Elevated Amyloid in Cognitively Normal Predicts Later MCI, Dementia

Batya Swift Yasgur, MA, LSW

May 21, 2018

Elevated brain amyloid in individuals without dementia is associated with a dramatically higher risk for subsequent amnestic mild cognitive impairment (aMCI) and clinically diagnosed Alzheimer's disease (AD), new research shows.

Investigators studied a sample of community-dwelling adults drawn from the total community in Olmsted County, Minnesota, and found that among those without cognitive impairment, amyloid-positive people were more than twice as likely as amyloid-negative people to develop aMCI.

Those with MCI and amyloid positivity were almost twice as likely to develop AD dementia as those with MCI who were amyloid negative, and the dementia risk of amyloid-positive participants with no cognitive impairment or with aMCI was 2.6-fold higher.

"This is the first large-scale, community-based trial on cognitively unimpaired people and we are confident that from within this population, the people who agreed to imaging were pretty representative of the whole population," study author Ronald Petersen, MD, PhD, professor of neurology, Mayo Clinic College of Medicine and director, Mayo Clinic Alzheimer's Disease Research Center, Rochester, Minnesota, told Medscape Medical News.

"Our estimates of the progression from nonimpairment to amnestic mild cognitive impairment in amyloid-positive people may provide reliable and vital data to inform future research and, from a public health perspective, provide necessary information for the government regarding how many people have these characteristics, so that if an amyloid-based therapy for AD is developed, the magnitude of cost of Medicare/Medicaid coverage can be taken into account," he said.

The study was published online April 30 in JAMA Neurology.

Complete Capture

Elevated brain amyloid is considered to be a "key biomarker for AD pathology," the authors note.

Analyzing the prevalence of amyloid positivity in a population without dementia "provides reliable and valid estimates of the burden of AD pathology, which are useful for sample size estimations in designing primary and secondary AD prevention trials in persons without dementia," they write.

The researchers' "first objective" was to "estimate the prevalence of amyloid positivity in a population without dementia," and the second was "to estimate outcomes of amyloid positivity in a large, prospective, population-based cohort."

In 2004, the researchers established the Mayo Clinic Study of Aging (MCSA) cohort to identify risk factors for MCI and dementia (Neuroepidemiology. 2008;30:58-69; Neurology. 2010;75:889-997) and enumerated the 70- to 89-year-olds in Olmsted County.

Participants were selected for the study by using an age- and sex-stratified sample scheme; patients with terminal illness, hospice admission, or dementia were excluded.

Beginning in 2012, the study recruited people age 50 to 69 years to "determine the timing of onset of brain pathology and cognitive impairment," and people with dementia were recruited beginning in 2014.

Participants underwent a battery of cognitive and neurologic tests, diagnostic assessments to determine potential MCI and dementia, and measurement of covariates, such as weight, height, and apolipoprotein E (ApoE) ε4 status.

Participants also underwent amyloid positron emission tomography (PET) imaging, which was initiated in 2008 and used carbon-11 Pittsburgh compound B.

The researchers compared characteristics of participants of both sexes and several age groups who were amyloid positive or amyloid negative and who had or did not have cognitive impairment.

Logistic regression models were used to adjust for nonparticipation bias in the MCSA cohort, and a series of statistical tests were conducted to apply findings in the study sample to the findings in the population who did not participate in the study.

"One of the advantages of this study is that it is truly population-based, as compared to virtually all the good work done on amyloid imaging, which has been in a referral clinic, university, or multicenter setting," Petersen said.

Because Olmsted has only two medical facilities that provide care to the community, "we have a unique opportunity to have complete capture of everyone who lives in this community," he said.

Age and Sex

Of 3894 participants (mean [SD], 71.3 [9.8] years; 53.4% male), 1671 underwent PET imaging and were included in the study.

Compared with participants who underwent amyloid imaging, nonparticipants were older, were more frequently female, had fewer mean years of education, had higher rates of hypertension and strokes, and had lower global cognitive z scores.

Of the participants, 10.7% (n = 179) had prevalent MCI and 28.3% (n = 470) were ApoE ε4 carriers.

Compared with those who were amyloid negative, those who were amyloid positive more frequently had the ApoE ε4 allele, regardless of the absence or presence of MCI and regardless of age.

Among study participants without dementia, the prevalence of amyloid positivity increased with age, both in those without cognitive impairment (from

2.7% in the 50- to 59-year-old age group to 41.3% in participants aged 80 to 89 years) and in those with MCI (from 0% in the 50- to 59-year-old group to 16.4% at age 80 to 89 years).

The total prevalence of amyloid positivity across all ages was 22.0% (18.9% to 30.5%), with a higher total prevalence of amyloid positivity in women (25.6%; 95% CI, 20.8% - 30.5%) vs men (17.8%; 95% CI, 14.2% - 21.4%).

In models adjusted by age, sex, and education, the hazard ratios were 2.26 (95% CI, 1.52 - 3.35; P < .001) for both sexes combined, 1.96 (95% CI, 1.05 - 3.67; P = .04) for women, and 2.42 (95% CI, 1.46 - 4.04; P < .001) for men.

A Question of Magnitude

For amyloid-positive participants with MCI vs amyloid-negative participants with MCI, the risk for AD dementia was 1.86 (95% CI, 0.89 - 3.88; P = .10), while for amyloid-positive participants vs amyloid-negative participants with aMCI, the risk was 1.63 (95% CI, 0.78 - 3.41; P = .20).

Amyloid-positive vs amyloid-negative participants who were cognitively unimpaired or who had aMCI had a risk of 2.56 (95% CI, 1.35 - 4.88; P = .004).

In amyloid-positive people, global cognitive and memory domain z scores declined significantly during follow-up from baseline to incident aMCI and from aMCI to incident AD dementia (mean [SD] follow-up time, 3.7 [1.9] years and 3.8 [2.0] years, respectively).

"These findings are consistent with amyloid as a biomarker of AD dementia," the authors note.

During this period, a higher proportion of deaths occurred in amyloid-positive vs amyloid-negative participants.

"This study addresses the critical question from a scientific but also a public health perspective — if we found an amyloid therapy or amyloid antibody, what is the magnitude of the audience, what is the age range, and what does amyloid positivity mean in the general population?" Petersen said.

He noted that a limitation of the study was that most older participants were white, although younger participants tended to be more racially and ethnically diverse, and the findings may not be generalizable to other groups.

"We are currently establishing a population-based sister study in Jackson, Mississippi, which will be equally weighted with African Americans and Caucasians," he reported.

Setting the Stage

Commenting on the study for Medscape Medical News, William Klunk, MD, PhD, distinguished professor of psychiatry, University of Pittsburgh School of Medicine, Pennsylvania, who was not involved with the study, called it the "largest study to date that defines the consequences of being amyloid-positive prior to having dementia."

He noted that early studies of amyloid positivity have led to treatment trials, such as the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study,  "even before definitive proof that amyloid positivity carries a big enough risk of clinically significant cognitive decline to warrant expensive, risky therapy."

The data from this study "gives us better information upon which we can design trials that follow A4 and are also intended to 'prevent' AD," he added.

Petersen emphasized that he is "not recommending that cognitively unimpaired people should have an amyloid imaging because we do not yet know what the results might mean for each individual, and the psychological impact of that scan on individuals might be variable."

However, "we are setting the stage for how to interpret amyloid-related findings," he said.

Petersen reports receiving personal fees as a consultant for Roche Inc. The other authors' disclosures are listed on the original study. Klunk is the coinventor of the Pittsburgh Compound B that was used to identify amyloid positivity in this study.

JAMA Neurol. Published online April 30, 2018.  Abstract

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