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New research suggests that what makes ‘SuperAgers’ unique are their large neurons. Image credit: Lauren Mulligan/Getty Images.
  • Researchers autopsied 24 brains, including six from people known as “SuperAgers.”
  • They found that SuperAgers had larger neurons than people almost 60 years their junior.
  • They noted that further research is needed to understand how larger neurons are linked to preserved memory capacity in SuperAgers.

Memory capacity typically declines with age. Around 40% of people aged 65 years and older have age-associated memory impairment, and approximately 1% of these cases progress into dementia each year.

SuperAgers” is a term commonly used to refer to individuals aged 80 years and older who score similarly to individuals aged 20-30 years younger in memory tests.

Further study into how SuperAgers maintain their memory capacity could help researchers develop preventative strategies and treatments for cognitive decline.

Recently, researchers autopsied the brains of 24 individuals, including six characterized as “cognitive SuperAgers.”

They found that SuperAgers’ neurons were larger than those aged 20–30 years younger and that their neurons did not have tau tangles — a hallmark of Alzheimer’s disease.

“For reasons that remain unknown, cell populations in the [brain’s] entorhinal cortex (ERC) are selectively vulnerable to ‘tau tangle’ formation during normal aging and in early stages of Alzheimer’s Disease,” Dr. Tamar Gefen, assistant professor of psychiatry and behavioral sciences at Northwestern University Feinberg School of Medicine in Chicago, and one of the study authors, told Medical News Today.

“In this study, we show that neuronal shrinkage (atrophy) in the ERC appears to be a characteristic marker of [Alzheimer’s disease]. We suspect this process is a function of ‘tau tangle’ formation in the affected cells, [and that it leads] to poor memory abilities in older age. Identifying this contributing factor is crucial for the early identification of Alzheimer’s, monitoring its course, and guiding treatment,” she explained.

The study appears in the Journal of Neuroscience.

For the study, the researchers autopsied the brains of:

  • six SuperAgers with an average age of 91 years
  • seven “cognitively average” elderly people with an average age of 89 years
  • six healthy younger adults aged between 26 and 61 years
  • five adults with mild cognitive impairment (MCI) at an average age of 92 years.

At the time of death, all participants could perform daily living activities, and all were free from clinical evidence or history of neurological or psychiatric conditions.

The researchers noted no difference in years of education, brain weight, or postmortem interval between the groups.

They also tested for ApoE genotypes using DNA from patient blood samples. Among the participants, only one person from the MCI group had the APOE-4 allele, a risk factor for Alzheimer’s disease.

The researchers assessed a cross-sectional layer of neurons from layers II, III, and V of participants’ ERC. The ERC comprises six neuronal layers and is among the first areas to develop signs of Alzheimer’s disease.

In particular, they assessed overall neuronal health and the presence of neurofibrillary tangles (NFT), also known as tau proteins that, when collected inside neurons, cause neuronal dysfunction.

In the end, the researchers found that layer II ERC neurons were significantly larger in SuperAgers than other groups, including younger controls, some of whom were 60 years their junior.

They further found that those in the “cognitively average” group of older individuals had over twice the NFT density of SuperAgers in layer II of the ERC.

When asked why SuperAgers’ neurons may be larger than those of their peers, Dr. James Giordano, professor of neurology and biochemistry at Georgetown University Medical Center in Washington told MNT:

“It’s possible that these represent mega neurons, which may have a genetic predisposition and/ or an environmentally acquired tendency to increase size so as to enable greater intra- and inter-cellular information processing. In this way, these neurons may have mechanisms that fortify both their functionality and their resistance or resilience to metabolic stress and degradation.”

“The increased size of these neurons may reflect a greater extent or diversity of intracellular functions, including a greater network of cellular machinery that enables detoxification, reduced susceptibility to inflammation, and enhanced stability of metabolic activity in and across a variety of micro- and macroenvironmental conditions,” he added.

Dr. Gefen noted: “One possibility for the greater size is that these neurons are protected from neurofibrillary tangles — a hallmark of Alzheimer’s disease. We are not yet sure why these neurons were larger in SuperAgers or why they are relatively protected from disease.”

The researchers wrote that this protection comes despite other age-related brain changes present in SuperAgers.

“It’s important to remember that SuperAgers, as described in the paper, are professional athletes of cognition,” Dr. Christopher Barnum, neuroimmunologist and Director of Neuroscience at INmune Bio, not involved in the study, told MNT.

“I suspect that neuron size will not be the only difference, super-agers will almost certainly have more synaptic connections, more and better-quality myelination, etc. Like everything else, the super-aging ‘result’ is a function of complex genetic-environment interactions,” he added.

The study authors also wrote that their findings suggest that increased NFT levels lead to neuronal shrinkage. They noted that this observation was particularly apparent in the MCI group, which had a significantly lower cell size than other groups.

They further explained that larger layer II ERC neurons among SuperAgers than their young peers might indicate that large ERC cells were present from birth and structurally maintained throughout life.

When asked how SuperAgers’ neurons may be more resistant to tangle formation, Dr. Adam Brickman, professor of neuropsychology at Columbia University Irving Medical Center, not involved in the study, told MNT:

“The simple answer is we just don’t know. [Not all adults are destined to develop tangles.] The factors that initiate tangle formation are poorly understood. There may be genes or lifestyle factors that moderate the risk of tangle formation.”

“Future in-depth studies are needed to understand how and why neuronal integrity is preserved in SuperAgers. I am interested in probing the cellular environment, for example — what are the chemical, metabolic, or genetic features of these cells that render them resilient?” added Dr. Gefen.

“We will also want to investigate other’ ‘hub’ along the memory circuit of the brain to better understand the spread of- or resistance to- disease,” she noted.

The researchers concluded that SuperAgers carry a unique biological signature comprised of larger, healthier ERC neurons that are relatively void of tau tangles.

When asked about the study’s limitations, Dr. Brickman said: “Like all autopsy studies, the findings are limited by the cross-sectional design. Because autopsy data can only be used to take a ‘snapshot’ at one point in time, it is unclear whether the SuperAgers’ [ERC] neurons were much larger at an earlier age but shrank at the same rate as their peers or if they were larger and maintained the same relative size throughout life.”

“It is also not possible to infer whether the larger neuronal size conferred resistance against Alzheimer’s pathology or whether some other factor(s) that reduced risk and progression of Alzheimer’s pathology protected the neurons from shrinking,” he added.

Dr. Gefen noted that their results are limited by their small sample size. She indicated that their small sample size was partially due to SuperAgers being “unique and rare.”

She continued: “Perhaps a most important message is that to understand brain disease, it is critical that we learn about human biology (both normal and abnormal) in life — and in death. Our SuperAgers commit to donating their autopsied brains to research. I have the fortunate opportunity to know my patients and research participants intimately in life and in death.”

Dr. Giordano noted that the study has opened the door to further study of the function of these “unique neurons” — “both alone and in concert with other cells, nodes, and networks of the brain, and body as well.”

“Another important question [for future investigation] is why and how some people develop these super-sized cells while others do not. Taken together, such studies can provide improved insights to SuperAgers’ cognitive functionality and relative resistance and/ or resilience to neurodegenerative diseases. In these ways, we may identify and develop new interventions that could potentially maintain cognitive function across the lifespan,” he added.