Microglia, the resident immune-competent cells of the brain, become dysfunctional in Alzheimer\'s disease (AD), and their aberrant immune responses contribute to the accumulation of pathological proteins and neuronal injury. Genetic studies implicate microglia in the development of AD, prompting interest in developing immunomodulatory therapies to prevent or ameliorate disease. However, microglia take on diverse functional states in disease, playing both protective and detrimental roles in AD, which largely overlap and may shift over the disease course, complicating the identification of effective therapeutic targets. Extensive evidence gathered using transgenic mouse models supports an active role of microglia in pathology progression, though results vary and can be contradictory between different types of models and the degree of pathology at the time of study. Here, we review microglial immune signaling and responses that contribute to the accumulation and spread of pathological proteins or directly affect neuronal health. We additionally explore the use of induced pluripotent stem cell (iPSC)-derived models to study living human microglia and how they have contributed to our knowledge of AD and may begin to fill in the gaps left by mouse models. Ultimately, mouse and iPSC-derived models have their own limitations, and a comprehensive understanding of microglial dysfunction in AD will only be established by an integrated view across models and an appreciation for their complementary viewpoints and limitations.

Pyroglutamate (pE)-modified amyloid-β (Aβ) peptides play a crucial role in the development of Alzheimer\'s disease. pEAβ3-42 can rapidly form oligomers that gradually elongate hydrophobic segments to form β-sheet-rich amyloid intermediates, ultimately resulting in the formation of mature amyloid fibrils. pEAβ3-42 can also catalyze the aggregation of Aβ species and subsequently accelerate the formation of amyloid senile plaques. Considering the recent clinical success of the pEAβ3-42-targeting antibody donanemab, molecules that strongly bind pEAβ3-42 and prevent its aggregation and catalytic effect on Aβs may also provide potential therapeutic options for Alzheimer\'s disease. Here, we demonstrate that the natural antibiotic cyclopeptide tyrocidine A (TA) not only strongly inhibits the aggregation of Aβ1-42 as previously reported, but also interacts with the hydrophobic C-terminus and middle domain of pEAβ3-42 to maintain an unordered conformation, effectively impeding the formation of initial oligomers and subsequently halting the aggregation of pEAβ3-42. Furthermore, TA can disrupt the \"catalytic effect\" of pEAβ3-42 on amyloid aggregates, effectively suppressing Aβ aggregation and ultimately preventing the pathological events induced by Aβs.

Disputes about the scientific validity of the amyloid-β hypothesis of Alzheimer\'s disease have been held since the early 1990s, with little constructive progress made between opposing sides despite recent therapeutic progress. Here, I argue that philosophy of science can improve the chance of constructive debate by giving researchers technical language to describe and assess scientific progress. To do so, I interpret the amyloid hypothesis using a modified version of the research programme concept from philosopher of science Imre Lakatos. I first outline the amyloid-β hypothesis and study critiques of its central place in Alzheimer\'s research. Then, I draw on the complexity of amyloid-β and Alzheimer\'s research to discuss the limits of using concepts from popular philosophers of science Karl Popper or Thomas Kuhn, before finally arguing that an adaptation of the research programme concept can foster constructive debates about the science of Alzheimer\'s and within it. I will argue that the amyloid-β hypothesis has contributed to significant progress in the Alzheimer\'s field based on what Lakatos called the \"positive heuristic\" (motivating the programme to test its predictions) and the \"negative heuristic\" (protecting the programme from refutation). I consider the amyloid research agenda to be progressive despite the fact that its claims about disease aetiology could be wrong.

The introduction of lecanemab has dramatically changed the field of dementia medicine. Lecanemab, defined as an anti-amyloid-β (Aβ) drug, comprises an antibody against Aβ, a protein structure believed to cause Alzheimer\'s disease. This drug represents a new direction in dementia treatment. In a phase III study, lecanemab was found to significantly slow cognitive decline, while showing manageable levels of amyloid-related imaging abnormalities, which are side-effects of lecanemab. Furthermore, lecanemab has been shown to effectively reduce Aβ accumulation in patients with early Alzheimer\'s disease, which might contribute not only to delaying the progression of cognitive decline, but also to improving the quality of life of patients and their families. However, there are conditions for the use of lecanemab, for which the Ministry of Health, Labor and Welfare has issued the Guidelines for Promotion of Optimal Use. These guidelines specify requirements for appropriate patient selection, prescribing physicians and administering medical institutions to ensure safe and effective use. Particular emphasis is placed on the confirmation of amyloid-β accumulation, amyloid-related imaging abnormalities risk management and appropriate handling of side-effects. The clinical use of lecanemab represents an important advancement in the treatment of dementia; however, the understanding and cooperation of healthcare professionals, patients and families are essential to maximize its efficacy and safety. Future issues to be addressed include the sustainability and long-term efficacy of treatment, improvement of clinical symptoms after removal of Aβ and motivation to administer the drug. Although lecanemab offers hope for the treatment of dementia, its use requires careful management. Geriatr Gerontol Int 2024; ••: ••-••.

OBJECTIVE: The co-occurrence of amyloid-β pathology in Parkinson\'s disease (PD) is common; however, the role of amyloid-β deposition in motor prognosis remains elusive. This study aimed to investigate the association between striatal amyloid deposition, motor complications and motor prognosis in patients with PD.
METHODS: Ninety-six patients with PD who underwent 18F florbetaben (FBB) positron emission tomography were retrospectively assessed. The ratio of the striatum to global (STG) FBB uptake was obtained for each individual, and patients were allotted into low and high STG groups according to the median value. The effect of STG group on regional amyloid deposition, the occurrence of motor complications and longitudinal change in levodopa equivalent dose (LED) requirement were investigated after controlling for age, sex, LED and disease duration at FBB scan.
RESULTS: The high STG group was associated with lower cortical FBB uptake in the parietal, occipital and posterior cingulate cortices and higher striatal FBB uptake compared to the low STG group. Patients in the high STG group had a higher risk of developing wearing off and levodopa-induced dyskinesia than those in the low STG group, whereas the risk for freezing of gait was comparable between the two groups. The high STG group showed a more rapid increase in LED requirements over time than the low STG group.
CONCLUSIONS: These findings suggest that relatively high striatal amyloid deposition is associated with poor motor outcomes in patients with PD.

OBJECTIVE: Alzheimer\'s disease (AD) pathology is featured by the extracellular accumulation of amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles in the brain. We studied whether Aβ and tau accumulation are independently associated with future cognitive decline in the AD continuum.
METHODS: Data were acquired from the Alzheimer\'s Disease Neuroimaging Initiative (ADNI) public database. A total of 1272 participants were selected based on the availability of Aβ-PET and CSF tau at baseline and of those 777 participants with follow-up visits.
RESULTS: We found that Aβ-PET and CSF tau pathology were related to cognitive decline across the AD clinical spectrum, both as potential predictors for dementia progression. Among them, Aβ-PET (A + T- subjects) is an independent reliable predictor of longitudinal cognitive decline in terms of ADAS-13, ADNI-MEM, and MMSE scores rather than tau pathology (A - T+ subjects), indicating tau accumulation is not closely correlated with future cognitive impairment without being driven by Aβ deposition. Of note, a high percentage of APOE ε4 carriers with Aβ pathology (A+) develop poor memory and learning capacity. Interestingly, this condition is not recurrence in terms of the ADNI-MEM domain when adding APOE ε4 status. Finally, the levels of Aβ-PET SUVR related to glucose hypometabolism more strongly in subjects with A + T- than A - T+ both happen at baseline and longitudinal changes.
CONCLUSIONS: In conclusion, Aβ-PET alone without tau pathology (A + T-) measure is an independent reliable predictor of longitudinal cognitive decline but may nonetheless forecast different status of dementia progression. However, tau accumulation alone without Aβ pathology background (A - T+) was not enough to be an independent predictor of cognitive worsening.

BACKGROUND: Despite parallel research indicating amyloid-β accumulation, alterations in cortical neurophysiological signaling, and multi-system neurotransmitter disruptions in Alzheimer\'s disease (AD), the relationships between these phenomena remains unclear.
METHODS: Using magnetoencephalography, positron emission tomography, and an atlas of 19 neurotransmitters, we studied the alignment between neurophysiological alterations, amyloid-β deposition, and the neurochemical gradients of the cortex.
RESULTS: In patients with mild cognitive impairment and AD, changes in cortical rhythms were topographically aligned with cholinergic, serotonergic, and dopaminergic systems. These alignments correlated with the severity of clinical impairments. Additionally, cortical amyloid-β plaques were preferentially deposited along neurochemical boundaries, influencing how neurophysiological alterations align with muscarinic acetylcholine receptors. Most of the amyloid-β-neurochemical and alpha-band neuro-physio-chemical alignments replicated in an independent dataset of individuals with asymptomatic amyloid-β accumulation.
CONCLUSIONS: Our findings demonstrate that AD pathology aligns topographically with the cortical distribution of chemical neuromodulator systems and scales with clinical severity, with implications for potential pharmacotherapeutic pathways.
CONCLUSIONS: Changes in cortical rhythms in Alzheimer\'s are organized along neurochemical boundaries. The strength of these alignments is related to clinical symptom severity. Deposition of amyloid-β (Aβ) is aligned with similar neurotransmitter systems. Aβ deposition mediates the alignment of beta rhythms with cholinergic systems. Most alignments replicate in participants with pre-clinical Alzheimer\'s pathology.

The fibrillation of amyloid-β (Aβ) is the critical causal factor in Alzheimer\'s disease (AD), the dissolution and clearance of which are promising for AD therapy. Although many Aβ inhibitors are developed, their low Aβ-binding affinity results in unsatisfactory effect. To solve this challenge, the Aβ sequence-matching strategy is proposed to tail-design dissociable nanosystem (B6-PNi NPs). Herein, B6-PNi NPs aim to improve Aβ-binding affinity for effective dissolution of amyloid fibrils, as well as to interfere with the in vivo fate of amyloid for Aβ clearance. Results show that B6-PNi NPs decompose into small nanostructures and expose Aβ-binding sites in response to AD microenvironment, and then capture Aβ via multiple interactions, including covalent linkage formed by nucleophilic substitution reaction. Such high Aβ-binding affinity disassembles Aβ fibrils into Aβ monomers, and induces the reassembly of Aβ&nanostructure composite, thereby promoting microglial Aβ phogocytosis/clearance via Aβ receptor-mediated endocytosis. After B6-PNi NPs treatment, the Aβ burden, neuroinflammation and cognitive impairments are relieved in AD transgenic mice. This work provides the Aβ sequence-matching strategy for Aβ inhibitor design in AD treatment, showing meaningful insight in biomedicine.

HDAC3 inhibition has been shown to improve memory and reduce amyloid-β (Aβ) in Alzheimer\'s disease (AD) models, but the underlying mechanisms are unclear. We investigated the molecular effects of HDAC3 inhibition on AD pathology, using in vitro and ex vivo models of AD, based on our finding that HDAC3 expression is increased in AD brains. For this purpose, N2a mouse neuroblastoma cells as well as organotypic brain cultures (OBCSs) of 5XFAD and wild-type mice were incubated with various concentrations of the HDAC3 selective inhibitor RGFP966 (0.1-10 μM) for 24 h. Treatment with RGFP966 or HDAC3 knockdown in N2a cells was associated with an increase on amyloid precursor protein (APP) and mRNA expressions, without alterations in Aβ42 secretion. In vitro chromatin immunoprecipitation analysis revealed enriched HDAC3 binding at APP promoter regions. The increase in APP expression was also detected in OBCSs from 5XFAD mice incubated with 1 μM RGFP966, without changes in Aβ. In addition, HDAC3 inhibition resulted in a reduction of activated Iba-1-positive microglia and astrocytes in 5XFAD slices, which was not observed in OBCSs from wild-type mice. mRNA sequencing analysis revealed that HDAC3 inhibition modulated neuronal regenerative pathways related to neurogenesis, differentiation, axonogenesis, and dendritic spine density in OBCSs. Our findings highlight the complexity and diversity of the effects of HDAC3 inhibition on AD models and suggest that HDAC3 may have multiple roles in the regulation of APP expression and processing, as well as in the modulation of neuroinflammatory and neuroprotective genes.

We assessed whether macro- and/or micro-structural white matter properties are associated with cognitive resilience to Alzheimer\'s disease pathology years prior to clinical onset.
We examined whether global efficiency, an indicator of communication efficiency in brain networks, and diffusion measurements within the limbic network and default mode network moderate the association between amyloid-β/tau pathology and cognitive decline. We also investigated whether demographic and health/risk factors are associated with white matter properties.
Higher global efficiency of the limbic network, as well as free-water corrected diffusion measures within the tracts of both networks, attenuated the impact of tau pathology on memory decline. Education, age, sex, white matter hyperintensities, and vascular risk factors were associated with white matter properties of both networks.
White matter can influence cognitive resilience against tau pathology, and promoting education and vascular health may enhance optimal white matter properties.
Aβ and tau were associated with longitudinal memory change over ∼7.5 years. White matter properties attenuated the impact of tau pathology on memory change. Health/risk factors were associated with white matter properties.