13 Jun 2008

The prevalence of Alzheimer disease increases exponentially after age 65, but that doesn’t mean all people will get the disease if they live long enough. A case in point is a “supercentenarian,” that is, someone who is 100 or older, from the Netherlands. At the age of 82, the woman donated her body to science, and Gert Holstege and colleagues from the University Medical Centre, Groningen, had the privilege of examining her brain postmortem when she died 33 years later at the age of 115. In this month’s Neurobiology of Aging online, the researchers report that amyloid-β (Aβ) deposits were undetectable in the woman’s brain, and evidence of hyperphosphorylated tau (Braak-stage II) was sparse. The findings support the idea that Alzheimer disease can be avoided, even by the oldest old.

With longevity increasing worldwide, the question of how to give people the opportunity to age with their cognitive skills intact has come to the fore. This supercentenarian had little cause for concern. At age 112, she scored 27 on the Mini-Mental State Exam (minus tests that relied on vision since her eyes started failing her around age 105). At 114, she scored 26—again on partial tests—still holding her own. The researchers concluded that for attention and working memory, she performed about as well at 112 as persons aged 60-75. Two years later some of her skills had declined, though she was still performing within the normal range for healthy older adults. “Our observations indicate that the limits of human cognitive function extend far beyond the range that is currently enjoyed by most individuals and that brain disease, even in supercentenarians, is not inevitable,” write the authors.

The paper has garnered commentary in the same journal. Kelly Del Tredici and Heiko Braak, Institute for Clinical Neuroanatomy, Frankfurt/Main, Germany, note that tau pathology—neurofibrillary tangles (NFTs) and neuropil threads (NTs)—can be found postmortem at all ages, even in people who died in their twenties, and constitute a true threat. “Thus, although NFTs/NTs are not inevitable, i.e., inevitably integral to aging, they are pathologic (nonbenign, premorbid) markers in neurons no matter at what age or end of the life spectrum they occur.”

In their commentary, Panteleimon Giannakopoulos, University Hospitals of Geneva, Switzerland, as well as Constantin Bouras and Patrick Hof at Mount Sinai School of Medicine, New York, raise the question of what protected this woman from neurodegeneration. The same question was echoed by Joseph Price, Washington University School of Medicine, in his commentary. Giannakopoulos and colleagues note that the biological background that makes people older than 90 resistant to the development of AD lesions is still poorly understood, but genetics no doubt plays a role. “Evidence from genetic studies of aging and AD implies that a number of susceptibility genes may modify or delay the onset of late-life brain failure,” they write. On that note, Price ask why den Dunnen et al. did not report the woman’s ApoE genotype. “This subject may have been one of those rare individuals who are homogenous for ApoE ε2,” he wrote. But he added that some centenarians who were ApoE4-positive yet disease-free have been reported as well.—Tom Fagan