Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology

Beatriz G. Perez-Nievas, Thor D. Stein, Hwan Ching Tai, Oriol Dols-Icardo, Thomas C. Scotton, Isabel Barroeta-Espar, Leticia Fernandez-Carballo, Estibaliz Lopez De Munain, Jesus Perez, Marta Marquie, Alberto Serrano-Pozo, Mathew P. Frosch, Val Lowe, Joseph E Parisi, Ronald Carl Petersen, Milos D. Ikonomovic, Oscar L. López, William Klunk, Bradley T. Hyman, Teresa Gómez-Isla

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

Clinico-pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer's pathology in their brains without experiencing dementia. Few details are known about the neuropathological phenotype of these unique cases that might prove relevant to understanding human resilience to Alzheimer's pathology. We conducted detailed quantitative histopathological and biochemical assessments on brains from non-demented individuals before death whose brains were free of substantial Alzheimer's pathology, non-demented individuals before death but whose post-mortem examination demonstrated significant amounts of Alzheimer's changes ('mismatches'), and demented Alzheimer's cases. Quantification of amyloid-β plaque burden, stereologically-based counts of neurofibrillary tangles, neurons and reactive glia, and morphological analyses of axons were performed in the multimodal association cortex lining the superior temporal sulcus. Levels of synaptic integrity markers, and soluble monomeric and multimeric amyloid-β and tau species were measured. Our results indicate that some individuals can accumulate equivalent loads of amyloid-β plaques and tangles to those found in demented Alzheimer's cases without experiencing dementia. Analyses revealed four main phenotypic differences among these two groups: (i) mismatches had striking preservation of neuron numbers, synaptic markers and axonal geometry compared to demented cases; (ii) demented cases had significantly higher burdens of fibrillar thioflavin-S-positive plaques and of oligomeric amyloid-β deposits reactive to conformer-specific antibody NAB61 than mismatches; (iii) strong and selective accumulation of hyperphosphorylated soluble tau multimers into the synaptic compartment was noted in demented cases compared with controls but not in mismatches; and (iv) the robust glial activation accompanying amyloid-β and tau pathologies in demented cases was remarkably reduced in mismatches. Further biochemical measurements of soluble amyloid-β species - monomers, dimers and higher molecular weight oligomers - in total brain homogenates and synaptoneurosomal preparations failed to demonstrate significant differences between mismatches and demented cases. Together, these data suggest that amyloid-β plaques and tangles do not inevitably result in neural system derangement and dementia in all individuals. We identified distinct phenotypic characteristics in the profile of brain fibrillar and soluble amyloid-β and tau accrual and in the glial response that discriminated demented and non-demented individuals with high loads of Alzheimer's pathology. Amyloid-β deposition in the form of fibrillar plaques and intimately related oligomeric amyloid-β assemblies, hyperphosphorylated soluble tau species localized in synapses, and glial activation emerged in this series as likely mediators of neurotoxicity and altered cognition, providing further insight into factors and pathways potentially involved in human susceptibility or resilience to Alzheimer's pathological changes.

Original languageEnglish (US)
Pages (from-to)2510-2526
Number of pages17
JournalBrain
Volume136
Issue number8
DOIs
StatePublished - Aug 2013

Fingerprint

Amyloid
Pathology
Amyloid Plaques
Neuroglia
Dementia
Brain
Neurons
Neurofibrillary Tangles
Brain Death
Temporal Lobe
Alzheimer
Resilience
Positron-Emission Tomography
Synapses
Cognition
Axons
Autopsy
Mismatch
Molecular Weight
Phenotype

Keywords

  • Alzheimers disease
  • Amyloid pathology
  • Astrocytes
  • Microglia
  • Resilience
  • Tau pathology

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Perez-Nievas, B. G., Stein, T. D., Tai, H. C., Dols-Icardo, O., Scotton, T. C., Barroeta-Espar, I., ... Gómez-Isla, T. (2013). Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology. Brain, 136(8), 2510-2526. https://doi.org/10.1093/brain/awt171

Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology. / Perez-Nievas, Beatriz G.; Stein, Thor D.; Tai, Hwan Ching; Dols-Icardo, Oriol; Scotton, Thomas C.; Barroeta-Espar, Isabel; Fernandez-Carballo, Leticia; De Munain, Estibaliz Lopez; Perez, Jesus; Marquie, Marta; Serrano-Pozo, Alberto; Frosch, Mathew P.; Lowe, Val; Parisi, Joseph E; Petersen, Ronald Carl; Ikonomovic, Milos D.; López, Oscar L.; Klunk, William; Hyman, Bradley T.; Gómez-Isla, Teresa.

In: Brain, Vol. 136, No. 8, 08.2013, p. 2510-2526.

Research output: Contribution to journalArticle

Perez-Nievas, BG, Stein, TD, Tai, HC, Dols-Icardo, O, Scotton, TC, Barroeta-Espar, I, Fernandez-Carballo, L, De Munain, EL, Perez, J, Marquie, M, Serrano-Pozo, A, Frosch, MP, Lowe, V, Parisi, JE, Petersen, RC, Ikonomovic, MD, López, OL, Klunk, W, Hyman, BT & Gómez-Isla, T 2013, 'Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology', Brain, vol. 136, no. 8, pp. 2510-2526. https://doi.org/10.1093/brain/awt171
Perez-Nievas BG, Stein TD, Tai HC, Dols-Icardo O, Scotton TC, Barroeta-Espar I et al. Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology. Brain. 2013 Aug;136(8):2510-2526. https://doi.org/10.1093/brain/awt171
Perez-Nievas, Beatriz G. ; Stein, Thor D. ; Tai, Hwan Ching ; Dols-Icardo, Oriol ; Scotton, Thomas C. ; Barroeta-Espar, Isabel ; Fernandez-Carballo, Leticia ; De Munain, Estibaliz Lopez ; Perez, Jesus ; Marquie, Marta ; Serrano-Pozo, Alberto ; Frosch, Mathew P. ; Lowe, Val ; Parisi, Joseph E ; Petersen, Ronald Carl ; Ikonomovic, Milos D. ; López, Oscar L. ; Klunk, William ; Hyman, Bradley T. ; Gómez-Isla, Teresa. / Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology. In: Brain. 2013 ; Vol. 136, No. 8. pp. 2510-2526.
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AU - Scotton, Thomas C.

AU - Barroeta-Espar, Isabel

AU - Fernandez-Carballo, Leticia

AU - De Munain, Estibaliz Lopez

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AU - Marquie, Marta

AU - Serrano-Pozo, Alberto

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AU - Lowe, Val

AU - Parisi, Joseph E

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AU - Ikonomovic, Milos D.

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N2 - Clinico-pathological correlation studies and positron emission tomography amyloid imaging studies have shown that some individuals can tolerate substantial amounts of Alzheimer's pathology in their brains without experiencing dementia. Few details are known about the neuropathological phenotype of these unique cases that might prove relevant to understanding human resilience to Alzheimer's pathology. We conducted detailed quantitative histopathological and biochemical assessments on brains from non-demented individuals before death whose brains were free of substantial Alzheimer's pathology, non-demented individuals before death but whose post-mortem examination demonstrated significant amounts of Alzheimer's changes ('mismatches'), and demented Alzheimer's cases. Quantification of amyloid-β plaque burden, stereologically-based counts of neurofibrillary tangles, neurons and reactive glia, and morphological analyses of axons were performed in the multimodal association cortex lining the superior temporal sulcus. Levels of synaptic integrity markers, and soluble monomeric and multimeric amyloid-β and tau species were measured. Our results indicate that some individuals can accumulate equivalent loads of amyloid-β plaques and tangles to those found in demented Alzheimer's cases without experiencing dementia. Analyses revealed four main phenotypic differences among these two groups: (i) mismatches had striking preservation of neuron numbers, synaptic markers and axonal geometry compared to demented cases; (ii) demented cases had significantly higher burdens of fibrillar thioflavin-S-positive plaques and of oligomeric amyloid-β deposits reactive to conformer-specific antibody NAB61 than mismatches; (iii) strong and selective accumulation of hyperphosphorylated soluble tau multimers into the synaptic compartment was noted in demented cases compared with controls but not in mismatches; and (iv) the robust glial activation accompanying amyloid-β and tau pathologies in demented cases was remarkably reduced in mismatches. Further biochemical measurements of soluble amyloid-β species - monomers, dimers and higher molecular weight oligomers - in total brain homogenates and synaptoneurosomal preparations failed to demonstrate significant differences between mismatches and demented cases. Together, these data suggest that amyloid-β plaques and tangles do not inevitably result in neural system derangement and dementia in all individuals. We identified distinct phenotypic characteristics in the profile of brain fibrillar and soluble amyloid-β and tau accrual and in the glial response that discriminated demented and non-demented individuals with high loads of Alzheimer's pathology. Amyloid-β deposition in the form of fibrillar plaques and intimately related oligomeric amyloid-β assemblies, hyperphosphorylated soluble tau species localized in synapses, and glial activation emerged in this series as likely mediators of neurotoxicity and altered cognition, providing further insight into factors and pathways potentially involved in human susceptibility or resilience to Alzheimer's pathological changes.

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