A new analysis of Alzheimer's disease progression finds the transition from moderate to severe AD in a year is slower than previous estimates but mortality rates are higher.
BOSTON–Patients progress from one stage of Alzheimer disease (AD) to another stage at a much slower rate than previously reported, Tufts Medical Center researchers said the annual American Neurological Association meeting here.
As an example, the previous 2001 estimate showed that 34 percent of patients would progress from moderate AD to severe AD over a one-year period. The Tufts analysis estimated that only about 8 percent of patients would transition from moderate to severe AD in one year.
Neurologists gathered around the poster presentation and Alzheimer's experts who spoke with Neurology Today agreed that the study is thought-provoking and that the findings are plausible. That said, the research would need to be replicated to have any real impact, such as, for example, for use in designing clinical trials, they said.
The study, which was funded by Pfizer, also found disease progression rates were slightly higher in men and in older patients, said principal investigator Natasha Olchanski, MS, a health economist and project director of the Center for the Evaluation of Value and Risk in Health at Tufts.
NEW ANALYSIS: YEARLY CHANGE FOR AD PROGRESSION RATES THE PROBABILITY OF PROGRESSING FROM ONE STAGE TO ANOTHER IN ONE YEAR.
Interestingly, while disease progression appears slower than previously estimated, mortality rates are higher, she said. In addition, there was striking similarity in the transition from mild to moderate AD and from moderate to severe AD, regardless of age.
Many factors may help explain why the newer analysis estimates such a slower rate of progression, but Olchanski believes that “differences in background therapy,” with more effective drugs now in the past are a major driving force.
The fact that the previous analysis “lumped MCI [mild cognitive impairment] with mild Alzheimer's” and that the earlier sample had younger patients are also key factors, she said.
Olchanski said there were two main reasons her group undertook the study. First, a previous estimate that is often cited calculated progression rates and transition probabilities based on Consortium to Establish a Registry for Alzheimer's Disease (CERAD) data — which were collected in 1990s; the data were published in 2001 in the AAN journal Neurology. Additionally, she said, “Scant evidence exists to examine transitions from MCI to more severe states.”
The new study utilized records in the Uniform Data Set (UDS) maintained by the National Alzheimer's Coordinating Center. The UDS is a large, longitudinal database with 918 variables, including demographics, medical history, features of symptom onset and course, and performance measures from neurologic and neuropsychologic examinations.
A total of 19,845 patients with MCI or AD aged 50 and older who had over 50,000 doctor-visits from 2005 to 2011 were selected; patients with any type of non-AD dementia were excluded.
DR. SAM GANDY: “Some dementia is due to cerebrovascular disease and there is evidence that cerebrovascular disease exacerbates Alzheimer's. There is good reason to predict that improved general cardiovascular health will be reflected in reduced incidence per capita and/or slower rates of progression, but this is still speculation at this moment.”
Researchers used clinical dementia rating scores recorded in the UDS to define disease severity: 0.5 (MCI), 1 (mild AD), 2 (moderate AD), 3 (severe AD). Age- and gender-specific disease progression rates and annual transition probabilities between each of the disease states were calculated using the Cox proportional hazard model.
While the proportion of men and women (about 40:60) was the same in CERAD as in UDS, approximately 17 percent of patients in the CERAD sample were under 65 years of age, 38 percent were between 65 and 74, and 45 percent were 75 or older. In contrast, the UDS sample had 12 percent under 65, 28 percent between 65 and 74, and 59 percent aged 75 or older.
Among the findings, the new analysis showed that the chance of progressing from mild AD to moderate AD in one year was 13 percent to 15 percent, depending on age and gender. In contrast, the older analysis found that 32 percent of patients progressed from MCI or mild AD — Clinical Disease Rating scores of 0.5 and 1.0 were grouped together — to moderate AD in one year.
In addition, the chance of progressing from severe AD to death was higher in the new analysis — 20 percent to 27 percent — compared with 15 percent in the older analysis. [For more data, see the table, “New Analysis: Yearly Change for AD Progression Rates.”]
“That could be due to the loss of follow-up of patients with the most severe disease stages or those transferring to nursing homes in the UDS,” Ms. Olchanski hypothesized. “They died or were so sick they couldn't come back,” she said.
Olchanski suggested that as a next step investigators could collect other scales to determine how progression happened by other measures — for example, MMSE (Mini-Mental State Exam), ADAS-Cog (Alzheimer's Disease Assessment Scale cognitive subscale), etc.”
Asked to comment on the findings, Sam Gandy, MD, PhD, Mount Sinai chair in Alzheimer's disease research at Mount Sinai School of Medicine and James J Peters VA Medical Center in New York, said: “One would predict that incidence per capita and rate of progression would be slowing down in the same way that stroke rates per capita are falling as cardiovascular health has been managed successfully since the development of statins.
“Some dementia is due to cerebrovascular disease and there is evidence that cerebrovascular disease exacerbates Alzheimer's. There is good reason to predict that improved general cardiovascular health will be reflected in reduced incidence per capita and/or slower rates of progression, but this is still speculation at this moment,” said Dr. Gandy, who is also director of the Mount Sinai Center for Cognitive Health and director of the NFL Neurological Center.
He noted that one of the goals of the Coalition Against Major Diseases (CAMD) — a project in which about a dozen pharmaceutical companies have agreed to pool placebo data to help guide researchers as they design clinical trials — is to find out whether dementia progression is slower now than it was 20 years ago. That analysis has not yet been done, though. Such information is critical for designing better trials, he said, noting that many researchers believe the failure of clinical trials for three AD therapies — bapineuzumab, tarenflurbil (Flurizan), and dimebon — resulted, at least in part, from the methodology used to evaluate them.