Appearance
Alzheimer disease.
Literature Information
| DOI | 10.1038/s41572-021-00269-y |
|---|---|
| PMID | 33986301 |
| Journal | Nature reviews. Disease primers |
| Impact Factor | 60.6 |
| JCR Quartile | Q1 |
| Publication Year | 2021 |
| Times Cited | 954 |
| Keywords | Alzheimer disease, β-amyloid, neurodegenerative disease, cognitive impairment |
| Literature Type | Journal Article, Research Support, N.I.H., Extramural, Review |
| ISSN | 2056-676X |
| Pages | 33 |
| Issue | 7(1) |
| Authors | David S Knopman, Helene Amieva, Ronald C Petersen, Gäel Chételat, David M Holtzman, Bradley T Hyman, Ralph A Nixon, David T Jones |
TL;DR
This Primer discusses Alzheimer's disease (AD) as a neurodegenerative disorder characterized by β-amyloid plaques and tau tangles, highlighting its complexity due to interactions with other conditions affecting cognitive impairment. It emphasizes the need for effective therapeutic targets within the disrupted synaptic homeostasis and endosomal/lysosomal clearance pathways, as current treatments have yet to significantly alter the disease's clinical trajectory.
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Alzheimer disease · β-amyloid · neurodegenerative disease · cognitive impairment
Abstract
Alzheimer disease (AD) is biologically defined by the presence of β-amyloid-containing plaques and tau-containing neurofibrillary tangles. AD is a genetic and sporadic neurodegenerative disease that causes an amnestic cognitive impairment in its prototypical presentation and non-amnestic cognitive impairment in its less common variants. AD is a common cause of cognitive impairment acquired in midlife and late-life but its clinical impact is modified by other neurodegenerative and cerebrovascular conditions. This Primer conceives of AD biology as the brain disorder that results from a complex interplay of loss of synaptic homeostasis and dysfunction in the highly interrelated endosomal/lysosomal clearance pathways in which the precursors, aggregated species and post-translationally modified products of Aβ and tau play important roles. Therapeutic endeavours are still struggling to find targets within this framework that substantially change the clinical course in persons with AD.
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Primary Questions Addressed
- What are the latest advancements in therapeutic strategies targeting β-amyloid and tau pathology in Alzheimer's disease?
- How do genetic factors influence the onset and progression of Alzheimer's disease in different populations?
- What role do lifestyle factors, such as diet and exercise, play in the prevention or mitigation of Alzheimer's disease symptoms?
- How do other neurodegenerative diseases interact with Alzheimer's disease in terms of cognitive impairment and disease progression?
- What are the implications of recent research on synaptic homeostasis for developing new treatments for Alzheimer's disease?
Key Findings
Research Background and Purpose
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by cognitive impairment, particularly in memory. The disease is marked by the accumulation of β-amyloid plaques and tau neurofibrillary tangles in the brain. This Primer aims to review the epidemiology, pathophysiology, clinical manifestations, diagnosis, and management of AD, emphasizing the interplay of genetic, environmental, and lifestyle factors in its development and progression.
Main Methods/Materials/Experimental Design
The Primer synthesizes current research findings, epidemiological data, and clinical practices regarding AD. The authors discuss various biomarkers (including cerebrospinal fluid and PET imaging), genetic risk factors, and clinical diagnostic criteria.
The methodological framework can be illustrated as follows:
Key Results and Findings
- Epidemiology: The incidence of AD is increasing globally, with a notable prevalence in older populations. Studies indicate a complex relationship between AD and other neurodegenerative diseases.
- Pathophysiology: AD is characterized by synaptic dysfunction, amyloid plaque accumulation, and tau pathology, leading to cognitive decline. The interplay between genetic factors (e.g., APOE ε4 allele) and lifestyle factors (e.g., diabetes, hypertension) significantly influences disease progression.
- Diagnosis: Advances in biomarkers (CSF and PET imaging) have improved diagnostic accuracy. The A-T-N (Amyloid-Tau-Neurodegeneration) framework helps classify individuals based on biomarker profiles.
- Management: Current pharmacological treatments, including cholinesterase inhibitors and NMDA receptor antagonists, provide modest symptomatic relief. Non-pharmacological interventions focusing on lifestyle modifications show promise in delaying cognitive decline.
Main Conclusions/Significance/Innovation
The Primer highlights the multifactorial nature of AD, emphasizing the need for an integrated approach to diagnosis and management. Understanding the complex interplay of genetic, biological, and environmental factors is crucial for developing effective interventions. The emphasis on biomarkers represents a significant advancement in early diagnosis and treatment personalization.
Research Limitations and Future Directions
- Limitations: The review is limited by the rapidly evolving nature of AD research and the complexity of its pathophysiology. Many findings are derived from studies with varying methodologies, which can affect the generalizability of results.
- Future Directions: Future research should focus on identifying modifiable risk factors, developing effective therapeutic strategies, and exploring the biological underpinnings of AD. Additionally, there is a need for longitudinal studies to better understand the disease's progression and the impact of early interventions.
Summary Table of Key Points
| Aspect | Findings |
|---|---|
| Epidemiology | Increasing incidence; complex co-pathologies |
| Pathophysiology | Synaptic dysfunction; amyloid and tau pathology |
| Diagnosis | Improved with biomarkers; A-T-N framework |
| Management | Modest pharmacological benefits; lifestyle interventions are promising |
| Future Directions | Focus on modifiable risk factors and biological mechanisms |
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Literatures Citing This Work
- Identification of Multi-Target Anti-AD Chemical Constituents From Traditional Chinese Medicine Formulae by Integrating Virtual Screening and In Vitro Validation. - Baoyue Zhang;Jun Zhao;Zhe Wang;Pengfei Guo;Ailin Liu;Guanhua Du - Frontiers in pharmacology (2021)
- Effects of Reactive Oxygen and Nitrogen Species on TrkA Expression and Signalling: Implications for proNGF in Aging and Alzheimer's Disease. - Erika Kropf;Margaret Fahnestock - Cells (2021)
- Artificial Intelligence for Alzheimer's Disease: Promise or Challenge? - Carlo Fabrizio;Andrea Termine;Carlo Caltagirone;Giulia Sancesario - Diagnostics (Basel, Switzerland) (2021)
- A novel missense variant in ACAA1 contributes to early-onset Alzheimer's disease, impairs lysosomal function, and facilitates amyloid-β pathology and cognitive decline. - Rongcan Luo;Yu Fan;Jing Yang;Maosen Ye;Deng-Feng Zhang;Kun Guo;Xiao Li;Rui Bi;Min Xu;Lu-Xiu Yang;Yu Li;Xiaoqian Ran;Hong-Yan Jiang;Chen Zhang;Liwen Tan;Nengyin Sheng;Yong-Gang Yao - Signal transduction and targeted therapy (2021)
- First-in-Class Isonipecotamide-Based Thrombin and Cholinesterase Dual Inhibitors with Potential for Alzheimer Disease. - Rosa Purgatorio;Nicola Gambacorta;Modesto de Candia;Marco Catto;Mariagrazia Rullo;Leonardo Pisani;Orazio Nicolotti;Cosimo D Altomare - Molecules (Basel, Switzerland) (2021)
- Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer's Disease Treatment. - Saghar Rabiei Poor;Miren Ettcheto;Amanda Cano;Elena Sanchez-Lopez;Patricia Regina Manzine;Jordi Olloquequi;Antoni Camins;Mohammad Javan - Pharmaceuticals (Basel, Switzerland) (2021)
- Antidepressants in Alzheimer's Disease: A Focus on the Role of Mirtazapine. - Ana Salomé Correia;Nuno Vale - Pharmaceuticals (Basel, Switzerland) (2021)
- NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load. - Theresa Pohlkamp;Xunde Xian;Connie H Wong;Murat S Durakoglugil;Gordon Chandler Werthmann;Takaomi C Saido;Bret M Evers;Charles L White;Jade Connor;Robert E Hammer;Joachim Herz - eLife (2021)
- Electroacupuncture Improves M2 Microglia Polarization and Glia Anti-inflammation of Hippocampus in Alzheimer's Disease. - Lushuang Xie;Yi Liu;Ning Zhang;Chenyu Li;Aaron F Sandhu;George Williams;Yan Shen;Hongying Li;Qiaofeng Wu;Shuguang Yu - Frontiers in neuroscience (2021)
- Magnolol upregulates CHRM1 to attenuate Amyloid-β-triggered neuronal injury through regulating the cAMP/PKA/CREB pathway. - Gemin Zhu;Yuan Fang;Xiaoli Cui;Ruihua Jia;Xiaogang Kang;Rui Zhao - Journal of natural medicines (2022)
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