directly relevant to this work. His research is supported by NIH (K23AG064029, U01AG057195, U01NS120901, U19AG032438). He serves as a consultant for Parabon Nanolabs Inc and as a Topic Editor (Dementia) for DynaMed (EBSCO). He is the co-Project PI for a clinical trial in anti-NMDAR encephalitis, which receives support from Amgen Pharmaceuticals, and a consultant for Arialys Therapeutics. He has developed educational materials for PeerView Media, Inc, and Continuing Education Inc. He owns stock in ANI pharmaceuticals. Dr. Day’s institution has received support from Eli Lilly for development and participation in an educational event promoting early diagnosis of symptomatic Alzheimer disease, and in-kind contributions of radiotracer precursors for tau-PET neuroimaging in studies of memory and aging (via Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly). RJP is Neuropathology Core Leader for the DIAN observational study and the DIAN Trials Unit. He receives research support for this work from the National Institute on Aging (U19 AG032438, U19AG032438-09S1, R01AG068319). His laboratory receives cost recovery funding from Biogen for tissue procurement and processing services related to ALS clinical trials. Neither he nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. FL has grants not related to this paper from NIH, DIAN, Enroll-HD and BIOGEN. JL reports speaker fees from Bayer Vital, Biogen, EISAI, TEVA, Zambon, Esteve, Merck and Roche, consulting fees from Axon Neuroscience, EISAI and Biogen, author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers and is inventor in a patent “Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies” (EP 23 156 122.6) filed by LMU Munich. In addition, he reports compensation for serving as chief medical officer for MODAG GmbH, is beneficiary of the phantom share program of MODAG GmbH and is inventor in a patent “Pharmaceutical Composition and Methods of Use” (EP 22 159 408.8) filed by MODAG GmbH, all activities outside the submitted work. SBB receives support from the National Institute on Aging (NIA) and the Michael J Fox Foundation. All other authors have nothing to disclose.