Current Alzheimer Research - Volume 20, Issue 10, 2023

Type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's Disease (AD). However, the detailed mechanism underlying T2DM-related AD remains unknown. In DM, many types of advanced glycation end-products (AGEs) are formed and accumulated. In our previous study, we demonstrated that Glyceraldehyde (GA)-derived Toxic Advanced Glycation End-products (Toxic AGEs, TAGE) strongly showed cytotoxicity against neurons and induced similar alterations to those observed in AD. Further, GA induced dysfunctional neurite outgrowth via TAGE-β-- tubulin aggregation, which resulted in the TAGE-dependent abnormal aggregation of β-tubulin and tau phosphorylation. Herein, we provide a perspective on the possibility that T2DM increases the probability of AD onset and accelerates its progression.

Psychosis and hyperactive behaviors, such as agitation and wandering, affect a significant proportion of patients with Alzheimer’s disease (AD). These symptoms are often treated with antipsychotics, usually in an off-label approach. This mini-review provides an updated perspective on the pharmacological approach for the neuropsychiatric symptoms (NPS) in AD. The results of new studies have provided a better understanding of AD-related NPS management, but high-quality evidence still needs to be obtained. Herein, we argue for a more cautious approach to the use of antipsychotics in AD and highlight the importance of exploring alternative treatments for NPS. By doing so, we can ensure that patients with AD receive optimal care that is both effective and safe.

Alzheimer’s disease (AD) is a highly hereditary disease with complex genetic susceptibility factors. Extensive genome-wide association studies have established a distinct susceptibility link between the protein tyrosine kinase 2β (PTK2B) gene and late-onset Alzheimer’s disease (LOAD), but the specific pathogenic mechanisms remain incompletely understood. PTK2B is known to be expressed in neurons, and recent research has revealed its more important significance in microglia. Elucidating the role of PTK2B high expression in microglia in AD’s progression is crucial for uncovering novel pathogenic mechanisms of the disease. Our review of existing studies suggests a close relationship between PTK2B/proline-rich tyrosine kinase 2 (Pyk2) and tau pathology, and this process might be β-amyloid (Aβ) dependence. Pyk2 is hypothesized as a pivotal target linking Aβ and tau pathologies. Concurrently, Aβ-activated Pyk2 participates in the regulation of microglial activation and its proinflammatory functions. Consequently, it is reasonable to presume that Pyk2 in microglia contributes to amyloid-induced tau pathology in AD via a neuroinflammatory pathway. Furthermore, many things remain unclear, such as identifying the specific pathways that lead to the release of downstream inflammatory factors due to Pyk2 phosphorylation and whether all types of inflammatory factors can activate neuronal kinase pathways. Additionally, further in vivo experiments are essential to validate this hypothesized pathway. Considering PTK2B/Pyk2's potential role in AD pathogenesis, targeting this pathway may offer innovative and promising therapeutic approaches for AD.

>Background: Indoleamine 2,3-dioxygenase (IDO1) inhibition is a promising target as an Alzheimer’s disease (AD) Disease-modifying therapy capable of downregulating immunopathic neuroinflammatory processes. Methods: To aid in the development of IDO inhibitors as potential AD therapeutics, we optimized a lipopolysaccharide (LPS) based mouse model of brain IDO1 inhibition by examining the dosedependent and time-course of the brain kynurenine:tryptophan (K:T) ratio to LPS via intraperitoneal dosing. Results: We determined the optimal LPS dose to increase IDO1 activity in the brain, and the ideal time point to quantify the brain K:T ratio after LPS administration. We then used a brain penetrant tool compound, EOS200271, to validate the model, determine the optimal dosing profile and found that a complete rescue of the K:T ratio was possible with the tool compound. Conclusion: This LPS-based model of IDO1 target engagement is a useful tool that can be used in the development of brain penetrant IDO1 inhibitors for AD. A limitation of the present study is the lack of quantification of potential clinically relevant biomarkers in this model, which could be addressed in future studies.

Background and Objective: Recent evidence suggests that blood-based biomarkers might be useful for Alzheimer’s disease (AD). Among them, we intend to investigate whether neurofilament light (NfL) and multimer detection system-oligomeric Aβ (MDS-OAβ) values can be useful in screening, predicting, and monitoring disease progression and how the relationship between NfL and MDS-OAβ values changes. Methods: Eighty participants with probable AD dementia, 50 with mild cognitive impairment (MCI), and 19 with subjective cognitive decline (SCD) underwent baseline and follow-up evaluations of the Mini-Mental Status Examination (MMSE) and both plasma biomarkers. Results: Baseline MDS-OAß (p = 0.016) and NfL (p = 0.002) plasma concentrations differed significantly among groups, but only NfL correlated with baseline MMSE scores (r = -0.278, p = 0.001). In follow-up, neither correlated with MMSE changes overall. However, in SCD and MCI participants (n = 32), baseline MDS-OAß correlated with follow-up MMSE scores (r = 0.532, p = 0.041). Linear regression revealed a relationship between baseline MDS-OAβ and follow-up MMSE scores. In SCD and MCI participants, plasma NfL changes correlated with MMSE changes (r = 0.564, p = 0.028). Conclusion: This study shows that only in participants with SCD and MCI, not including AD dementia, can MDS-OAß predict the longitudinal cognitive decline measured by follow-up MMSE. Changes of NfL, not MDS-OAß, parallel the changes of MMSE. Further studies with larger samples and longer durations could strengthen these results.

>Objectives: Alzheimer's disease (AD) and/or dementia is a prevalent neurocognitive disorder primarily affecting individuals over the age of 65. Identifying specific causes of AD and/or dementia can be challenging, with emerging evidence suggesting a potential association with autoimmune inflammatory conditions such as rheumatoid arthritis (RA). This study aimed to assess the prevalence rate of AD and/or dementia among Medicare beneficiaries reporting an autoimmune disorder. Additionally, this study sought to identify the comparative prevalence of AD and/or dementia in patients with an autoimmune disorder who were using disease-modifying antirheumatic drugs (DMARDs) compared to those not using DMARDs. Methods: Cross-sectional secondary data analyses were conducted on Medicare Current Beneficiary Survey (MCBS) data from 2017 and 2018. The MCBS data consists of a nationally representative sample of the Medicare population, a population that is largely 65 and older, and provides de-identified patient information. Patients from this dataset with a self-reported autoimmune disorder were included in the analyses. Descriptive analyses were conducted on demographic variables, chronic conditions, and medication use. The prevalence of AD and/or dementia was compared between patients with and without an autoimmune disorder. A backward stepwise selection regression was used to identify the risk factors associated with the prevalence of AD and/or dementia. Results: The study included 18,929 Medicare beneficiaries, with 4,405 identified as having one autoimmune disorder. The prevalence of AD and/or dementia was significantly higher in patients with an autoimmune disorder. The multivariate regression showed that RA was significantly associated with a higher risk of AD and/or dementia. Other demographic factors, including advanced age, African-American or Hispanic ethnicity, low body mass index, and chronic conditions of ischemic heart disease, history of myocardial infarction, history of stroke, depression, mental health disorder(s), and traumatic brain injury also showed statistically significant associations with AD and/or dementia. Patients using DMARDs demonstrated a reduced likelihood of having AD and/or dementia, compared to patients not using DMARDs. Conclusion: This study provides evidence of an association between RA and increased risk of AD and/or dementia. The findings suggest that DMARD use may have a protective effect against the development of AD and/or dementia in patients with an autoimmune disorder.