Table 1 Pivotal studies of molecular and cellular studies on resilience in AD
Study | Main focus | Brain regions | Resilient cases (N) | Key findings | Amount of AD pathology | Remarks on the inclusion determinants of resilience |
|---|---|---|---|---|---|---|
Arenaza-Urquijo et al., 2019 [64] | FDG-PET in resilient donors | FDG-PET | Large cohort n = 192 | FDG-PET uptake in bilateral anterior cingulate cortex and anterior temporal pole was associated with baseline cognition despite presence of established AD biomarkers | - | Resilience based on cognition over time, ranging from 2 to 10 years and PiB-PET signal |
Azarpazhooz et al., 2019 [52] | Systemic review on prevalence of resilient donors in community dwelling elderly | Diagnostic neuropathological assessments | Pooled from 17 large cohorts | Significant portion of population is resilient to a certain extend | CERAD none-frequent, Braak 0-VI | Large sample size but wide spread of pathology (low and high amounts of AD pathology mixed in the resilient group) |
Arnold et al., 2013 [65] | Cellular and synaptic proteome | Medial prefrontal cortex | 10 | Preservation of synaptic density and neurons, decrease in astrocytes. In addition, alterations in apoptosis, cell-cycle proteins and ion transport | CERAD moderate – frequent, Braak III-V | Excluded cases with pathological comorbidities (abundant LBs, infarcts, HS), reduced amount of NPs in resilient versus AD, annual cognitive testing |
Barker et al., 2021 [66] | MEF2C | Anterior prefrontal cortex | 9 | Upregulation of MEF2C and an enrichment of MEF2C target in cortical excitatory neurons of resilient individuals. MEF2 increased after EE and overexpression rescues cognitive deficits in tauopathy mouse model | CERAD none – frequent, Braak III-V | Included only female cases, PMD ≤ 20 h, four resilient cases exhibited no amyloid pathology, annual cognitive tests |
Barroeta-Espar et al., 2019 [67] | Cytokine and growth factors | Entorhinal cortex and superior temporal sulcus | 11 | Protein analysis of the cytokine profile in resilience was associated with enhanced neuroprotection, reduced activation of glial cells (GFAP and CD68) | CERAD, moderate – frequent, Braak V-VI | Both high probability and low probability resilient donors used, which both differ from AD, cognition assessed within 2 years prior to death or by absence of MCI or dementia in clinical records |
Bilousova et al., 2016 [68] | Synaptic oligomeric burden | Parietal cortex, superior parietal cortex, entorhinal cortex and hippocampus | 16 | p-Tau and Aβ oligomeric burden in synaptosomes was only present in later stages of AD pathology and not in the non-demented (resilient) cases | CERAD non-moderate, Braak III-IV | Proportion of resilient donors with cognitive impairments, resilient donors compared to both early and late AD (based on Braak stage), cognition based on MMSE |
Bjorklund et al., 2012 [69] | Postsynaptic localization of Aβ oligomers | Dentate gyrus and CA3 | 10 | LMW Aβ oligomers were shown to be elevated at the post-synaptic density of demented patients. Reduced ZnT3 mRNA, resulting in an increase in Zn2+ in the synaptic cleft, facilitating LMW Aβ oligomers to bind | CERAD moderate, Braak V (only median) | Moderate density of neuritic plaques (CERAD = B), cognition based on MMSE |
Boros et al., 2017 [70] | Dendritic spines | Dorsolateral prefrontal cortex | 8 | Resilient individuals showed an overall increase in dendritic spine density and extent | CERAD Moderate – frequent, Braak I-IV | No or sparse frontal NFTs compared to dementia cases with moderate/frequent NFTs Cognition based on MMSE |
Briley et al., 2016 [71] | Neurogenesis | Dentate gyrus | 4 | Number of SOX2 cells increased in resilience, increased expression of miRNA’s related to neurogenesis | CERAD NA, Braak IV-V | PMD of 40 h in one case, majority of post-mortem tissue from females, n is low, cognition based on MMSE |
Buciuc et al., 2020 [72] | Comorbid AD pathology | Diagnostic neuropathological assessments | 21 | Lower frequency of TPD-43 pathology in resilient compared to non-resilient donors | CERAD Moderate – frequent, Braak IV-VI | AD and resilient cases matched well based on CERAD and Braak, annual cognitive testing |
Cain et al., 2023 [73] | Cellular states and communities related to AD and cognition | DLPFC | 6 | Model cellular states and communities derived from snRNA-seq. donors in a larger dataset of bulk-RNAseq. Specific cellular communities are related to cognitive decline with high amounts of ptau or maintenance of cognition with lower levels of ptau | CERAD and Braak NA (AD diagnosis confirmed by neuropathologist) Quantified AD pathology in eight different brain regions | Annual cognitive tests, higher ptau load in AD samples compared to resilient samples |
Carlyle et al., 2021 [74] | Proteomics of synaptomes | Angular gyrus | 25 | Proteins involved in the serotonin neurotransmitter release and oxidative phosphorylation were upregulated in resilience. Glycolysis, glutathione metabolism and proteasome components were downregulated | CERAD NA, Braak V | Three cases with Lewy Body pathology, resilient individuals exhibit a significantly lower global AD pathology compared to demented patients, annual cognitive tests |
Dumitrescu et al., 2020 [75] | GWAS for resilience | Amyloid PET screening or autopsy based diagnostics | 337 autopsy 2980 PET | Single SNP related to resilience upstream of ATP8B1 | CERAD none-frequent, Braak NA | Resilience based on amyloid-plaques (neuritic plaques) or PET signal, annual cognitive testing |
Eissman et al., 2022 [76] | Sex-specific GWAS for resilience | Amyloid PET screening or autopsy based diagnostics | 5024 PET and autopsy | Female-specific SNP in chromatin loops that interact with genes related to RNA-processing (GATA3) | CERAD none-frequent, Braak NA | Extensive cognitive tests, harmonized cognitive data across the different cohorts, resilience based on NPs or PET signal |
Esparza et al., 2013 [77] | Aβ oligomers | Frontal and parietal cortex | 24 | Reduced amounts of oAβ in resilient compared to mild AD | CERAD and Braak NA, Resilient and AD donors stratified by % plaques (IHC) | Cognition determined based on CDR (0 for resilient and 1 for AD) |
Fracassi et al., 2023 [78] | Microglia activation | Frontal cortex | 6 | Hyperactive microglia around resilient plaques, based on TYROBP, TREM2 and CD68 | Braak III-VI | Braak lower in resilient than AD, unclear which resilient donors were used, cognition based on MMSE |
Heuer et al., 2020 [60] | Co-expression modules in AD-BDX animals related to cognition | Hippocampus | 71 | Fgf2 potential regulator of networks related to working memory and short term memory | 5xFAD mice crossed with AD-BDX panel | Cognition based on y-maze, and fear conditioning paradigms at 6 or 14 months of age |
Hurst et al., 2023 [79] | Proteomic networks on cortical resilient tissue | Frontal and temporal cortex | 53 | NR1N identified as regulator of protein network related to synapses based on proteomic data, NR1N prevents AB-induced spine loss and synaptic plasticity hyperexcitability | CERAD moderate-frequent, Braak II-VI | Increased MAPT/tau burden in AD compared to resilient, cognition based on MMSE |
Iacono et al., 2008 [80] | Nuclear hypertrophy | Anterior cingulate gyrus, posterior cingulate gyrus, primary visual cortex | 15 | Hypertrophy of neuronal cells in CA1 of hippocampus and anterior cingulate gyrus in resilient versus AD and control donors | CERAD moderate-frequent, Braak 0-IV | Resilient donors fewer neuritic and lower Braak stages than demented groups, cognition based on multiple cognitive tests |
Jiang et al., 2021 [81] | Synaptotoxicity by Aβ- and tau | Frontal cortex | 6 | No significant differences in soluble high molecular weight Aβ oligomers and soluble ptau | NA | Unclear what pathological load is between groups, cognition based on CDR |
Johnson et al., 2020 [82] | Proteomics | Frontal cortex and temporal cortex | 53 | Dementia associated with upregulation of MAPK/metabolism, ubiquitination, axonogenesis and downregulation of postsynaptic density proteins, mitochondria, and RNA splicing | CERAD, moderate – frequent, Braak III-VI | Cognition based on MMSE or CDR (MMSE≤24 or CDR≥1 for AD). |
Kobayashi et al., 2018 [83] | Reactive astrocytes | Entorhinal cortex | 10 | GLT-1 reactive astrocytes are associated with a preserved cognition in the presence of AD pathology | CERAD non-frequent, Braak III-V | Cognition based on CDR, (control and resilient = 0 – 0,5, AD = 2–3). Pathology well matched between AD and resilient cases |
Latimer et al., 2019 [84] | ptau burden and LATE-NC | Many cerebral regions and dentate gyrus | 7 | Resilient donors exhibited a lower cortical ptau burden, plaque burden and less LATE-NC | CERAD, frequent, Braak IV | Resilience is matched to demented patients with a similar ABC score, but demented patients show a significant increase in LATE-NC and macroinfarcts, cognition tested every two years with CASI |
Lee et al., 2019 [85] | Network activity | 116 different regions | Network efficiency related to resilience and the right middle-temporal pole might center for neural substrates | Based on Tau and Aβ PET | Network efficiency related to resilience determined by residual approach of resilience (estimating difference between actual and estimated performance of cognition based on pathology, atrophy) | |
Lee et al., 2021 [86] | ptau burden by deep learning technique | Medial frontal cortex and amygdala | 7 | Resilient donors exhibited a lower cortical ptau burden (despite ptau in neurites) and reduced LATE-NC | CERAD frequent, Braak VI | CERAD and Braak matched between AD and resilient donors, cognition based on CASI within 2 years of death |
Maarouf et al., 2011 [87] | Biochemical assessment | Frontal cortex | 8 | Resilient individuals lack Aβ-related biochemical changes and the authors suggested that not only Aβ but additionally ptau and microvascular dysfunction play a role in cognitive deterioration | CERAD, moderate – frequent, Braak III-V | Did not included healthy controls as reference MMSE ≥ 27 for resilient donors and ≤ 19 for the AD group while the Braak and WMR was slightly lower in the resilient group |
Mathys et al., 2023 [88] | Single nucleus RNA-sequencing | Frontal cortex | Large community sample n = 427 | Resilient individuals have a higher proportion of inhibitory subtypes | CERAD moderate – frequent, Braak II-VI | Used cognitive resilience score (CR score) as the difference between observed cognition and cognition predicted by a linear regression model, based on global AD pathology and separately for neuritic plaque burden, neurofibrillary tangle burden and tangle density |
Neuner et al., 2017 [89] | Proteomics in resilient 5xFAD mice | Hippocampus | 4 | Changes in neuronal excitability and synaptic plasticity, HDAC4 and REST | High plaque load expected at 8 months of age, pathology has not been investigated | Resilient 5xFAD animals based on contextual fear memory at 8 months of age, N is low |
Montine et al., 2022 [90] | Comorbid pathology | Diagnostic neuropathological assessments | Large community sample n = 367 | Mainly LATE-NC influences cognition | Full neuropathological assessment of 90 + study | Clinicopathologic correlations with donors which had cognitive testing in last 6 months (n = 260) |
Perez-Nievas et al., 2013 [91] | Resilience phenotype | Superior temporal sulcus | 8 | Resilient individuals show a preservation of neurons, synapses, and axons. In addition, they have a lower plaque and oligomeric Aβ burden and not soluble ptau accumulation was observed in the synapses | CERAD frequent, Braak V-VI | Divided resilient donors in intermediate probability and high probability, high probability same pathological load as AD cases, annual clinical testing or MMSE within 2 years of death |
Perez-Gonzalez et al., 2020 | Transcriptomics on cognitively intact Tg2576 animals | Hippocampus | 4–5 | PLA2G4E is upregulated in resilient Tg2576 animals, overexpression of PLA2G4E increased dendritic spines and improved cognition in APP/PS1 animals | No differences in amount of pathology in resilient and non-resilient animals | Cognitively intact Tg2576 animals at 16–18 months of age identified with Morris water maze, N is low |
Ramos-Miguel et al., 2021 [92] | Proteomics on large community cohort | Prefrontal cortex | Large community sample n = 1209 | Alterations in SNARE proteins associated with resilience | Ranging from none to high amounts | Proteins related to resilience identified by controlling for cognition and pathology in large-community sample, annual cognitive tests |
Scheff et al., 2016 [93] | Synaptic protein levels and oxidative stress | Hippocampus | 15 | No change in pre- and post-synaptic proteins and trend to lower levels of markers related to oxidative stress between resilient and MCI donors | CERAD moderate-frequent, Braak III-V | Cognition based on MMSE score, divided resilient donors in low pathology and high pathology groups, compared with individuals with MCI, amount of pathology not quantified |
Seyfried et al., 2017 [94] | Network analyses of transcriptomics and proteomics | Dorsolateral prefrontal cortex and precuneus | 15 | Resilience was associated with an upregulation of ECM proteins, and downregulation of the synaptogenesis and synaptic function | CERAD sparse -frequent, Braak II-VI | Cognition based on annual testing, resilient donors can be characterized intermediate to high amounts of AD pathology |
Silva et al., 2014 [95] | DNA damage, cell-cycle, and cell death | CA1 | 12 | Immunohistochemistry of TMA reported more DNA repair markers and cell cycle inhibitors in resilience, but also a reduction in DNA damage and apoptosis | CERAD moderate – frequent, Braak ≥ III | Cognition based on CDR score, average lower Braak in resilient compared to AD cases |
Singh et al., 2020 [96] | Synaptic integrity and ptau oligomers | Frontal cortex and hippocampus | 13 | Decreased oligomeric ptau in the synaptosomes of resilient individuals correlated with a preserved synaptic integrity, in addition the cortical and hippocampal synaptosomes of resilient individuals indicated preservation or increase in GluA1 | CERAD: NA (N = 6), moderate (N = 2), frequent (N = 5), Braak IV-VI | Cognition based on MMSE score, plaque status was NA for several cases, Braak stages on average lower in resilient compared to AD cases |
Taddei et al., 2022 [53] | IHC of glial phenotypes and cortical cell damage | Temporal and occipital cortex | 20 | Demented patients show an elevation of the inflammatory-induced glial-phenotype together with an increase of cellular damage in brain areas with and without NFT distribution | CERAD none ‑ frequent, Braak III-IV | Cognition based on MMSE score, CERAD and Braak score of resilient similar to AD cases |
Taddei et al., 2023 [97] | Tau oligomers in synaptosomes | Occipital cortex | 13 | Demented patients showed synapse losses, higher proportions of internalized synapses in glial cells and more synapses with oligomeric tau compared to both resilient and control donors. In demented donors, proportion of tau containing synapses in glial cells was higher compared to control donors | CERAD none ‑ frequent, Braak III-IV | Cognition based on MMSE score, CERAD and Braak score of resilient similar to AD cases |
Walker et al., 2022 [98] | Proteomics of NFT-bearing neurons and their micro-environment | Posterior hippocampal CA1 | 8 | GeoMx™ DSP, containing 86 antibodies revealed 11 proteins that were differentially expressed in NFT-bearing neurons of the resilience, indicating a decrease in energetic and oxidative stress and a maintained synaptic integrity by intact axons, dendrites, and synapses | CERAD sparse – frequent, Braak IV-VI | Cognition based on MMSE (≤19 for AD, ⪰26 for resilient, two resilient outliers with MCI, MMSE ⪰19), CERAD higher in AD |
Yu et al., 2020 [99] | Proteomics | Dorsolateral prefrontal cortex | Large community sample n = 391 | Eight cortical proteins identified with resilience: NR1N, EPHX4, RPH3A, SGTB, CPLX1, SH3GL1 and UBA1 | Ranging from none to high amounts | Proteins related to resilience identified by correlating with cognition based on annual cognitive tests and AD (comorbid) pathology in a large sample size |
Zolochevska et al., 2018 [100] | Proteomics of the hippocampal PSD | Medial part of the hippocampus CA1 | 8 | MALDI MS/MS, 2DE and Western blot revealed that most protein alterations were related to the cytoskeleton, calcium signaling or PTM | CERAD NA, Braak ≥ IV | Cognition based on MMSE, although high spread of MMSE scores in AD group (12–28), similar braak between resilient and AD cases |
Zammit et al., 2022 [101] | Proteomics | Dorsolateral prefrontal cortex | Large community sample N > 1000 | Identified 52 proteins related to resilience, involved in mitochondria, synaptic signaling and related to cell structure and function | Ranging from none to high amounts | Proteins related to resilience identified by correlating with cognition based on annual cognitive tests and AD (comorbid) pathology in a large sample size |