Journal of Alzheimer's Disease - Volume 97, issue 1

Article Type: Editorial

DOI: 10.3233/JAD-249000

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 1-1, 2024

Authors: Hauer, Klaus | Dutzi, Ilona | Werner, Christian | Bauer, Jürgen | Ullrich, Phoebe

Article Type: Review Article

Abstract: Background: No systematic review on delirium prevention within early, hospital-based rehabilitation on implementation of approaches specifically tailored for patients with cognitive impairment (PwCI), such as Alzheimer’s disease or vascular dementia, has been published despite the high relevance of specific medical care in this vulnerable population. Objective: To document design and effectiveness of delirium prevention programs by early rehabilitation during acute, hospital-based medical care and implementation of programs specifically tailored to PwCI. Methods: In a three-step approach, we first identified published systematic reviews of hospital-based, early rehabilitation interventions for older persons (>65 years) in relevant databases. In …a second step, we screened each single trial of included reviews according to predefined inclusion criteria. In a third step, we analyzed studies with focus on delirium prevention. Results: Among n  = 25 studies identified, almost all intervention programs did not specifically target cognitive impairment (CI). Interventions were heterogeneous (modules: n  = 2–19); almost all study samples were mixed/unspecified for cognitive status with more affected patients excluded. Only one study exclusively included delirium patients, and only one included CI patients. Results of random effect meta-analysis showed significant effects of generic programs to reduce delirium incidence during hospitalization by 41% (p  < 0.001, odds ratio, 95% confidence interval: 0.59 [0.49, 0.71] with modest heterogeneity (I2 : 30%). Conclusions: Study results document a lack of implementation for delirium prevention programs specifically tailored to PwCI by early, hospital-based rehabilitation. Specifying existing rehab concepts or augmenting them by CI-specific modules may help to develop, optimize, and implement innovative delirium prevention in PwCI in acute medical care. Show more

Keywords: Alzheimer’s disease, delirium, dementia, hospitalization, early rehabilitation, prevention, scoping review, vascular dementia

DOI: 10.3233/JAD-230644

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 3-29, 2024

Authors: Johnson, Carrie E. | Duncan, Marilyn J. | Murphy, M. Paul

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) affects more women than men, with women throughout the menopausal transition potentially being the most under researched and at-risk group. Sleep disruptions, which are an established risk factor for AD, increase in prevalence with normal aging and are exacerbated in women during menopause. Sex differences showing more disrupted sleep patterns and increased AD pathology in women and female animal models have been established in literature, with much emphasis placed on loss of circulating gonadal hormones with age. Interestingly, increases in gonadotropins such as follicle stimulating hormone are emerging to be a major contributor to AD pathogenesis and …may also play a role in sleep disruption, perhaps in combination with other lesser studied hormones. Several sleep influencing regions of the brain appear to be affected early in AD progression and some may exhibit sexual dimorphisms that may contribute to increased sleep disruptions in women with age. Additionally, some of the most common sleep disorders, as well as multiple health conditions that impair sleep quality, are more prevalent and more severe in women. These conditions are often comorbid with AD and have bi-directional relationships that contribute synergistically to cognitive decline and neuropathology. The association during aging of increased sleep disruption and sleep disorders, dramatic hormonal changes during and after menopause, and increased AD pathology may be interacting and contributing factors that lead to the increased number of women living with AD. Show more

Keywords: Alzheimer’s disease, hormones, menopause, sex differences, sleep, women

DOI: 10.3233/JAD-230527

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 31-74, 2024

Authors: Li, Yunfeng | Chen, Xiongjin | Zhou, Mulan | Feng, Sifan | Peng, Xiaoping | Wang, Yan

Article Type: Review Article

Abstract: Alzheimer’s disease is a pervasive neurodegenerative disease that is estimated to represent approximately 70% of dementia cases worldwide, and the molecular complexity that has been highlighted remains poorly understood. The accumulation of extracellular amyloid-β (Aβ), intracellular neurofibrillary tangles formed by tau hyperphosphorylation, and neuroinflammation are the major pathological features of Alzheimer’s disease (AD). Over the years, there has been no apparent breakthrough in drug discovery based on the Aβ and tau hypotheses. Neuroinflammation has gradually become a hot spot in AD treatment research. As the primary cells of innate immunity in the central nervous system, microglia play a key role …in neuroinflammation. Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain-like receptor 3 (NLRP3) inflammasomes are vital molecules in neuroinflammation. In the pathological context of AD, the complex interplay between TLR4 and the NLRP3 inflammasomes in microglia influences AD pathology via neuroinflammation. In this review, the effect of the activation and inhibition of TLR4 and NLRP3 in microglia on AD pathology, as well as the cross-talk between TLR4 and the NLRP3 inflammasome, and the influence of essential molecules in the relevant signaling pathway on AD pathology, were expounded. In addition, the feasibility of these factors in representing a potential treatment option for AD has been clarified. Show more

Keywords: Alzheimer’s disease, microglia, NLRP3 inflammasomes, TLR4

DOI: 10.3233/JAD-230273

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 75-88, 2024

Authors: Chu, Chenyin | Low, Yi Ling Clare | Ma, Liwei | Wang, Yihan | Cox, Timothy | Doré, Vincent | Masters, Colin L. | Goudey, Benjamin | Jin, Liang | Pan, Yijun

Article Type: Review Article

Abstract: The accumulation of amyloid-β (Aβ) plaques in the brain is considered a hallmark of Alzheimer’s disease (AD). Mathematical modeling, capable of predicting the motion and accumulation of Aβ, has obtained increasing interest as a potential alternative to aid the diagnosis of AD and predict disease prognosis. These mathematical models have provided insights into the pathogenesis and progression of AD that are difficult to obtain through experimental studies alone. Mathematical modeling can also simulate the effects of therapeutics on brain Aβ levels, thereby holding potential for drug efficacy simulation and the optimization of personalized treatment approaches. In this review, we provide …an overview of the mathematical models that have been used to simulate brain levels of Aβ (oligomers, protofibrils, and/or plaques). We classify the models into five categories: the general ordinary differential equation models, the general partial differential equation models, the network models, the linear optimal ordinary differential equation models, and the modified partial differential equation models (i.e., Smoluchowski equation models). The assumptions, advantages and limitations of these models are discussed. Given the popularity of using the Smoluchowski equation models to simulate brain levels of Aβ, our review summarizes the history and major advancements in these models (e.g., their application to predict the onset of AD and their combined use with network models). This review is intended to bring mathematical modeling to the attention of more scientists and clinical researchers working on AD to promote cross-disciplinary research. Show more

Keywords: Alzheimer’s disease, amyloid-β, disease progression, mathematical modeling, Smoluchowski equation

DOI: 10.3233/JAD-230938

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 89-100, 2024

Authors: Martin, Jissa | Reid, Natasha | Ward, David D. | King, Shannon | Hubbard, Ruth E. | Gordon, Emily H.

Article Type: Systematic Review

Abstract: Background: Developing effective strategies for reducing dementia risk requires a detailed understanding of the risk and protective factors associated with the progression of mild cognitive impairment (MCI) to dementia. Objective: We aimed to systematically review the evidence for sex differences in these factors. Methods: Five online databases (PubMed/CINAHL/EMBASE/PsycINFO/Cochrane) were searched from inception until 17 October 2022 for cohort studies that focused on sex differences in risk and protective factors in the progression of MCI to dementia. Results: A total of 2,972 studies were identified, of which 12 studies from five countries were included in …the systematic review. There was substantial variability in study designs, study populations and outcome measures. Sex differences were present in the associations of sociodemographic, health, psychological factors, genetic and other biomarkers with the progression of MCI to dementia. APOE ɛ4 status and depression appeared to increase the risk of progression for females, whereas history of stroke, MRI markers and cerebrospinal fluid biomarkers appeared to increase the risk of progression for males. APOE ɛ2 status and marital status (unmarried) were observed to reduce risk of progression in males and females, respectively. Conclusions: The ability of studies to accurately detail risk factors for dementia are likely limited when solely controlling for the effects of sex. Although the heterogeneity and underpowered nature of the studies made it difficult to synthesize the findings for each risk factor, this study highlights the apparent need for further research examining risk factors for dementia in males and females with MCI separately. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, protective factors, risk factors, sex characteristics

DOI: 10.3233/JAD-230700

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 101-119, 2024

Authors: Carpi, Matteo | Fernandes, Mariana | Mercuri, Nicola Biagio | Liguori, Claudio

Article Type: Systematic Review

Abstract: Background: Sleep disturbances are considered a hallmark of dementia, and strong evidence supports the association between alterations in sleep parameters and cognitive decline in patients with mild cognitive impairment and Alzheimer’s disease (AD). Objective: This systematic review aims to summarize the existing evidence on the longitudinal association between sleep parameters and cognitive decline, with the goal of identifying potential sleep biomarkers of AD-related neurodegeneration. Methods: Literature search was conducted in PubMed, Web of Science, and Scopus databases from inception to 28 March 2023. Longitudinal studies investigating the association between baseline objectively-measured sleep parameters …and cognitive decline were assessed for eligibility. Results: Seventeen studies were included in the qualitative synthesis. Sleep fragmentation, reduced sleep efficiency, reduced REM sleep, increased light sleep, and sleep-disordered breathing were identified as predictors of cognitive decline. Sleep duration exhibited a U-shaped relation with subsequent neurodegeneration. Additionally, several sleep microstructural parameters were associated with cognitive decline, although inconsistencies were observed across studies. Conclusions: These findings suggest that sleep alterations hold promise as early biomarker of cognitive decline, but the current evidence is limited due to substantial methodological heterogeneity among studies. Further research is necessary to identify the most reliable sleep parameters for predicting cognitive impairment and AD, and to investigate interventions targeting sleep that can assist clinicians in the early recognition and treatment of cognitive decline. Standardized procedures for longitudinal studies evaluating sleep and cognition should be developed and the use of continuous sleep monitoring techniques, such as actigraphy or EEG headband, might be encouraged. Show more

Keywords: Alzheimer’s disease, cognitive decline, neurodegeneration, objective sleep evaluation, sleep alterations, sleep biomarkers

DOI: 10.3233/JAD-230933

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 121-143, 2024

Authors: Anschuetz, Anne | Schwab, Karima | Harrington, Charles R. | Wischik, Claude M. | Riedel, Gernot

Article Type: Systematic Review

Abstract: Background: A key aspect of synaptic dysfunction in Alzheimer’s disease (AD) is loss of synaptic proteins. Previous publications showed that the presynaptic machinery is more strongly affected than postsynaptic proteins. However, it has also been reported that presynaptic protein loss is highly variable and shows region- and protein-specificity. Objective: The objective of this meta-analysis was to provide an update on the available literature and to further characterize patterns of presynaptic protein loss in AD. Methods: Systematic literature search was conducted for studies published between 2015–2022 which quantified presynaptic proteins in postmortem tissue from AD patients and …healthy controls. Three-level random effects meta-analyses of twenty-two identified studies was performed to characterize overall presynaptic protein loss and changes in specific regions, proteins, protein families, and functional categories. Results: Meta-analysis confirmed overall loss of presynaptic proteins in AD patients. Subgroup analysis revealed region specificity of protein loss, with largest effects in temporal and frontal cortex. Results concerning different groups of proteins were also highly variable. Strongest and most consistently affected was the family of synaptosome associated proteins, especially SNAP25. Among the most severely affected were proteins regulating dense core vesicle exocytosis and the synaptic vesicle cycle. Conclusions: Results confirm previous literature related to presynaptic protein loss in AD patients and provide further in-depth characterization of most affected proteins and presynaptic functions. Show more

Keywords: Alzheimer’s disease, meta-analysis, presynaptic terminals, synaptic vesicles

DOI: 10.3233/JAD-231034

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 145-162, 2024

Authors: Ukraintseva, Svetlana | Duan, Hongzhe | Holmes, Rachel | Bagley, Olivia | Wu, Deqing | Yashkin, Arseniy | Kulminski, Alexander | Akushevich, Igor | Whitson, Heather | Stallard, Eric | Yashin, Anatoliy | Arbeev, Konstantin

Article Type: Short Communication

Abstract: Relationships between patterns of aging-changes in bodyweight and AD are not fully understood. We compared mean age-trajectories of weight between those who did and did not develop late-onset-AD, and evaluated impact of age at maximum weight (AgeMax), and slope of decline in weight, on AD risk. Women with late-onset-AD had lower weight three or more decades before AD onset, and ∼10 years younger AgeMax, compared to AD-free women. APOE4 carriers had younger AgeMax and steeper slope. Older AgeMax and flatter slope predicted lower AD risk. Premature decline in weight could be a sign of accelerated …physical aging contributing to AD. Show more

Keywords: Aging, Alzheimer’s disease, APOE4 , Framingham Heart Study, Health and Retirement Study, weight

DOI: 10.3233/JAD-220998

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 163-170, 2024

Authors: Lapeyre, Lina | Piret, Jocelyne | Rhéaume, Chantal | Pons, Vincent | Uyar, Olus | Préfontaine, Paul | Rivest, Serge | Boivin, Guy

Article Type: Short Communication

Abstract: Using APP/PS1 mice that overproduce amyloid-β (Aβ) peptides, we investigated whether intranasal infection with a neurovirulent clinical strain of herpes simplex virus 1 (HSV-1) before Aβ deposition could accelerate or increase Alzheimer’s disease-like pathology. After HSV-1 infection, APP/PS1 mice presented a similar disease as wild type animals based on body weight changes, clinical symptoms, and survival rates. The number and volume of Aβ plaques, the number of microglia, and the percentages of circulating monocyte subsets were similar in APP/PS1 mice infected or not with HSV-1. Thus, intranasal infection with HSV-1 does not alter Aβ pathology in this mouse model.

Keywords: Alzheimer’s disease, amyloid-β , amyloid protein precursor, APP/PS1 mice, herpes simplex virus 1, microglia, monocytes, presenilin-1

DOI: 10.3233/JAD-230746

Citation: Journal of Alzheimer's Disease, vol. 97, no. 1, pp. 171-178, 2024