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Neurology Reviews. 2018 January;26(1):25, 29-31
LITERATURE REVIEW —Michele G. Sullivan
As Many as 47 Million Americans May Have Preclinical Alzheimer’s Disease
Researchers predict that 75.7 million Americans may be in one of the Alzheimer’s disease states by 2060.
A treatment that would reduce the risk of developing amyloid plaques in the brain by 50% could save more than four million Americans from mild cognitive impairment (MCI) and 2.5 million Americans from Alzheimer’s disease by 2060, according to a study published online ahead of print November 29 in Alzheimer’s & Dementia.
The conclusion that modestly effective preventive therapy could greatly improve the Alzheimer’s disease outlook is especially important, given another finding in a new mathematical modeling study by Ron Brookmeyer, PhD, a biostatistician at the University of California, Los Angeles, and colleagues. They assert that 47 million cognitively normal people in the United States may have brain amyloidosis, the physical finding used to define preclinical Alzheimer’s disease.
This study is the first to quantify the number of cognitively healthy US residents who could eventually experience cognitive changes that put them at risk of developing Alzheimer’s dementia, according to a statement from the Alzheimer’s Association.
Model Predicted Increase in Preclinical Alzheimer’s Disease
“This is the first major attempt to forecast these proposed preclinical Alzheimer’s disease and [MCI] due to Alzheimer’s disease numbers. If confirmed, these data [will] provide essential information for public health planning and for informing and guiding the public and private investment in Alzheimer’s and dementia research,” said Dr. Brookmeyer. “We need more research to confirm the findings from this model, and more Alzheimer’s disease and dementia research that includes diverse populations.”
“I want to emphasize that of the 47 million [people] with these Alzheimer’s brain changes, but without clinical symptoms, most will not progress to clinical disease during their lifetimes. In fact, perhaps only one in seven will progress to full-blown dementia.” Nevertheless, the numbers represent a reality that must be confronted and managed proactively, said Dr. Brookmeyer.
The results may sound alarming, he said, “but I have every confidence in them. And they are important because they allow us to understand how many people could potentially benefit from treatment, at what point on the disease continuum it would be useful to implement treatment, and how those treatments could impact public health.”
Studies Provided Rates of Transition Between Disease States
To create predictive models, Dr. Brookmeyer used data from two prospective longitudinal cohort studies: the Mayo Clinic Study of Aging and a study conducted by Stephanie J. Vos, PhD, a postdoctoral researcher at Maastricht University in the Netherlands.
The Mayo Clinic study followed 1,541 cognitively normal older adults and provided data on the rate of transition from normal cognition to MCI. The study by Dr. Vos and her associates followed 353 patients with MCI and brain amyloid and 222 patients with late MCI as they progressed. It is the largest prospective study of progression from MCI to Alzheimer’s disease that also contains data on baseline neurodegeneration and amyloid burden.
“These studies gave us the rates of transition from one state to another,” said Dr. Brookmeyer. “For example, the Mayo Clinic study gave us rates of transition from normal [health] to amyloidosis: 3% of normal 60-year-olds will convert to this state every year.”
Dr. Vos’s study determined rates of progression from MCI to Alzheimer’s dementia, given two preclinical states: asymptomatic amyloid brain plaques alone, or plaques with evidence of neurodegeneration and cognitive signs, said Dr. Brookmeyer. Both of these transitional states were first defined in 2011 in a joint paper by the Alzheimer’s Association and the National Institute on Aging. While acknowledging that the root causes of Alzheimer’s disease are unknown, the paper hypothesized a pathophysiologic time line beginning with a three-stage preclinical phase.
Asymptomatic cerebral amyloidosis is the first stage. It entails amyloid-positive PET brain imaging with an amyloid-binding ligand, a CSF assay with a low level of amyloid-beta 42 in the presence of normal cognition, or both. Stage 2 is one of amyloid positivity and evidence of synaptic dysfunction or early neurodegeneration in the presence of normal cognition. Finally, stage 3 entails amyloid positivity with evidence of neurodegeneration in the presence of subtle cognitive decline.
“Using those definitions, and piecing together the numbers from these studies, we constructed a computer model based on US census population projections to [estimate] how many people might be in these different states of disease,” said Dr. Brookmeyer.
In 2017, six million Americans were in one of the clinical disease states (ie, MCI due to Alzheimer’s disease, early clinical Alzheimer’s disease, or late clinical Alzheimer’s disease). Dr. Brookmeyer and his colleagues predicted that that number would grow to 15 million by 2060. Similarly, in 2017, about 47 million Americans were in one of the preclinical Alzheimer’s disease states, including 22 million with amyloidosis, 8.3 million with neurodegeneration alone, and 16.2 million with both. He projects that this number will increase to 75.7 million by 2060.
The team remodeled those numbers in three hypothetical intervention scenarios. Researchers say that a treatment that slows decline by at least 30% would have a meaningful clinical, financial, and societal impact. However, Dr. Brookmeyer modeled treatment scenarios with a greater effect.
A primary prevention method that reduced the annual risk of new amyloidosis by 50% could decrease the prevalence of MCI by about 700,000 in 2060. A secondary prevention strategy that reduced the annual risk progression to MCI by 50% would decrease the prevalence of MCI by more than two million and the prevalence of Alzheimer’s disease by about 3.8 million.
The results were more complicated with a secondary prevention strategy that would reduce annual risk of conversion from MCI to Alzheimer’s disease by 50%. In this scenario, the prevalence of MCI in 2060 would increase by 2.8 million, but the prevalence of Alzheimer’s disease would decrease by 2.5 million. These scenarios developed over different time courses, said the researchers.
“We find that the highly effective primary prevention strategy resulted in the lowest Alzheimer’s disease prevalence by the year 2060. However, [it] was associated with the largest Alzheimer’s disease prevalence in the 15 years immediately after its introduction ... The explanation for this finding is that the full benefits of delaying amyloidosis, in terms of reduced Alzheimer’s disease prevalence, are not realized for many years because of the long lag time between amyloidosis and clinical Alzheimer’s disease. A take-home message is that the full impact on disease burden of primary prevention that targets the early stages of the pathogenesis of Alzheimer’s disease may not be realized for decades.”
Decreasing preclinical conversion to MCI with a secondary prevention strategy would result in the highest Alzheimer’s disease prevalence reduction for most of the period. But the reduction resulting from the primary prevention strategy would surpass it by 2054.
The intervention targeting conversion from MCI to Alzheimer’s disease would reduce Alzheimer’s disease prevalence the quickest, with a slight decrease in the first three years after introduction. “The explanation for this finding is that MCI is proximate to clinical Alzheimer’s disease diagnosis, and thus the impact of delaying progression of MCI will be seen relatively quickly on Alzheimer’s disease prevalence, compared to interventions that delay onset of amyloidosis or MCI.
“By focusing attention on a concerning reality—that tens of millions of American adults may face the possibility of dementia due to Alzheimer’s disease—the results reported in this new article, if confirmed, illustrate and greatly amplify the need for more research to develop effective treatments and proven prevention strategies for Alzheimer’s disease,” said Dr. Brookmeyer. “This is especially true as we get better at early detection and are able to more accurately identify people who have the early brain changes associated with Alzheimer’s disease and other dementias.”
Dr. Brookmeyer reported receiving fees from Takeda for serving as a member of a data safety monitoring board.
—Michele G. Sullivan
Brookmeyer R, Abdalla N, Kawas CH, Corrada MM. Forecasting the prevalence of preclinical and clinical Alzheimer’s disease in the United States. Alzheimers Dement. 2017 Nov 29 [Epub ahead of print].
Derby CA, Katz MJ, Lipton RB, Hall CB. Trends in dementia incidence in a birth cohort analysis of the Einstein Aging Study. JAMA Neurol. 2017;74(11):1345-1351.
Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):280-292.
Vos SJ, Verhey F, Frölich L, et al. Prevalence and prognosis of Alzheimer’s disease at the mild cognitive impairment stage. Brain. 2015;138(Pt 5):1327-1338.