Comparison and aggregation of event sequences across ten cohorts to describe the consensus biomarker evolution in Alzheimer's disease

Background: Previous models of Alzheimer's disease (AD) progression were primarily hypothetical or based on data originating from single cohort studies. However, cohort datasets are subject to specific inclusion and exclusion criteria that influence the signals observed in their collected data. Furthermore, each study measures only a subset of AD-relevant variables. To gain a comprehensive understanding of AD progression, the heterogeneity and robustness of estimated progression patterns must be understood, and complementary information contained in cohort datasets be leveraged. Methods: We compared ten event-based models that we fit to ten independent AD cohort datasets. Additionally, we designed and applied a novel rank aggregation algorithm that combines partially overlapping, individual event sequences into a meta-sequence containing the complementary information from each cohort. Results: We observed overall consistency across the ten event-based model sequences, despite variance in the positioning of mainly imaging variables. The changes described in the aggregated meta-sequence are broadly consistent with current understanding of AD progression, starting with cerebrospinal fluid amyloid beta, followed by memory impairment, tauopathy, FDG-PET, and ultimately brain deterioration and impairment of visual memory. Conclusion: Overall, the event-based models demonstrated similar and robust disease cascades across independent AD cohorts. Aggregation of data-driven results can combine complementary strengths and information of patient-level datasets. Accordingly, the derived meta-sequence draws a more complete picture of AD pathology compared to models relying on single cohorts.

Download Full-text

Loss of ferroportin induces memory impairment by promoting ferroptosis in Alzheimer’s disease

Cell Death and Differentiation ◽

10.1038/s41418-020-00685-9 ◽

2021 ◽

Author(s):

Wen-Dai Bao ◽

Pei Pang ◽

Xiao-Ting Zhou ◽

Fan Hu ◽

Wan Xiong ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Memory Impairment ◽

Iron Homeostasis ◽

Critical Role ◽

Gene Set Enrichment Analysis ◽

Molecular Characteristics ◽

Intracellular Iron

AbstractIron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer’s mouse model and Alzheimer’s patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpnfl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpnfl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.

Download Full-text

The Semantic Memory Impairment of Alzheimer's Disease: Category-Specific?

Cortex ◽

10.1016/s0010-9452(96)80023-2 ◽

1996 ◽

Vol 32 (1) ◽

pp. 143-153 ◽

Cited By ~ 49

Author(s):

Lynette J. Tippett ◽

Murray Grossman ◽

Martha J. Farah

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Semantic Memory ◽

Memory Impairment ◽

Disease Category

Download Full-text

P4-093: Semantic memory impairment in Alzheimer's disease and frontotemporal dementia is associated with semantic network degradation

Alzheimer s & Dementia ◽

10.1016/j.jalz.2011.05.2114 ◽

2011 ◽

Vol 7 ◽

pp. S734-S734

Author(s):

Kimiko Domoto-Reilly ◽

Daisy Sapolsky ◽

Michael Brickhouse ◽

Mark Hollenbeck ◽

Brad Dickerson

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Frontotemporal Dementia ◽

Semantic Memory ◽

Memory Impairment ◽

Semantic Network

Download Full-text

WEB-BASED SOFTWARE FOR REAL-TIME SIMULATION-ASSISTED TRIAL DESIGN IN ALZHEIMER’S DISEASE

Journal of Prevention of Alzheimer's Disease ◽

10.14283/jpad.2015.54 ◽

2015 ◽

pp. 1-4

Author(s):

D. Polhamus ◽

J. Kang ◽

J. Rogers ◽

M. Gastonguay

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Statistical Power ◽

Operating Characteristics ◽

Longitudinal Models ◽

Exclusion Criteria ◽

Web Based ◽

Correct Dose ◽

Time Simulation ◽

Simulation Based

Clinical trials for Alzheimer’s Disease (AD) are necessarily designed in the presence of substantial quantitative uncertainty. Certain important aspects of this uncertainty can be mitigated by developing longitudinal models for AD progression and by using these models to simulate virtual trials and estimate operating characteristics (such as statistical power, the probability of stopping at an interim analysis, the probability of identifying the correct dose, etc.) as a function of candidate design features, such as inclusion / exclusion criteria. In this brief report we describe the development and deployment of a customized software solution that allows such simulation-based results to be generated “on the fly” in the context of a drug development team meeting. This solution leverages a number of recent practical advances in statistical and scientific computing that could be much more broadly leveraged to assure more quantitatively grounded trial designs in Alzheimer’s Disease.

Download Full-text

Effects of Gossypium herbaceam Extract Administration on the Learning and Memory Function in the Naturally Aged Rats: Neuronal Niche Improvement1

Journal of Alzheimer s Disease ◽

10.3233/jad-2012-112153 ◽

2012 ◽

Vol 31 (1) ◽

pp. 101-111 ◽

Cited By ~ 4

Author(s):

Yanyong Liu ◽

Haji Akber Aisa ◽

Chao Ji ◽

Nan Yang ◽

Haibo Zhu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Learning And Memory ◽

Memory Impairment ◽

Neuroprotective Effect ◽

Memory Function ◽

Aged Rats

Aging-associated cognitive impairment is an important health care issue since individuals with mild cognitive impairment are more likely to develop Alzheimer’s disease. In the present study, the protective effect of Gossypium herbaceam extracts (GHE) on learning and memory impairment associated with aging were examined in vivo using Morris water maze and step through task. Furthermore, the antioxidant activity and neuroprotective effect of GHE was investigated with methods of histochemistry and biochemistry. These data showed that oral administration with GHE at the doses of 35, 70, and 140 mg/kg exerted an improved effect on the learning and memory impairment in aged rats. Subsequently, GHE afforded a beneficial action on eradication of free radicals without influence on the activity of glutathione peroxidase and superoxide dismutase. GHE treatment enhanced the expression levels of nerve growth factor. Meanwhile, proliferation of neural progenitor cells was elevated in hippocampus after treatment with GHE. Taken together, neurogenic niche improvement could be involved in the mechanism underlying neuroprotection of GHE against aging-associated cognitive impairment. These findings suggested that GHE might be a potential agent as cognitive-enhancing drugs that delay or halt mild cognitive impairment progression to Alzheimer’s disease or treatment of aging-associated cognitive impairment.

Download Full-text