Including nearly 20,000 participants, the largest study on amyloid prevalence to date estimates that a third of cognitively normal people older than 70 have amyloid building up in their brains.
Published January 31 in JAMA Neurology and led by Olin Janssen and Willemijn Jansen at Maastricht University in the Netherlands, the meta-analysis compiled amyloid PET and cerebrospinal fluid (CSF) biomarker data from participants in research and memory clinic cohorts that are part of the Amyloid Biomarker Study, an ongoing, international, data-sharing initiative that started in 2013. The new analysis doubles the size of a 2015 meta-analysis published by the same group.
Among other findings, it reports that even among cognitively sharp 50-year-olds, 17 percent already have amyloid, and that CSF Aβ42 bested amyloid-PET in detecting amyloid build-up, at least among people without dementia. For those with AD dementia, amyloid-PET outperformed CSF Aβ42.
Elderly couple. Image credit: Bicanski via Pixnio, CC0 Public Domain
In 2015, the Amyloid Biomarker Study published two separate meta-analyses of amyloid prevalence. In one, the researchers combined data from 91 studies that measured amyloid in more than 7,500 people without dementia, and in the other, they meta-analyzed data from studies of more than 1,800 people with different types of dementia, including AD (May 2015 news). They found that among people without dementia, amyloid prevalence rose with age, and was higher among ApoE4 carriers.
Overall, the study found that whether amyloid status was determined by amyloid-PET or CSF Aβ42, one-quarter of people with normal cognition or subjective cognitive decline had amyloid plaques, as did half of people with mild cognitive impairment, and nearly 90 percent of people with a clinical diagnosis of AD dementia. This percentage decreased at high ages, likely due to the increasing prevalence of non-amyloid pathologies that contribute to dementia in older people.
At 19,097 participants, the 2022 study more than doubles the size of the previous one. Jansen and Janssen and colleagues compared amyloid prevalence across age, cognitive status, ApoE genotype, and by biomarker modality (i.e., CSF versus PET). A total of 10,139 participants in 50 cohorts had undergone amyloid-PET scans, while 8,958 participants across 51 cohorts had had CSF Aβ42 measured; only 1,571 underwent both.
When the researchers relied on the cutoffs for amyloid positivity provided by each cohort included in the meta-analysis, they arrived at similar estimates of amyloid prevalence as they had in 2015. Among those without dementia, amyloid cropped up in 24 percent of those with normal cognition, 27 percent of people with subjective cognitive decline, and 51 percent of people with MCI.
Findings were similar whether amyloid-PET or CSF Aβ42 was used. However, when the scientists recalculated cutoffs based on the distribution of biomarker measurements observed in each cohort, they found that CSF Aβ42 flagged 10 percent more amyloid-positive cases than did PET, raising the prevalence in cognitively normal people to a third. This difference between PET and CSF may change once newer fluid marker assays become widely adopted.
Amyloid prevalence increased with age among those without dementia. For example, based on the adjusted CSF Aβ42 measurements, 17 percent of cognitively normal people between the ages of 50-54 had evidence of amyloid. By age 70, a third did, and by age 95, more than half did.
“These patterns imply that at least during the early stages of AD and before dementia onset, CSF may be a more sensitive marker of amyloid accumulation than PET,” wrote Christina Young and Elizabeth Mormino of Stanford University in a JAMA Neurology editorial. “This finding is consistent with work showing that discordant cases with CSF-based amyloid positivity and PET-based amyloid negativity are more likely to become amyloid-positive on PET at follow up,” they added. Work from other groups also indicates that CSF Aβ levels drop before plaques can be detected by PET (Aug 2016 conference news).
The size of this study gave the researchers enough statistical power to compare amyloid prevalence across different ApoE genotypes. E4/E4 carriers started accumulating amyloid at the youngest age, followed by E3/E4, E2/E4, E3/E3, and E2/E3 carriers. Notably, the amyloid prevalence among E3/E4 carriers was 10 percent higher than it was among E2/E4 carriers across all groups without dementia, highlighting a protective effect of the E2 allele that had not been observed in the smaller, 2015 study.
For people with a clinical diagnosis of AD dementia, the trends were different. For one, amyloid-PET consistently detected a slightly higher percentage of amyloid-positive people than did CSF Aβ42, even when the scientists recalculated the cutoffs. As reported in 2015, the prevalence of amyloid dipped slightly with advancing age among those with AD dementia, ranging from 91 percent at age 50 to 81 percent by age 95. However, in the current study, this dip was no longer statistically significant. ApoE4 carriers with dementia were more likely to harbor amyloid pathology than their noncarrier counterparts, with a prevalence of 97 percent for homozygotes, 87 percent for heterozygotes, and 80 percent for noncarriers.
As in 2015, amyloid accumulation was similar between the sexes, regardless of age or cognitive status. Among those without dementia, people with more education tended to have more amyloid, suggestive of cognitive reserve in the face of pathology. In people with AD dementia, educational level correlated with more amyloid, but only up to age 60.
“Overall, the present study is valuable because it reflects a large, coordinated effort across 85 cohorts to estimate the prevalence of abnormal amyloid accumulation, an initial key pathological change of AD,” wrote Mormino and Young. “These prevalence estimates can improve recruitment efficiency for clinical trials that target individuals with biomarker positivity.” However, they noted that at the group level, amyloid alone is insufficient to indicate future clinically meaningful progression.
Young and Mormino bemoaned that the study lacks information about race and ethnicity. “It is alarming that a large-scale effort that examined the data of more than 19,000 individuals and characterized them by PET or CSF measures was not positioned to report the role of race and ethnicity or the proportion of individuals composing various racial and ethnic groups to give a sense of the cohort’s demographic characteristics and generalizability of findings,” they wrote.
Gil Rabinovici, University of California, San Francisco, agreed, noting that 94.6 percent of the participants came from North America and Europe. “We must do better as a field in recruiting a more diverse, global, and representative sample of research participants to AD biomarker studies,” he wrote (comment below).
Particularly for people in the younger age groups without dementia, the present study found a significantly higher proportion with amyloid pathology than did a smaller, population-based study by the Mayo Clinic Study of Aging (Roberts et al., 2018). While Jansen et al. report that 17 percent of cognitively normal people in their 50s had amyloid, the MCSA study found that only 3 percent in this age group did. Jansen and colleagues found the prevalence of amyloid was also much higher in people with MCI than was reported by the MCSA scientists.
The authors attribute the discrepancy to differences in the study populations. Whereas the MCSA is a population-based survey of Olmsted County, Minnesota, the Jansen study comprised numerous research-based and clinical cohorts—likely to be flush with people concerned about their cognitive health.—Jessica Shugart
Source: Alzforum