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The Case for Documenting Mixed Mortality — Alzheimer's-Related Mortality Is Under-Reported

Kreimer, Susan

doi: 10.1097/01.NT.0000446551.43690.82
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Study authors say it might be time to consider the analogous concept of “mixed mortality” to more accurately reflect the contribution of multiple disease processes to dying, including Alzheimer's.

Mortality attributable to Alzheimer's disease (AD) in the US is far greater than previous estimates, according to a new landmark study. The revised figures, published in the March 5 online edition of Neurology, reposition AD dementia from the sixth to the third leading cause of death, while making the case for more research funding to find a cure and treatments to delay onset and halt progression.

“Just as the field has embraced the concept of mixed dementia, acknowledging that multiple neuropathologies may contribute to the expression of dementia beyond AD pathology alone, it may be time to consider the analogous concept of ‘mixed mortality’ to more accurately reflect the contribution of multiple disease processes to dying,” the study authors wrote. “This more nuanced view of ‘cause of death’ is needed for an accurate understanding of the contributions of chronic diseases such as AD to death in rapidly aging populations.”

Clinical investigators hope to elevate recognition of AD dementia as “not just a condition that people die with but actually a disease that people die from,” Bryan D. James, PhD, the study's lead author and an assistant professor of neurology at the Alzheimer's Disease Center at Rush University Medical Center in Chicago, told Neurology Today. “This changes the framing of the burden of Alzheimer's to our society,” he said, adding, statistically, this indicates that only heart disease and cancer claim more lives in the US.

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To measure the burden of US mortality linked to AD dementia, the researchers assessed data from 2,566 people from two ongoing cohort studies of aging — the Religious Orders Study, whose participants include older Catholic nuns, priests, and brothers from across the country, and the Rush Memory and Aging Project, which includes community-dwelling residents of retirement communities and subsidized senior housing facilities across northeastern Illinois.

In each study, participants without known dementia at baseline consented to annual detailed clinical evaluation and brain and tissue donation at the time of death. Identical clinical and diagnostic procedures across the two studies allowed them to be pooled for analysis. Follow-up among living participants reached very high rates, surpassing 90 percent.

The results revealed that over an average of eight years, 559 participants (21.8 percent) without dementia at baseline developed AD dementia and 1,090 (42.4 percent) died. Median time from AD dementia diagnosis to death was 3.8 years. The population attributable risk percentage — the number (or proportion) of cases that would not occur in a population if the factor (AD dementia) were eliminated — was 37 percent for people aged 75–84, and 35.8 percent for those aged 85 and older. Based on the data, they were able to attribute an estimated 503,400 deaths in Americans aged 75 years and older to AD dementia in 2010.

This calculation is significantly higher than the 83,494 deaths in 2010 tabulated by the Centers for Disease Control and Prevention, which listed Alzheimer's as the sixth leading cause of death in the United States. As many as five million Americans currently live with AD dementia, a disease with an average time from diagnosis to death of three to nine years, the study's authors noted.

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“This is the first peer-reviewed report to indicate that the official count of Alzheimer-related deaths in the United States is way low. It will be important to see the findings of this study replicated with other cohorts,” said Dallas W. Anderson, PhD, science administrator for population studies of Alzheimer's disease and dementia at the NIH National Institute on Aging.

Dr. Anderson told Neurology Today that he “was not surprised that the official count (of AD dementia) was low. But that it could be off by several orders of magnitude was a surprise.”

Dr. Anderson explained that “the death record actually allows for the concept of mixed mortality — embracing the immediate cause of death and one or more underlying causes. The problem comes from how the form is completed. Perhaps this study will help to sensitize physicians to the importance of providing as much detail as possible about the cause of death in Alzheimer's patients,” he said.







Measuring the “population attributable risk” (PAR) of death becomes more complex when a person with AD dementia has multiple other medical conditions. “This can be very tricky, especially if you begin to consider persons exposed to four or five simultaneous causes,” Walter A. Kukull, PhD, a professor of epidemiology and director of the National Alzheimer's Coordinating Center at the University of Washington in Seattle, told Neurology Today.

However, “you cannot add up PAR percentage for individual diseases — AD dementia, heart disease, diabetes — to get the PAR for persons with all three conditions; you would easily get more than 100 percent. You have to find the group exposed to all three and observe their mortality rate and compare that with the population,” added Dr. Kukull, who was not involved in conducting the new study but found the authors' methodology to be sound. “There are relatively well-established methods to do such an analysis correctly, however. Frequently, though, the incorrect simple sum is what ends up being reported by the unsuspecting.”

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A host of challenges surrounds the concept of “mixed mortality,” regarding the process of dying in an era of multiple chronic conditions. “Eventually, severe dementia causes complications such as swallowing disorders and malnutrition that can lead to fatal conditions such as pneumonia,” the authors noted in the study. “These more proximate causes are listed on the death certificate as immediate cause of death, while dementia is often omitted as an underlying cause.”

Identifying a single primary acute event that led to a patient's death is ingrained in medical training, and it should remain the cornerstone of documentation on death certificates, Dr. James said. However, a more comprehensive view from a public health perspective would entail “paying attention to Alzheimer's disease as the initiator of this cumulative chain of events that results in death.” This revised outlook “could potentially prevent or delay as many deaths in the long run as a focus on the acute causes of death,” he added.

Nonetheless, the authors conceded that their research has limitations. Because the two cohort studies are not population-based and participants agreed to autopsy, mortality rates and attributable risk may not be representative of the general population. “Although we adjusted for potential confounders of the relationship between AD dementia and death, residual confounding may remain,” they acknowledged.

For instance, the authors were only able to estimate deaths attributable to AD dementia for individuals aged 75 years and older. They did not include deaths associated with mild cognitive impairment due to AD as recognized by the newly recommended diagnostic criteria. As a result, “we likely underestimated the true number of deaths attributable to AD; prior work has found that mild cognitive impairment is associated with mortality,” the authors wrote.

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Even so, as more Americans are diagnosed with Alzheimer's in the near future, the study makes a strong case to boost funding for treatment and care beyond the $500 million allocated by the federal government in 2014. Currently, the costs total $200 billion per year in Medicare and families' out-of-pocket expenses — and they eventually could bankrupt the health care system, Dr. James said.

“This type of study is very important for us to use as an instrument going to the US Congress,” said Ronald C. Petersen, MD, PhD, director of the Mayo Alzheimer's Disease Research Center in Rochester, MN. In October 2013, the US Department of Health and Human Services re-appointed Dr. Petersen chair of the Advisory Council on Alzheimer's Research, Care, and Services to the National Plan to Address Alzheimer's Disease.

“From the big picture, everyone in the field has suspected that Alzheimer's disease as a cause of death or contribution of death was under-rated — that it was just tabulated incorrectly,” Dr. Petersen told Neurology Today. “This is not just an aging problem. This is a major cause of death. Alzheimer's disease is irreversible and fatal.”

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•. James BD, Leurgans SE, Hebert LE, et al. Contribution of Alzheimer disease to mortality in the United States. Neurology 2014: E-pub 2014 Mar. 5.
    •. Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2010. In: National Vital Statistics Reports [online]:
      •. The Religious Orders Study:
        •. The Rush Memory and Aging Project:
          © 2014 American Academy of Neurology