From the Journals

Up to 47 million Americans may have “preclinical” Alzheimer’s disease, study estimates

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Study heightens awareness but at what cost?

The study by Brookmeyer and colleagues is a logical and thoughtful attempt to “size” the potential impact of Alzheimer’s disease now and in the future, updating “old technology” estimates based on actual diagnoses with new technologically derived diagnoses of preclinical neurodegenerative states. They acknowledge that the uncertainty in the actual disease burden we will face is centered on the question of conversion rates, which vary between studies and are far less certain in the preclinical stages than the symptomatic ones.

Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic in Scottsdale, Ariz., and associate director and clinical core director of Mayo’s Alzheimer’s Disease Center.

Dr. Richard J. Caselli

Scientific interest aside, the main purpose of an article like this is to heighten awareness and concern by demonstrating that symptomatic AD is literally the tip of a much larger iceberg and so warrants more funding for research (and clinical care). The worry that articles like this create for me however – or rather the media attention they garner – is that they potentially contribute to a growing public panic at a time when we still lack truly meaningful therapy. As a doctor, I want to give my patients with mild cognitive impairment and dementia some reason to believe they still have a meaningful life and that there is hope rather than having them feel I have just pronounced a death sentence.

The attention paid by the Alzheimer’s Association is understandable given its mission of increasing awareness and supporting more funding, but it omits mention of another important article that is showing that dementia rates are actually declining (JAMA Neurol. 2017;74[11]:1345-51) when adjusted for our aging population (observed vs. expected).

In my opinion, we need some rational balance between maintaining public awareness without creating unnecessary panic. There is no question that AD is a major public health issue that warrants all the funding we can provide to researchers seeking a cure. How to balance that need with the need to give our population hope that all is not lost when they misplace their keys is the challenge this article raises in my mind.

Richard J. Caselli, MD, is professor of neurology at the Mayo Clinic Arizona in Scottsdale. He is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center. He has no relevant disclosures.



A treatment that would cut the risk of developing amyloid plaques in the brain by 50% could save more than 4 million U.S. 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 by Ron Brookmeyer, PhD, and his colleagues: Right now, they assert, almost 47 million cognitively normal people in the United States may have brain amyloidosis, the physical finding used to define preclinical Alzheimer’s disease.

Dr. Ron Brookmeyer UCLA Fielding School of Public Health

Dr. Ron Brookmeyer

The study, published online in Alzheimer’s & Dementia, is the first to quantify the number of cognitively healthy U.S. 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 to Alzheimer’s disease numbers. If confirmed, these data provide essential information for public health planning, and for informing and guiding the public and 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 that includes diverse populations.”

In an interview, Dr. Brookmeyer, a biostatistician 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 1 in 7 will progress to full-blown dementia.”

Nevertheless, the numbers are disturbing and represent a reality that must be confronted and managed proactively if at all possible, Dr. Brookmeyer said.

“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 the modeling, Dr. Brookmeyer extrapolated from data in two prospective longitudinal cohort studies: the Mayo Clinic Study of Aging, and one by Stephanie J. Vos, PhD, of Maastricht (the Netherlands) University.

The Mayo study followed 1,541 cognitively normal older 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 progressed. It’s the largest prospective study of progression from MCI to AD that also contains data on baseline neurodegeneration and amyloid burden (Brain. 2015;138[5]:1327-38).

“These studies gave us the rates of transition from one state to another,” Dr. Brookmeyer said. “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, Dr. Brookmeyer said, 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. 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 (Alzheimers Dement. 2011;7[3]:280-92). While acknowledging that the root causes of Alzheimer’s are unknown, and probably multifactorial, the paper hypothesized a pathophysiologic time line beginning with a 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 normal cognition.

• Stage 3: 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 U.S. census population projections to simulate how many people might be in these different states of disease,” Dr. Brookmeyer said.

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

The team then remodeled those numbers in three hypothetical intervention scenarios. In general, Alzheimer’s researchers say 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 than that.

A primary prevention 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 2 million and the prevalence of AD by about 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 prevalence by the year 2060. However, [it] was associated with the largest AD 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 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 the 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 MCI-AD conversion would reduce AD prevalence the quickest, with a slight decrease in the first 3 years after introduction. “The explanation for this finding is that MCI is proximate to clinical AD diagnosis, and thus, the impact of delaying progression of MCI will be seen relatively quickly on AD prevalence compared to interventions that delay onset of amyloidosis or MCI.”

The study sharply illustrates two futures: one with an 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 hope for the primary and secondary treatments currently in clinical trials, the AD community is nowhere close to finding even a modestly effective therapy.

Seen in this light, Dr. Brookmeyer’s projections are a cry for action, the Alzheimer’s Association statement proclaimed.

“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. 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.

SOURCE: Brookemeyer R et al. Alzheimers Dement. 2017 Dec 6. doi: 10.1016/j.jalz.2017.10.009

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