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No Signs of Cognitive Decline in Brain of Oldest Living Woman


Postmortem examination of a 115-year-old Dutch woman's brain — the oldest brain to be autopsied — revealed few signs of Alzheimer disease and the cognitive dysfunction typically associated with aging.

Postmortem examination of the brain of a 115-year-old woman — recorded as the oldest living person in the world at the time of her death in 2005 — revealed few signs of Alzheimer disease (AD); cognitive dysfunction typically associated with aging was also absent, with almost no atheroscleroctic changes in cerebral vessels or amyloid-beta plaque in the brain. Moreover, at the age of 112 and 113, the Dutch woman, Henrikjje van Andel Schipperr, performed better on neuropsychological assessments than the average 60- to 75-year-old adult.

Gert Holstege, MD, PhD, professor and chairman of the Center of Uroneurology, and colleagues at the Groningen University Medical Center in the Netherlands conducted the study, which was published in August in the journal Neurobiology of Aging. Dr. Holstege told Neurology Today in an e-mail that van Andel Schipperr had no plaques, amyloid-beta depositions, demyelination, or atherosclerosis, and only a slight amount of tau pathology (neurofibrillary tangles). She died of gastric cancer at 115.


Dr. Gert Holstege explained that the postmortem examinations of the subjects brain showed no plaques, amyloid- beta depositions, demyelination, or atherosclerosis, and only a slight amount of tau pathology (neurofibrillary tangles).


Previous studies had demonstrated that some centenarians are not demented and some show no signs of AD pathology, but this is the oldest brain to be healthy and autopsied, said Nikos Scarmeas, MD, assistant professor of neurology at Columbia University Medical Center, who was not involved with the study.


An overview of the hippocampal complex of Henrikjje van Angel Schipperr stained for hyperphosphylated tau protein.

He noted that postmortem studies show that the proportion of brains with plaques and tangles — AD pathology — increases with age: the likelihood of dementia for those over 65 is 10 percent, while between 30- and 60-percent of those 85 and older have dementia (the vast majority of which caused by AD). The pool increases by 10- to 20-percent if those with mild cognitive impairment (MCI) are included, he said.

Although it is hard to say if the woman would have developed dementia or AD as she aged, Dr. Scarmeas noted that the neuropathological results showing slight tau-pathology (Braak-stage 2) did demonstrate she already had signs of mild cognitive dysfunction. [The initial clinical symptoms of AD pathology correspond with Braak-stage 4, and stages 5 and 6 correspond with the fully developed disease, according to the study authors.]


What might have contributed to van Andel Schipperr's longevity and healthy brain? Experts speculated that her lifestyle (she did not smoke), gender, and diet (she drank a glass of wine and did not eat much) might have played a role. Dr. Holstege told Neurology Today she had been taught at home by her schoolteacher father, so that while other children were in school, she was running and playing in the woods.

Also, longevity ran in her family, he noted. The subject's mother lived to age 100 and her maternal grandparents died in their 80s. She weighed only three and a half pounds when she was born in 1890, and was expected to die soon after birth. The association between BMI and AD is complicated, Dr. Scarmeas said, but since “animal studies indicate prolonged survival for low total caloric intake,” it would be worthwhile to study the woman's BMI and weight course through her life.

Some autopsies reveal extensive plaques and tangles in the brains of people who appeared cognitively normal prior to death, said Yaakov Stern, MD, professor of clinical neuropsychology at Columbia University in New York, NY, and director of neuropsychology at the New York State Psychiatric Institute's Memory Disorders Center.

“Some people seem to tolerate the pathology more than others,” Dr. Stern explained, which is illustrated in a 2006 Neurology study by David A. Bennett, MD, the Robert C. Borwell Professor of Neurological Sciences and the director of the Rush Alzheimer's Disease Center at Rush University Medical Center in Chicago, which reported that about one-third of people without dementia or MCI still meet pathologic criteria for AD at autopsy.

One possible explanation for this, according to Dr. Scarmeas, is that investigators do not have the optimal pathological correlate of AD — there may be a correlation between cognitive performance and tangles, but not with plaques.

“Neuronal dysfunction caused by soluble amyloid or amyloid oligomers or other pathological markers might be more reliable indicators of AD,” he said. A second explanation is that of cognitive reserve: that is, some people may have built-in “redundancy in the brain so that healthy brain regions or other brain networks may take over and compensate for areas with plaques and tangles (therefore maintaining cognitive performance).”

However, the findings in this woman do provide insight into what normal aging might be, said Dr. Stern. Some people age successfully and others don't, so continued studies like Dr. Holstege's should help to explain this degree of variability.

More studies are needed to study the factors that predispose centenarians to cognitive change, vascular changes, and AD pathology over the coming decades, said David Knopman, MD, professor of neurology at the Mayo Clinic in Rochester, MN.

“One of the great challenges in understanding aging at the extreme of human longevity is trying to interpret what survival means in these few centenarians, who account for an infinitesimally small fraction of even persons living past age 65,” he said. “What do risk factors for disease mean in someone who made it to age 90?”


• den Dunnen WF, Brouwer WH, Holstege G, et al. No disease in the brain of a 115-year-old woman. Neurobiol Aging 2008;29(8):1127–32. E-pub 2008 June 4.
    • Bennett DA, Schneider JA, Arvanitakis Z, et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006;66:1837–1844.