The concept of resilience to Alzheimer’s Disease: current definitions and cellular and molecular mechanisms

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Abstract

Some individuals are able to maintain their cognitive abilities despite the presence of significant Alzheimer’s Disease (AD) neuropathological changes. This discrepancy between cognition and pathology has been labeled as resilience and has evolved into a widely debated concept. External factors such as cognitive stimulation are associated with resilience to AD, but the exact cellular and molecular underpinnings are not completely understood. In this review, we discuss the current definitions used in the field, highlight the translational approaches used to investigate resilience to AD and summarize the underlying cellular and molecular substrates of resilience that have been derived from human and animal studies, which have received more and more attention in the last few years. From these studies the picture emerges that resilient individuals are different from AD patients in terms of specific pathological species and their cellular reaction to AD pathology, which possibly helps to maintain cognition up to a certain tipping point. Studying these rare resilient individuals can be of great importance as it could pave the way to novel therapeutic avenues for AD.

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NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

Clifford R. Jack, David Bennett, Kaj Blennow … (2018)

In 2011, the National Institute on Aging and Alzheimer’s Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer’s disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer’s Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer’s Association Research Framework, Alzheimer’s disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.

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Neuroinflammation in Alzheimer's disease.

Michael T Heneka, Monica Carson, Joseph El Khoury … (2015)

Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

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Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.

Otto Valladares, Eliecer Coto, Kara L. Hamilton-Nelson … (2014)

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

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Author and article information

Contributors

Luuk E. de Vries:

ORCID: http://orcid.org/0009-0005-6133-1043

l.de.vries@nin.knaw.nl

Journal

Journal ID (nlm-ta): Mol Neurodegener

Journal ID (iso-abbrev): Mol Neurodegener

Title: Molecular Neurodegeneration

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-1326

Publication date (Electronic): 8 April 2024

Publication date PMC-release: 8 April 2024

Publication date Collection: 2024

Volume: 19

Electronic Location Identifier: 33

Affiliations

[1 ]GRID grid.419918.c, ISNI 0000 0001 2171 8263, Department of Neuroregeneration, , Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and Sciences, ; 1105 BA Amsterdam, The Netherlands

[2 ]GRID grid.419918.c, ISNI 0000 0001 2171 8263, Department of Neuroimmunology, , Netherlands Institute for Neuroscience, Institute of the Royal Netherlands Academy of Arts and Sciences, ; 1105 BA Amsterdam, The Netherlands

[3 ]GRID grid.484519.5, Swammerdam Institute for Life Sciences, Amsterdam Neuroscience, University of Amsterdam, ; 1098 XH Amsterdam, the Netherlands

[4 ]GRID grid.419918.c, ISNI 0000 0001 2171 8263, Department of Neuropsychiatric Disorders, , Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, ; 1105 BA Amsterdam, Netherlands

[5 ]Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, ( https://ror.org/01x2d9f70) Boelelaan 1085, 1081 HV Amsterdam, The Netherlands

Author information

Luuk E. de Vries http://orcid.org/0009-0005-6133-1043

Inge Huitinga http://orcid.org/0000-0002-4878-8920

Helmut W. Kessels http://orcid.org/0000-0002-1122-745X

Dick F. Swaab http://orcid.org/0000-0002-9665-7845

Joost Verhaagen http://orcid.org/0000-0002-8341-1096

Article

Publisher ID: 719

DOI: 10.1186/s13024-024-00719-7

PMC ID: 11003087

PubMed ID: 38589893

SO-VID: 04c036aa-23f7-4ebb-94ff-ca6f20a177c7

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 23 August 2023

Date accepted : 20 March 2024

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100008358, Hersenstichting;

Award ID: DR-2018-00252

Funded by: FundRef http://dx.doi.org/10.13039/501100010969, Alzheimer Nederland;

Award ID: WE.03-2022-02

Award Recipient : Joost Verhaagen

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ScienceOpen disciplines: Neurosciences

Keywords: alzheimer’s disease,animal models,cognition,molecular biology,neuropathology,post-mortem human brain,resilience

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ScienceOpen disciplines: Neurosciences

Keywords: alzheimer’s disease, animal models, cognition, molecular biology, neuropathology, post-mortem human brain, resilience

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The concept of resilience to Alzheimer’s Disease: current definitions and cellular and molecular mechanisms

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Karger: Neurology and Neuroscience

Most cited references 305

NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease

Neuroinflammation in Alzheimer's disease.

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.

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