Two meta-analyses offer up the largest data sets to date on how commonly amyloid builds up in people’s brains. Published May 19 in JAMA and led by Pieter Jelle Visser at VU University Medical Center in Amsterdam and Maastricht University, both in The Netherlands, the two studies compiled amyloid PET and cerebrospinal fluid (CSF) biomarker data from thousands of participants. One meta-analysis looked at the prevalence of amyloid in cognitively normal people, and concluded that amyloid creeps into the brain 20 to 30 years before dementia can be diagnosed. This was particularly true for people who carry an ApoE4 allele; indeed, they developed amyloid at a younger age. In their second study, Visser and colleagues compared amyloid prevalence among people clinically diagnosed with AD or other dementias, including dementia with Lewy bodies, frontotemporal dementia, and corticobasal syndrome. They found that the prevalence of brain amyloid in people diagnosed with most non-AD dementias was higher with increasing age. They concluded that older people may be likelier to have multiple pathologies, or to have been misdiagnosed. The data may help researchers set inclusion criteria for clinical trials, or make better diagnoses.
“These are outstanding meta-analyses,” commented Michael Weiner of the University of California, San Francisco. The lag between the appearance of amyloid and the onset of dementia is a bit longer than previous estimates, Weiner wrote. He also cited limits on interpreting the results—such as the study’s cross-sectional design and the idea that people with high cognitive reserve may stave off dementia longer than others. “The final answer will come from large longitudinal studies,” he wrote.
Knowing the prevalence of amyloid pathology in people without dementia is crucial for designing AD prevention trials. Anywhere from 10 to 60 percent of people without dementia harbor amyloid plaques upon autopsy, and studies that rely on biomarkers, such as amyloid PET or CSF Aβ42, as a proxy for amyloid are equally variable (see Murayama et al., 2004; Bennett et al., 2005; Lin et al., 2009; Rowe et al., 2010; Randall et al., 2013). Another problem that dogs trial design is misdiagnosis and/or mixed pathology. Some people diagnosed with AD have turned out to harbor no amyloid in the brain, whereas some others diagnosed with a non-AD dementia do have underlying amyloid pathology that could be a factor in their disease. Moreover, this issue can make it difficult for a physician to choose the best course of treatment for a given patient.
Visser sought to clarify and bring consensus to these issues by performing the two meta-analyses. To assess the prevalence of amyloid positivity in people without dementia, first author Willemijn Jansen of Maastricht University, The Netherlands, and colleagues scoured the literature for studies that assessed amyloid PET and/or CSF Aβ42, and ApoE status. They identified 91 papers; of these, the authors of 54 agreed to share participant-level data, while another shared group-level data. These 55 papers included 45 single-center and 10 multicenter cohorts. About half of the studies used amyloid-PET and half CSF Aβ42. They included 7,583 participants, of whom 2,914 were cognitively normal, 697 had subjective cognitive impairment (SCI), and 3,972 were diagnosed with mild cognitive impairment (MCI).
In people with normal cognition, the prevalence of amyloid increased with age, from 10 percent in 50-year-olds to 23 percent in 70-year-olds to 43 percent in nonagenarians. The prevalence was similar among people with SCI, but double that in the MCI group. This suggests that MCI, though defined somewhat differently across reports in the meta-analysis, represents a true stage on the AD spectrum, while SCI does not, the authors concluded.
In general, the prevalence of amyloid was two to three times greater in ApoE4 carriers than non-carriers. The exact number of this increased prevalence depended on their age and cognitive diagnosis. The gap between ApoE4 carriers and non-carriers widened with age, and was similar among people with normal cognition, SCI, or MCI. Age-related prevalence differed across ApoE genotypes. For example, the age at which 15 percent of participants with normal cognition tested positive for amyloid was 40 years for E4/E4 carriers, and then steadily increased among E2/E4, E3/E4, E3/E3, and E2/E3 carriers, who were over 85 (see figure below). None of the 10 E2/E2 carriers included in the analysis had amyloid. While the E2 allele fended off amyloid, this protection crumbled when the E4 allele was also present, as the difference in amyloid prevalence between E2/E4 and E3/E4 carriers was not significant. Among 90-year-olds with normal cognition, 40 percent of ApoE4 non-carriers and 80 percent of carriers had amyloid. The researchers obtained similar results from studies that used amyloid PET or CSF Aβ42.
ApoE: the 600-Pound Gorilla? People carrying the ApoE4 allele were more likely to become amyloid positive earlier in life. Shading indicates 95 percent confidence interval for each curve. [Image courtesy of Jansen et al., copyright 2015 American Medical Association.]
Years of education also affected amyloid. Its prevalence was 5 percent higher among cognitively normal 70-year-olds with above-average education than among their less-educated peers. This result agrees with the idea of cognitive reserve, the researchers said, because education could protect people from the damaging effects of amyloid pathology, allowing them to remain cognitively normal with a higher amyloid burden than less-educated people. Finally, the researchers compared the prevalence of amyloid with that of Alzheimer’s dementia. As has been reported by the Australian Imaging, Biomarkers, and Lifestyle (AIBL) study, the Dutch meta-analysis also found that amyloid precedes dementia by about 20 years. In other words, if the prevalence of amyloid positivity is 30 percent at age X in a given population, then that same population’s prevalence of dementia is 30 percent at age X+20 years.
“This study is the most definitive statement to date on the prevalence of amyloid and how it relates to ApoE,” commented Christopher Rowe of the University of Melbourne in Australia. He said the large numbers of participants in the studies bring more certainty to previously reported findings. “The information is important, not only for researchers, but for identifying appropriate cohorts for clinical trials,” said Rowe, who contributed amyloid PET data from more than 200 people in AIBL to the meta-analysis.
In the second paper, first author Rik Ossenkoppele of VU University Medical Center in Amsterdam meta-analyzed rates of amyloid positivity in people with AD or other dementias. They searched the literature for studies that assessed amyloid PET, ApoE genotype, and listed dementia diagnoses that were based on clinical criteria, rather than the results of the PET scan. In all, they analyzed 185 articles on 29 cohorts of patients. Of the 1,897 patients, 1,359 were clinically diagnosed with AD, 288 with frontotemporal dementia (FTD), 138 with vascular dementia (VaD), 51 with dementia with Lewy bodies (DLB), and 61 with corticobasal syndrome (CBS). As reference populations, the researchers also incorporated data on 1,849 healthy controls, and 1,369 patients with confirmed AD at autopsy.
People diagnosed with AD had the highest prevalence of amyloid—88 percent. Interestingly, prevalence was higher in younger people, ranging from 93 percent in 50-year-olds to 79 percent in 90-year-olds. The likeliest explanation for this trend, Visser speculated, is misdiagnosis. The prevalence of other pathologies that mimic AD, such as hippocampal sclerosis, increases with age, he noted. This means older people may be more likely to be misdiagnosed with AD than younger people who are at a lower risk for these other morbidities. Claudia Kawas of the University of California, Irvine, agreed with that hypothesis. She added that despite the low numbers of very old people included in the studies, the results agreed with observations from the 90+ Study of the oldest old: “Amyloid positivity increases with age and with ApoE4, but its relationship with dementia diminishes with age,” Kawas said. Another possible explanation is that some older people had low levels of amyloid pathology that were not detected on the scans, yet due to their age were enough to cause dementia, Visser offered.
Clifford Jack of the Mayo Clinic in Rochester, Minnesota, who was not involved in the study, melded these two possibilities together. He suggested other pathologies make older people more susceptible to the effects of amyloid. “Young people need a lot of AD pathology to become demented because they have few other pathologies driving down cognition,” he wrote. “An older person with a little amyloid (i.e., AD pathology) can become demented because of the presence of additional age-related pathologies.”
Among ApoE4 carriers diagnosed with AD, amyloid prevalence was consistently 90 percent, regardless of age. Autopsy data on AD patients revealed similar rates of amyloid positivity as the PET scans did.
Amyloid varied considerably across non-AD dementias. For example, 51 percent of people diagnosed with DLB harbored amyloid, as did 30 percent of people with VaD, 12 percent of people with FTD, 38 percent of people with CBS, and 22 percent of healthy controls. Therefore, all dementias except FTD had higher amyloid prevalence than healthy controls did. In contrast to the trend seen in AD patients, people with DLB, VaD, or FTD had increasing amyloid prevalence with age (see figure below). Corticobasal syndrome was the exception; like people with AD, older CBS patients were less likely to have amyloid. Across all syndromes, amyloid prevalence was higher in ApoE4 carriers than non-carriers.
What does amyloid in people with non-AD dementias mean? They may have been misdiagnosed and had AD, or they may have had AD pathology in addition to the dominant pathology that drove their other diagnosis. While either of these possibilities could be true for a given person, Visser speculated that mixed pathology is more likely. While amyloid prevalence increases with age in people with non-AD dementias just as it does in cognitively normal people, he believes another disease-specific pathology, such as tau or TDP-43, could dictate the course of their diseases and diagnoses. This is not to say that amyloid does not affect those with non-AD dementia—in fact, the presence of amyloid correlated with lower MMSE scores in these groups. People with non-AD dementia who also harbor amyloid could have AD or prodromal AD in addition to their other condition, Visser said.
In the case of CBS, Visser said the underlying pathology of the disease is highly heterogeneous. At autopsy, amyloid plaques were revealed as the primary driver of the disease in 25 percent of patients (see Dickson et al., 2002; Lee et al., 2011). Visser speculated that amyloid drives the disease in younger people diagnosed with CBS, while tau predominates in the older population. This will become clear as tau tracers become available, he said.
David Holtzman of Washington University in St. Louis, who was not involved in the study, offered similar explanations for the trends. “Amyloid deposition gets more common the older one is after age 50 in cognitively normal people, so it is not surprising it gets more common in the setting of these other diseases with aging,” he wrote to Alzforum. “In corticobasal syndrome, the syndrome may be due to AD. In the case of FTD and vascular dementia, it may be that many of these people are developing preclinical AD, which gets more common the older people are.” (See full comment below.)
What does this data mean for the use of PET scans in diagnosis? It more sharply defines its usefulness in certain subgroups. For example, the rise in amyloid positivity with age among most non-AD dementias indicates that amyloid PET scans may be less useful for differential diagnosis at older ages, Visser said. “In elderly subjects, the ability of amyloid positivity to differentiate between AD and other conditions becomes weak,” he said. In the case of ApoE4 carriers with a diagnosis of AD, PET scans may be unnecessary to confirm a diagnosis, given that 90 percent of them will have amyloid regardless of their age, he added.
“The value of these observations is that amyloid imaging may be most critical in making the correct diagnosis in early onset dementia, especially to rule in AD dementia,” wrote Roger Rosenberg from the University of Texas Southwestern Medical Center at Dallas in an accompanying editorial in JAMA. He added that the data will aid in the design of prevention trials.—Jessica Shugart
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