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Why Are Some People Resistant to Dementia?: Analysis of Alzheimer's Pathological Lesions Offers Clues

Samson, Kurt

doi: 10.1097/01.NT.0000437154.17340.a8
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Investigators reported — based on histopathological and biochemical assessment of 50 brains — that factors other than plaques and tangles may be more directly related to cognitive impairment and to neuronal and synaptic damage in Alzheimer's disease.

For decades it has been believed that dementia in Alzheimer disease (AD) results from accumulation of amyloid-beta (Abeta) plaques and neurofibrillary tangles in the cerebral cortex and some subcortical areas, but recent postmortem brain studies have found similar degrees of pathological changes in some individuals who did not develop dementia.

In the August issue of the journal Brain, investigators from Harvard University and Massachusetts General Hospital, the Mayo Clinic, and the University of Pittsburgh, reported — based on histopathological and biochemical assessment of 50 brains — that factors other than plaques and tangles may be more directly related to cognitive impairment and to neuronal and synaptic damage in Alzheimer's disease. The findings support the idea that some individuals may resist the insult of classical Alzheimer's lesions in their brains.

The brains were divided into four categories: a control group of non-demented individuals where postmortem examination showed a low probability of AD; non-demented individuals with intermediate probability of the disease; those without dementia but whose brains showed a high likelihood of AD; and brains from individuals with dementia where postmortem examination showed a high likelihood of the disease. [For more on the criteria, see “Study Criteria for Probability of Developing Alzheimer's Disease.”]

The researchers found that some individuals accumulate equivalent loads of Abeta plaques and tangles with those found in demented Alzheimer's cases without experiencing dementia while alive; the authors refer to these cases as mismatches. The mismatches had a striking preservation of neuron numbers, synaptic markers and axonal geometry, a lower burden of fibrillar thioflavin S-positive plaques and oligomeric Abeta deposits, a decreased amount of soluble tau in synapses, and a remarkable reduction in glial activation when compared to demented Alzheimer's cases.



“Our data support the idea that Abeta plaque deposition and tangle formation do not inevitably result in dementia and neuronal damage in all individuals,” lead author Teresa Gómez-Isla, MD, PhD, an associate professor of neurology at Harvard Medical School and Massachusetts General Hospital in Boston, told Neurology Today.

“Detailed quantitative assessments demonstrated that our group of mismatches with a high likelihood of AD by pathological criteria were well matched to demented cases with Alzheimer's disease with regards to Abeta plaques and neurofibrillary tangles in the association cortex that forms the superior temporal sulcus. Therefore, we feel these cases are likely to represent individuals who seem resilient to Alzheimer's disease pathology.”

One-third of the non-demented cases, including three out of eight individuals whose brains showed a high probability of AD, had undergone cognitive evaluation within two years of death; the other two-thirds of medical records and death certificates did not report any dementia. The fact that formal neuropsychological evaluation close to death was not available in all cases may somewhat limit the findings, according to the researchers.

“Because of this, subtle cognitive declines cannot be ruled out in individuals where dementia was not recorded,” Dr. Gómez-Isla told Neurology Today.

According to the study, the most likely mediators of neurotoxicity and altered cognition included Abeta accumulation in the form of fibrillar dense-cored plaques thioflavin-S-positive and intimately related oligomeric Abeta assemblies, hyperphosphorylated soluble tau species localized in synapses, and glial cell activation.

“These factors provide insight into factors and pathways potentially involved in human susceptibility or resilience to Alzheimer's pathological changes,” she said. [For more on the analysis, see “Phenotypic Differences: Demented Vs. Nondemented Brains.”]

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There is a great deal of interest and a number of studies on why some individuals with significant AD pathology do not develop dementia symptoms, said David A. Wolk, MD, assistant professor of neurology and assistant director of the Penn Memory Center, at the University of Pennsylvania's Perelman School of Medicine, in Philadelphia.

“I think this paper is interesting and adds to our knowledge of what mechanisms might be involved, and provides investigators with a direction to better explore these differences,” he told Neurology Today in a telephone interview.

There is a possibility that the patients without dementia may not have been as far along as the others in disease progression, he noted. However, he said, “the researchers did a good job in matching brains with similar degrees of Abeta and tau accumulation.”

AD researchers have focused on two potential explanations for the phenomenon. The first is cognitive reserve — that individuals with greater intellectual capacity, especially those who regularly engage in problem solving tasks, may have greater ability to compensate for neuronal loss. The other is the concept of brain reserve — that some individuals have more developed redundant systems for countering problems when something in their cerebral cortex goes wrong.

“But this paper suggests that neither are primary drivers of cognitive preservation because there was actually less neuronal loss or reduction in cortical thickness in patients without dementia. This suggests that perhaps they are just more resistant to AD-related pathology and its neurodegenerative effects,” he told Neurology Today.

While the lack of clinical neuropsychological records for all patients is a potential confounder, it is “unlikely to be the sole explanation,” Dr. Wolk said.

“Not only were there cognitive differences in the non-demented subjects, but their brains also appeared to be structurally different.”

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The researchers identified four main phenotypic differences in the brains of individuals who did not develop dementia despite abundant plaques and tangles, including the absence of a significant loss of neurons and synaptic markers, and a much better preserved geometry of axons when compared to demented Alzheimer's cases.

The brains of demented individuals had significantly higher burdens of fibrillar dense-cored plaques thioflavin-S-positive that stain with thioflavin-S, and more oligomeric Abeta deposits labeled by conformation selective monoclonal antibody NAB61, which detects an epitope present in dimeric, small oligomeric, and higher order Abeta structures, but not full-length Abeta precursor protein or C-terminal protein fragments.

There was also strong and selective accumulation of hyperphosphorylated soluble tau monomeric and multimeric species into the synaptic compartment in demented individuals compared with controls, and the robust activation of astrocytes and microglia activation typically seen in demented Alzheimer's cases accompanying plaques and tangles was strikingly decreased in mismatches.

Further biochemical measurements of soluble Abeta species — monomers, dimers, and higher molecular weight oligomers — did not show any significant differences between demented and non-demented cases, however. The authors believe that these apparently conflicting results derived from biochemical and immunohistological assessments highlight the need for development and validation of tools to measure oligomeric Abeta, as different techniques may report different species of oligomers.

Interestingly, one of the main differences between groups was a significant reduction of glial activation in mismatches compared to demented Alzheimer's cases, further favoring the idea that aberrant activation of glial elements and inflammation may also contribute to dementia and neuronal damage in Alzheimer's disease.

“If these cases simply had greater ‘reserve’ of neurons and synapses, one would expect equivalent degrees of local damage around plaques and equally robust glial inflammatory changes,” the researchers said. However, this was not the case.

Instead, detailed pathological analysis provided evidence that neuronal populations and the morphology of neurites were “remarkably” well preserved compared to the massive neuronal depopulation and dramatic distortion of neurite architecture seen in demented cases with Alzheimer's disease.

“Together, these data suggest that Abeta plaques and tangles do not inevitably result in neural system derangement and dementia in all individuals.”

—Kurt Samson

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In this study, cases were scored by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scale for neuritic plaques, and the Braak staging method for evaluating neurofibrillary tangles (0–VI).

The CERAD scale was established in 1986 by the Institute on Aging (NIA) to standardize procedures for evaluating and diagnosing Alzheimer disease (AD). CERAD rates cases from A to C, with C representing brains with the greatest degree of plaque load and high probability of AD.

Braak staging is a method developed in 1991 by Professor Heiko Braak, MD, at the Institute for Clinical Neuroanatomy of the Johann Wolfgang Goethe University in Frankfort, Germany. It rates neurofibrillary tangles from 0 to VI, with V and VI representing the greatest probability of AD.

Using these standardized, validated measures, and criteria from National Institute on Aging and the Reagan Institute, the researchers divided brains into these categories:

  • High probability: Frequent neuritic plaques (CERAD level C) and a high Braak stage of neurofibrillary tangles (V/VI).
  • Intermediate probability: Moderate density of neuritic plaques and neurofibrillary tangles in a limbic distribution (CERAD B, Braak III/IV).
  • Low probability: Scarce distribution of neuritic plaques and neurofibrillary tangles (CERAD A and Braak I/II).

—Kurt Samson

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•. Perez-Nievas BG, Stein TD, Tai HC, et al. Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology. Brain 2013;136(Pt 8):2510–2526.E-pub 2013 Jul 3.
    •. Serrano-Pozo A, Gómez-Isla T, Growdon JH, et al. A phenotypic change but not proliferation underlies glial responses in Alzheimer disease. Am J Pathol 2013;182(6):2332–2344.E-pub 2013 Apr 18.
      •. Neurology Today archive on Alzheimer's disease:
        •. Neurology Today video on amyloid-beta, brain volume, and dementia:
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