This shows an older man.
But how is it possible that they did not experience any symptoms while others did? Credit: Neuroscience News

Resilience to Dementia: Having Alzheimer’s Pathology with No Symptoms

Summary: A new study found that some individuals show no Alzheimer’s symptoms despite having the disease’s brain processes. This “resilient” group has unique molecular and cellular characteristics, including higher antioxidant production by astrocytes and less active microglia pathways.

These findings suggest genetics and lifestyle play a role in resilience, offering potential targets for new Alzheimer’s treatments. The study highlights the importance of continuous cognitive and social engagement for brain health.

Key Facts:

  1. Resilient Brains: Some people have Alzheimer’s pathology but no clinical symptoms.
  2. Protective Cells: Resilient individuals’ astrocytes produce more antioxidants, and microglia are less active.
  3. Potential Treatments: Understanding these resilience mechanisms could lead to new Alzheimer’s therapies.

Source: KNAW

Everyone experiences aging in their own way, and factors such as genetics, lifestyle and environment play a role in this process. Some individuals reach the age of 90 or even 100 in good health, without medications or brain disease. But how do these individuals maintain their health as they age?

Luuk de Vries from Joost Verhaagen’s group, and his colleagues Dick Swaab and Inge Huitinga, looked at brains from the Netherlands Brain Bank. The Netherlands Brain Bank stores brain tissue from more than 5,000 deceased brain donors with a wide range of different brain diseases.

What makes the Netherlands Brain Bank so unique is that, in addition to the stored tissue with very precise neuropathological diagnoses, they also keep the documented medical history and detailed disease course with the symptoms of each donor.

Resilient group

The team found a subgroup of people who had Alzheimer’s disease processes in their brains, but did not show any clinical symptoms while alive. A so-called ‘resilient’ group. But how is it possible that they did not experience any symptoms while others did?

Luuk de Vries: “what is happening in these people at a molecular and cellular level was not clear yet. We therefore searched for donors with brain tissue abnormalities who did not show cognitive decline in the Brain Bank.

“Of all the donors we found 12, so it is quite rare. We think that genetics and lifestyle play an important role in resilience, but the exact mechanism is still unknown.”

Keep challenging yourself

“Exercise or being cognitively active and having a lot of social contacts can help in delaying the onset of Alzheimer’s disease. It has recently also been found that those who receive a lot of cognitive stimuli, like through a complex job, can build up more Alzheimer’s pathology before developing symptoms.

“If we can find the molecular basis for resilience, then we have new starting points for the development of medication, which could activate processes related to resilience in Alzheimer’s patients.”

Alzheimer’s versus resilient group

“When we looked at gene expression, we saw that a number of processes were altered in the resilient group. First of all, the astrocytes appeared to produce more of the antioxidant metallothionein.

“Astrocytes are like garbage collectors and provide a protective role for the brain. Astrocytes often also ask for help from microglia, but because they can be quite aggressive, they sometimes worsen inflammation.

“In the resilient group a microglia pathway that’s often linked to Alzheimer’s disease appeared to be less active. In addition, we saw that the so-called ‘unfolded protein response’, a reaction in brain cells that automatically removes a misfolded toxic protein, was affected in Alzheimer’s patients, but was relatively normal in resilient individuals.

“Finally, we found indicators that there may also be more mitochondria in the brain cells resilient individuals, which ensures better energy production.”

But what do these differences in processes mean? And is there cause or effect? ‘It remains difficult to determine from human data which process initiates the disease process. You can only demonstrate this by changing something in cells or animal models and seeing what happens next. That is the first thing we have to do now.’

About this Alzheimer’s disease research news

Author: Eline Feenstra
Source: KNAW
Contact: Eline Feenstra – KNAW
Image: The image is credited to Neuroscience News

Original Research: Open access.
Gene-expression profiling of individuals resilient to Alzheimer’s disease reveals higher expression of genes related to metallothionein and mitochondrial processes and no changes in the unfolded protein response” by Joost Verhaagen et al. Acta Neuropathologica Communications


Abstract

Gene-expression profiling of individuals resilient to Alzheimer’s disease reveals higher expression of genes related to metallothionein and mitochondrial processes and no changes in the unfolded protein response

Some individuals show a discrepancy between cognition and the amount of neuropathological changes characteristic for Alzheimer’s disease (AD). This phenomenon has been referred to as ‘resilience’. The molecular and cellular underpinnings of resilience remain poorly understood.

To obtain an unbiased understanding of the molecular changes underlying resilience, we investigated global changes in gene expression in the superior frontal gyrus of a cohort of cognitively and pathologically well-defined AD patients, resilient individuals and age-matched controls (n = 11–12 per group). 897 genes were significantly altered between AD and control, 1121 between resilient and control and 6 between resilient and AD. Gene set enrichment analysis (GSEA) revealed that the expression of metallothionein (MT) and of genes related to mitochondrial processes was higher in the resilient donors.

Weighted gene co-expression network analysis (WGCNA) identified gene modules related to the unfolded protein response, mitochondrial processes and synaptic signaling to be differentially associated with resilience or dementia.

As changes in MT, mitochondria, heat shock proteins and the unfolded protein response (UPR) were the most pronounced changes in the GSEA and/or WGCNA, immunohistochemistry was used to further validate these processes.

MT was significantly increased in astrocytes in resilient individuals. A higher proportion of the mitochondrial gene MT-CO1 was detected outside the cell body versus inside the cell body in the resilient compared to the control group and there were higher levels of heat shock protein 70 (HSP70) and X-box-binding protein 1 spliced (XBP1s), two proteins related to heat shock proteins and the UPR, in the AD donors.

Finally, we show evidence for putative sex-specific alterations in resilience, including gene expression differences related to autophagy in females compared to males.

Taken together, these results show possible mechanisms involving MTs, mitochondrial processes and the UPR by which individuals might maintain cognition despite the presence of AD pathology.

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