Studies Examine Amyloid Deposits in Adults Groups
Two studies in the May 19 issue of JAMA analyze the prevalence of the plaque amyloid among adults of varying ages, both with and without dementia, and its association with cognitive impairment.

Alzheimer's disease (AD) is the most common cause of dementia, with a worldwide prevalence of about 25 million in 2010 that is expected to double by 2030 because of increased life expectancy. The earliest recognizable pathological event in AD is cerebral amyloid-β aggregation (protein fragments that clump together to form plaque). This pathology may be present up to 20 years before the onset of dementia. Prevalence estimates of amyloid pathology in people without dementia are needed to better understand the development of AD and to facilitate the design of AD prevention studies. Initiation of treatment for AD in the pre-dementia phase, when neuronal damage is still limited, may be crucial to have clinical benefit.

In one study, Willemijn J. Jansen, MSc, and Pieter Jelle Visser, MD, PhD, of Maastricht University, in Maastricht, the Netherlands, and colleagues used individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers (via PET or in cerebrospinal fluid) in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). Databases were searched to identify relevant biomarker studies, which were included if they provided individual participant data for participants without dementia. Individual records were provided for 2,914 participants with normal cognition, 697 with SCI, and 3,972 with MCI (ages 18 to 100 years) from 55 studies.

The researchers found that the prevalence of amyloid pathology increased from age 50 to 90 years from 10% to 44% among participants with normal cognition; from 12% to 43% among patients with SCI; and from 27% to 71% among patients with MCI. Apolipoprotein E (APOE)-ε4 (a gene associated with an increased risk of developing AD) carriers had two to three times higher prevalence estimates than noncarriers. The age at onset of amyloid positivity was associated with cognitive status and the APOE genotype. At age 90, about 40% of the APOE-ε4 noncarriers and more than 80% of APOE-ε4 carriers with normal cognition were amyloid positive.

The researchers wrote that this study has several implications for understanding the development of AD. "The observation that key risk factors for AD-type dementia are also risk factors for amyloid positivity in cognitively normal persons provides further evidence for the hypothesis that amyloid positivity in these individuals reflects early AD. … Our study also indicates that development of AD pathology can start as early as age 30, depending on the APOE genotype. Comparison with prevalence and lifetime risk estimates of AD-type dementia suggests a 20- to 30-year interval between amyloid positivity and dementia, implying that there is a large window of opportunity to start preventive treatments."

The authors note that the exact interval between the onset of amyloid positivity and onset of AD-type dementia needs to be assessed by long-term follow-up studies because not all people with amyloid pathology will develop dementia during their lifetime, and not all individuals with a clinical diagnosis of AD-type dementia have amyloid pathology. "Because of the uncertainty about whether and when an amyloid-positive individual without dementia will develop dementia, amyloid positivity in these individuals should not be equated with impending clinical dementia but rather be seen as a risk state. Our prevalence rates can be used as an inexpensive and noninvasive approach to select people at risk for amyloid positivity."

In another study, Rik Ossenkoppele, PhD, of VU University Medical Center in Amsterdam, the Netherlands, and colleagues used individual participant data meta-analysis to estimate the prevalence of amyloid positivity on PET in a wide variety of dementia syndromes.

The clinical utility of amyloid PET imaging is potentially limited by a proportion of patients with non-AD dementia and cerebral amyloid-β plaques. To correctly interpret the clinical significance of amyloid PET results, clinicians need to understand the prevalence of amyloid positivity across different types of dementia and how this is associated with demographic, genetic, and cognitive factors. Most amyloid PET studies to date come from single centers with modest sample sizes, according to background information in the article.

After a search of databases for amyloid PET studies, the authors included data for 1,359 participants with clinically diagnosed AD and 538 participants with non-AD dementia. The reference groups were 1,849 healthy control participants (based on amyloid PET) and an independent sample of 1,369 AD participants (based on autopsy).

In AD dementia, the average prevalence of amyloid positivity was 88%. The prevalence decreased with age from 93% at age 50 to 79% at age 90. This association differed according to APOE ε4 status. In APOE ε4 carriers, the prevalence remained at least 90% regardless of age, whereas the prevalence in noncarriers declined from 86% at age 50 to 68% at age 90. Similar associations of age and APOE ε4 with amyloid positivity were observed in participants with AD dementia at autopsy. In most non-AD dementias, amyloid positivity increased with both age (from 60 to 80 years) and APOE ε4 carriership.

"The main findings of this individual participant meta-analysis were that the prevalence of amyloid on PET decreased with age in participants diagnosed with AD (greatest in APOE ε4 noncarriers) and increased with age in most non-AD dementias. The convergence of amyloid positivity across dementias with increasing age suggests that amyloid imaging might have the potential to be most helpful for differential diagnosis in early-onset dementia, particularly if the goal is to rule-in AD dementia," the authors wrote.

"However, the high concordance between PET and pathology suggests that amyloid imaging might have the potential to be used to rule out AD dementia regardless of age. Furthermore, amyloid in non-AD dementia may be clinically important as amyloid positivity was associated with worse global cognition. Data from this study may inform research into the clinical application of amyloid PET and highlight the necessity of biomarker-based participant selection for clinical trials."
SOURCE: The JAMA Network