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Why is it that some individuals are able to live well into old age while maintaining their full cognitive abilities while other elderly individuals are being faced with memory loss and the development of Alzheimer’s disease (AD)? While it has been assumed that age is the number one driving factor for dementia and AD, scientists have yet to fully understand what exactly sets apart those who live well into their elder years with optimal cognitive abilities (e.g. those with a long health span) and those who suffer from cognitive impairments. Could this be due to major differences in the development of degenerative brain changes? Or are there other factors that allow many elderly to maintain cognitive function despite the unavoidable development of age related neurodegenerative changes?

Researchers at the University of California, Irvine conducted a study to try to find an adequate explanation to further understand how the changes in the brain compare from individuals who exhibit impressive cognitive abilities for their age (so called “SuperAgers”) and individuals who are diagnosed with memory-related illnesses like AD. There is limited research on the physical brain changes of individuals aged ninety and older (“oldest-old”) who are able to maintain excellent cognitive function despite their old age.

“In the United States alone, the number of adults who live beyond ninety has tripled in the past few decades. Additionally, this number is expected to quadruple in the next few decades.”

90+ Study began in 2003 and set out to understand the link between longevity and dementia. Researchers began studying the oldest groups of the elderly population in the United States (“oldest-old”) to see if there was a potential link between neurodegenerative diseases and age. The study had a total of 1,600 participants enrolled making it one of the largest studies of its kind throughout the whole world. In the United States alone, the number of adults who live beyond ninety has tripled in the past few decades, and is expected to quadruple in the next few decades.

One major goal of the 90+ study was to identify pathological brain changes in SuperAgers and compare them with brain changes observed in same age individuals with cognitive decline. They found that SuperAgers, individuals who are ninety years old and over with superior cognitive abilities for their age, displayed some of the same brain pathology as observed in those with AD as well as other neuropathological signs. However, the ability to withstand these neural changes and maintain full cognitive function was one of the main features that differentiated those with full cognitive abilities from those with cognitive decline.

Previous autopsy studies on the 90+ Study participants had reported that individual and multiple comorbid neuropathologic features were common in “oldest-old” individuals and were associated with increased likelihood and severity of cognitive impairment. As expected, the presence of higher levels of multiple neuropathologic features were associated with a lower likelihood of superior cognitive performance. AD neuropathological changes (ADNCs) considered biomarkers of AD (such as neurofibrillary tangles and amyloid plaques) were found in 87% of study participants but surprisingly, were not associated with cognitive performance. This finding was not unexpected given that ADNCs are almost ubiquitous in this “oldest-old” cohort, and it has been commonly reported in individuals without dementia in a recent meta-analysis on 17 population-based autopsy studies with age of death 65 years and above. Furthermore, a previous analysis on eight participants from The 90+ Study reported the presence of plaques and tangles—the hallmarks of ADNC—in the brains of “SuperAgers”.

“Despite some of the brain pathology being the same, these SuperAgers had the ability to resist the changes and maintain their cognition.”

When viewed together, the current and previous study results indicate that superior cognitive performance in “oldest-old” can be explained by concepts of both resilience and resistance. In cognitively normal “oldest-old”, the superior global cognitive performers were resilient to ADNC, i.e., they maintained superior cognition despite having AD-specific neurodegenerative changes. On the other hand, other neurodegenerative neuropathologic features, particularly Lewy Body disease and a particular form of degeneration of the hippocampus, the major brain area concerned with memory, were very rare indicating resistance, i.e., their ability to escape the development of these changes in the brains.

“If scientists were successful in understanding this, they could determine ways to detect dementia and potentially treat it in early stages.”

Since individuals in the United States and other parts of the world are beginning to live far past ninety years old, so it is important to start to develop a better understanding how to increase the health span (longevity without disease even through old age) of individuals. Alzheimer’s disease is on the rise and becoming increasingly more common in older adults. Since age is such a prominent factor, it is very critical to understand the link between age and dementia. Luckily, the 90+ Study has been doing just that for over the last twenty years. While the factors influencing the correlation between pathological brain changes and clinical performance remain incompletely understood, we now know that it is not that SuperAgers do not experience brain changes, but they are more resilient to them. In addition to promoting lifestyle factors that promote resistance to the development of ADNCs, including diet, exercise, sleep and social interactions, it will be essential to explore the driving factors behind the ability of SuperAgers to remain resilient despite the physical changes in their brain.

By Amanda Johnson and Emeran Mayer, MD