Up to 47 million Americans may have brain amyloidosis

A treatment that cut the risk of developing amyloid plaques in the brain by 50 percent could save more than 4 million US residents from mild cognitive impairment and 2.5 million from Alzheimer’s disease by 2060.

The conclusion that even modestly effective preventive therapy could vastly improve the Alzheimer’s outlook is especially important given another startling finding in a new mathematical modeling study. Right now, almost 47 million cognitively normal people in the United States may have brain amyloidosis, the physical finding used to define preclinical Alzheimer’s disease (AD).

The study, published online in Alzheimer’s & Dementia, is the first to quantify the number of cognitively healthy US residents who could eventually experience cognitive changes that put them on the path to Alzheimer’s Dementia, According to a statement released by the Alzheimer’s Association.

“This is the first major attempt to forecast these proposed preclinical Alzheimer’s disease and [mild cognitive impairment] due Alzheimer’s disease numbers,” “if confirmed, these data provide essential information for public health planning, and for informing and guiding the public and the private investment in Alzheimer’s and dementia research. We need more research to confirm the findings from this model, and more Alzheimer’s and dementia research includes diverse populations.”

In an interview, a biostatician at the University of California, Los Angeles, attempted to put those numbers into perspective.

“I want to emphasize that, of the 47 million 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 are disturbing and represented reality that must be confronted and managed proactively if at all possible.

“The numbers are what they are,” he said. “They may sound alarmist, but I have every confidence in them. And they’re 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.”

To carry out a modelling, a doctor extrapolated from data into two prospective longitudinal cohort studies: the Mayo Clinic Study of Aging, and one by Maastricht (the Netherlands) University.

The Mayo study followed 1,541 cognitively normal adults and provided data on the rate of transition from normal cognition to mild cognitive impairment (MCI). The study by Dr. Vos and her associates followed 353 subjects with MCI and brain amyloid, and 222 with late MCI as they progress.  It’s the largest prospective study of progression from MCI to AD and also contains data on baseline neurodegeneration and amyloid burden.

“These studies gave us the rates of transition from one state to another; for example, the Mayo study gave us rates of transition from normal to amyloidosis: 3% of normal 60-year-olds will convert to this state every year.”

The Vos study, determined rates of progression of MCI to Alzheimer’s dementia, given two preclinical states: asymptomatic amyoid brain plaques alone, or plaques with evidence of neurodegeneration and cognitive signs. Both of these transitional states were first defined in 2011 in a joint paper by Alzheimer’s Association and the National Institute of Aging. While acknowledging that the root cause of Alzheimer’s are unknown, and probably multifactorial, the paper hypothesized a pathophysiologic time line beginning with three-stage preclinical phase:

• Stage 1: Asymptomatic cerebral amyloidosis: amyloid – positive PET brain imaging with an amyloid-binding ligand and/or a cerebrospinal fluid assay with low-amyloid-beta 42 in the presence of normal cognition.

• Stage 2: Amyloid positivity and evidence of synaptic dysfunction and/or early neurodegeneration in the presence of subtle cognitive decline.

• Stage 3: Amyloids positivity with the evidence of neurodegenaration 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 projection to simulate how many people might be in these different states of disease.”

In 2017, 6 million Americans were in one of the clinical disease states (MCI due to AD, early clinical AD, or late clinical AD). Colleagues predicted the number will grow to 15 million by 2060. Similarly, in 2017, about 47 million American were in one of the preclinical AD states: 22 million with amyloidosis, 8.3 million with neurodegeneration, and 16.2 million with both. He projects that number will increase to 75.7 million by 2060.

The team then remodelled those numbers in three hypothetical interventions scenarios. In general, Alzheimer’s researchers says a treatment that slows decline by 30% would have a meaningful clinical, financial, and societal impact. However they modelled treatment scenarios with a greater effect than that.

A primary prevention that reduced the annual risk of new amyloidosis by 50% would decrease the prevalence of MCI by more than 2 million and the prevalence of AD by 3.8 million.

The results were more complicated with a secondary prevention strategy that would reduce annual risk of MCI-AD conversion by 50%. In this scenario, the prevalence of MCI in 2060 would actually increase by 2.8 million, but the prevalence of AD would decrease by 2.5 million.

These scenarios also developed over different time courses, the researchers wrote.

“We find that the highly effective primary prevention strategy resulted in the lowest AD prevention strategy resulted in the lowest AD prevalence by the year 2060. However [it] was associated with the largest AD prevalence in 15 years immediately after the introduction. The explanation for this finding is that the full benefits of delaying amyloidosis in terms of reduced AD prevalence are not realized for many years because of the long lag time between amyloidosis and clinical AD. A take-home message is that the full impact on disease burden of primary prevention that targets the early stages of these pathogenesis of AD on clinical disease burden may not be realized for decades.”

Decreasing preclinical conversion to MCI with a secondary prevention strategy would result in the highest AD prevalence reduction for most of the period. But by 2054, the primary prevention strategy would surpass it.

The intervention targeting the MCI-Ad conversion would reduce AD prevalence the quickest, with a slight decrease in the first 3 years after introduction.

The study sharply illustrates two futures: one with unimpeded tsunami of Alzheimer’s cases, and one in which prevention strategies, while not a floodgate, at least stem the tide somewhat. And while researchers hold out for the primary and secondary treatment currently in clinical trials, the AD community is nowhere close to finding even a modestly effective therapy.