Lewy body diseases (LBD) are pathologically defined as the accumulation of Lewy bodies composed of an aggregation of α-synuclein (αSyn). In LBD, not only the sole aggregation of αSyn but also the co-aggregation of amyloidogenic proteins, such as amyloid-β (Aβ) and tau, has been reported. In this review, the pathophysiology of co-aggregation of αSyn, Aβ, and tau protein and the advancement in imaging and fluid biomarkers that can detect αSyn and co-occurring Aβ and/or tau pathologies are discussed. Additionally, the αSyn-targeted disease-modifying therapies in clinical trials are summarized.

We report two cases of superficial siderosis (SS) of the central nervous system (CNS), which is caused by chronic haemorrhaging into the subarachnoid space with haemosiderin deposition in the superficial portion of the CNS. Patient 1 had fluid collection in the spinal canal, which was reported as the source of the chronic bleeding. Patient 2 was bleeding from thickened dura at the level of the sacral vertebrae. Both of the patients had xanthochromic cerebrospinal fluid. We surgically repaired the sources of bleeding. Subsequently the cerebrospinal fluid (CSF) cleared and their symptoms were not aggravated for about 1 year. We measured several CSF markers of SS before and after surgery. Total tau protein (CSF-t-tau), phosphorylated tau protein (CSF-p-tau), iron (CSF-iron) and ferritin (CSF-ferritin) in the CSF were highly elevated at diagnosis. After surgery, the levels of CSF-t-tau and CSF-p-tau were markedly reduced while CSF-iron and CSF-ferritin had not decreased. It is suggested that CSF-t-tau and CSF-p-tau reflected the neural damage in SS and were useful to evaluate the effectiveness of SS therapies.

Alzheimer's disease (AD) is the most prevalent age‐related neurodegenerative disorder, mainly characterized by amyloid β (Aβ) accumulation in the brain. Numerous new agents are currently undergoing clinical trials as disease‐modifying therapies (DMTs) targeting Aβ. ALZ‐801 is a promising candidate DMT for AD, with a phase 3 trial of ALZ‐801 ongoing specifically for apolipoprotein E (APOE) ε4 homozygous patients with early‐stage AD. This study aimed to examine the effects of ALZ‐801 on Aβ assembly and explore its toxicological profile. Thioflavin T (ThT) assays and two imaging modalities—transmission electron microscopy (TEM) and high‐speed atomic force microscopy (HS‐AFM)—were used to evaluate ALZ‐801's effects on Aβ assembly. To assess the effect of ALZ‐801 on Aβ ₄₂ ‐induced cytotoxicity, 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assays and lactate dehydrogenase (LDH) assays were performed. ThT assays revealed increased lag time and decreased fluorescence in the presence of ALZ‐801, confirming inhibition of Aβ ₄₂ fibril formation, as confirmed by TEM. Real‐time observation using HS‐AFM revealed that ALZ‐801 inhibited the formation of Aβ ₄₂ fibril from low‐molecular‐weight (LMW)‐Aβ ₄₂ in the presence of Aβ ₄₂ seeds. HS‐AFM also revealed that globular aggregates from LMW‐Aβ ₄₂ were significantly larger with ALZ‐801, with few fibrils noted. MTT and LDH assays indicated that ALZ‐801 prevented LMW‐Aβ ₄₂ ‐induced cytotoxicity but did not reduce cytotoxicity induced by high‐molecular‐weight‐Aβ ₄₂ . ALZ‐801 can inhibit Aβ ₄₂ aggregation by preventing both nucleus formation and fibril elongation, while promoting large globular oligomer formation, and can significantly reduce LMW‐Aβ ₄₂ ‐induced cytotoxicity. These findings underscore the potential of ALZ‐801 as an effective DMT for APOE ε4 homozygous patients with AD.

This study aimed to develop a new computerized assessment battery for cognition (C-ABC) to detect mild cognitive impairment (MCI) and dementia. We performed C-ABC in subjects with dementia (n = 422), MCI (n = 145), and normal cognition (NC; n = 574), and analyzed by age stratum (50s, 60s, and 70–85 years). To distinguish MCI from NC, the C-ABC total combined score, which were calculated by dividing the C-ABC total score by the C-ABC required time, revealed the best area under the curves (AUC) at 0.838 and 0.735 in the 50s and 60s age groups, respectively; notably, this entire procedure took approximately 5 min. To distinguish dementia from NC and MCI, the partial items of C-ABC (items 3 + 6 combined score) revealed the best AUCs at 0.910, 0.874, and 0.882 in the 50s, 60s, and 70–85 age groups, respectively. Furthermore, the items 3 + 6 combined score established the best AUC at 0.794 in the 70–85 age group to distinguish MCI from NC; this entire procedure took around 2 min. Hence, this study suggests that C-ABC could be a useful tool for detecting dementia or MCI in a short time.

Objective: The Clarity AD phase III trial showed that lecanemab reduced amyloid markers in early Alzheimer's disease (AD) and resulted in less decline on measures of cognition and function than placebo. Herein, we aimed to characterize amyloid‐β (Aβ) protofibril (PF) captured by lecanemab in human cerebrospinal fluid (CSF) from living participants with different stages in AD, which enable an enhanced understanding of the dynamic changes of lecanemab‐associated Aβ‐PF (Lec‐PF) in vivo.Methods: We newly developed a unique and highly sensitive immunoassay method using lecanemab that selectively captures Lec‐PF. The CSF level of Lec‐PF, Aβ42, Aβ40, p‐tau181, p‐tau 217, total tau, and neurogranin were measured in Japanese participants (n = 163). The participants in this study consisted of 48 cognitively unimpaired Aβ‐negative (CU–), 8 cognitively impaired diagnosed as suspected non‐Alzheimer's disease pathophysiology, 9 cognitively unimpaired Aβ‐positive (CU+), 34 Aβ‐positive with mild cognitive impairment (MCI+), and 64 Aβ‐positive with AD dementia (AD+).Results: The CSF Lec‐PF levels significantly increased in the groups of MCI+ and AD+ compared with CU– group. Notably, CSF Lec‐PF showed modest correlation with plaque‐associated biomarkers in Aβ‐positive participants and stronger correlation with neurodegeneration biomarkers, such as CSF total tau and neurogranin, suggesting that CSF Lec‐PF levels proximally reflect neurodegeneration as well as the amount of senile amyloid plaques.Interpretation: This is the first report describing Aβ‐PF species captured by lecanemab in human CSF and supporting that Lec‐PF is correlated with neurodegeneration in AD and may explain the mechanism of the clinical effect of lecanemab. ANN NEUROL 2025;97:993–1006

We investigated associations of glycemic measures, and insulin resistance and secretion measures with hippocampal and subfield volumes. In this cross-sectional study, 7400 community-dwelling participants underwent brain MRI and health checkups between 2016 and 2018. Hemoglobin A_1c (HbA_1c), glycated albumin (GA), homeostasis model assessment for insulin resistance (HOMA-IR), and HOMA of percent β-cell function (HOMA-β) were evaluated. The associations of each measure with a smaller volume of the hippocampus and twelve hippocampal subfields were investigated. As a result, higher HbA_1c or GA and lower HOMA-β levels were significantly associated with smaller volumes in multiple hippocampal subfields. Furthermore, even when we analyzed non-diabetic individuals, substantial associations remained between higher GA or lower HOMA-β levels and smaller volumes of the whole hippocampus or the fimbria. Our findings indicate that postprandial glucose fluctuations, postprandial hyperglycemia, and low insulin secretion have a specific effect on the development of smaller hippocampal volume, suggesting that primary prevention of diabetes and/or sufficient glucose control are important for the prevention of dementia.