Amyloid Pathology Starts at Age 50, PET Scans Reveal

Fran Lowry

May 19, 2015

By age 50 years, 10% of individuals with normal cognitive function are storing amyloid in their brain, and by age 90 years, 44% of individuals show evidence of amyloid, a harbinger of Alzheimer's disease (AD).

Moreover, people start to store amyloid in their brain decades before the onset of dementia, with individuals who possess the apolipoprotein E ε4 genotype (APOE-ε4) most vulnerable to amyloid aggregation.

These findings, from two new meta-analyses of the prevalence of amyloid pathology shown on positron-emission tomography (PET) scans of the brain, were published in the May 19 issue of JAMA.

Early Treatment

Dr Pieter Jelle Visser

"The finding that amyloid aggregation starts decades before the onset of dementia gives an opportunity for early treatment in the future, but such treatments are not available yet," senior author of the first study, Pieter Jelle Visser, MD, PhD, from Maastrict University in the Netherlands, told Medscape Medical News.

"APOE genotype has a strong impact on amyloid aggregation and could be a target for treatment," added the lead author on that article, Willemijn Jansen, MSc, also from Maastricht University.

Willemijn Jansen

"We wanted to study the prevalence of amyloid pathology in the brains of people who do not have dementia because there have been conflicting findings on this prevalence," Jansen told Medscape Medical News. "Previous studies were typically small or used variable methods," she said.

The researchers pooled data from 55 studies published before April 2015 into a large dataset of 7000 subjects.

They then calculated the prevalence for amyloid positivity by age, as well as how this positivity was dependent on APOE genotype, sex, and education.

The analysis showed that the prevalence of amyloid pathology increased from age 50 years to age 90 years in patients with normal cognition, subjective cognitive impairment, and mild cognitive impairment (MCI).

Table. Prevalence of Amyloid Pathology With Age by Cognitive Status

Cognitive Status Age 50 Years (%; 95% Confidence Interval) Age 90 Years (%; 95% Confidence Interval)
Normal (n = 2914) 10 (8-13) 44 (37-51)
Subjective cognitive impairment (n = 697) 12 (8-18) 43 (32-55)
MCI (n = 3972) 27 (23-32) 71 (66-76)

Carriers of APOE-ε4, a gene allele associated with an increased risk of developing AD, had two to three times higher prevalence estimates than noncarriers.

APOE-ε4 carriers also showed evidence of amyloid positivity at an earlier age.

The age at which 15% of the participants with normal cognition were amyloid-positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers.

Amyloid positivity was more common in highly educated participants but was not associated with sex or biomarker modalities.

"Nondemented individuals with a high level of education have a greater cognitive reserve, which lets them sustain more amyloid pathology before showing signs of dementia," Dr Visser said.

"Another reason for the finding could be that highly educated people with amyloid pathology may be overrepresented in the studies or in clinical care seeking due to self-selection bias," he said.

Studies are ongoing to determine whether targeting APOE will slow the development of AD, Dr Visser said.

"The idea is to make carriers of the APOE-ε4 variant more APOE-ε2-like, because that variant binds amyloid better than the APOE-ε4 variant," he said.

"Doctors can discuss in subjects with MCI that they could be tested for amyloid pathology if they so wish," Jansen said.

"A subject with MCI has a 50% risk for [AD]. By testing for amyloid pathology, the uncertainty can be reduced. In the case of amyloid positivity, there is a very high risk for [AD], and in the case of normal amyloid, there is a very low risk for [AD]," she said.

"Amyloid-positive subjects are likely to decline to dementia, but that can still vary between 0.5 to 10 years," Dr Visser said.

There is no need to screen all individuals with a PET scan, he added.

"Screening depends, so for subjects with normal cognition or those with subjective cognitive impairment, I would say no to PET screening. Patients with mild cognitive impairment could be screened only if the patient wants to know the underlying pathology, but they should not be screened routinely, either. Patients with dementia should undergo PET if the underlying pathology is unclear."

PET Tracers

The second study was led by Rik Ossenkoppele, PhD, from VU University Medical Center, Amsterdam, the Netherlands.

Dr Ossenkoppele and colleagues used individual participant data meta-analysis of amyloid studies using MEDLINE and Web of Science databases from January 2004 to April 2015 to estimate the prevalence of amyloid positivity on PET in a wide variety of dementia syndromes.

Dr Rik Ossenkoppele

"Since 2004, several PET tracers have been developed that measure fibrillary amyloid-β plaques, a neuropathological hallmark of [AD]," Dr Ossenkoppele told Medscape Medical News.

This has allowed physicians to determine the presence or absence of amyloid pathology in the living human brain, but because a proportion of patients have other types of dementia other than [AD], this limits the clinical use of amyloid imaging, he said.

"When ordering amyloid PET scans, and in order to correctly interpret the significance of amyloid PET results, clinicians need to understand the prevalence of amyloid positivity across different types of dementia," he said.

"It is also important to be aware of the relationships of amyloid-positivity prevalence and demographic factors such as age and sex, cognitive, and genetic factors; for instance, the presence of the [AD] risk allele apolipoprotein E-ε4," Dr Ossenkoppele said.

Most amyloid PET studies done to date are from single centers with modest sample sizes. The data for the current study came from 29 cohorts worldwide, including 1359 patients with clinically diagnosed AD and 538 patients with non-Alzheimer's dementia.

Also included were 1849 healthy control patients with amyloid PET data and an independent sample of 1369 patients with AD with autopsy data from the National Alzheimer's Coordinating Center database.

The researchers found that in AD dementia, the average prevalence of amyloid positivity was 88%. The prevalence decreased with age, from 93% at age 50 years to 79% at age 90 years.

This association differed according to APOE-ε4 status. In APOE-ε4 carriers, the prevalence remained 90% or higher regardless of age, whereas the prevalence in noncarriers declined from 86% at age 50 years to 68% at age 90 years.

Similar associations of age and APOE-ε4 with amyloid positivity were observed in participants with AD dementia at autopsy.

In addition, in most non-AD dementias, amyloid positivity increased with both age, from 60 to 80 years, and APOE-ε4 carriership.

"Diagnosis, age, and APOE-ε4 are important factors to take into account when ordering and interpreting clinical amyloid PET scans," Dr Ossenkoppele said.

"Further, the convergence of amyloid-positivity between AD and non-AD dementias with increasing age suggests that amyloid imaging may be most useful for differential diagnosis in patients with early-onset dementia before age 65, since the risk of incidental amyloid pathology is relatively low in young patients," he said.

Dr Ossenkoppele added that the correspondence of amyloid positivity in patients with AD with PET, as well as at autopsy, was "reassuringly high," and that this suggests that amyloid imaging can be "used to rule out AD as the causative pathology, regardless of age."

Ordering an amyloid PET scan is not justified in known APOE ε4 carriers diagnosed with AD, as the prevalence of amyloid positivity in this group is more than 90%, regardless of age, he noted.

"On the other hand, amyloid PET may be informative in APOE ε4 noncarriers over age 70 with a clinical diagnosis of [AD], since the prevalence of amyloid-positivity declined to 78% and further decreased to 68% at age 90," Dr Ossenkoppele said.

"Considerable Clinical Value"

In an accompanying editorial commenting on both studies, Roger N. Rosenberg, MD, from University of Texas Southwestern Medical Center, Dallas, writes that the authors "provide succinct meta-analyses of considerable clinical value."

The data from both studies "show the immense potential clinical use of amyloid imaging to make the correct diagnosis in early-onset dementia and, more specifically, to establish the diagnosis of AD-type dementia and noncarrier APOE-ε4 genotype among persons older than 70 years," Dr Rosenberg writes.

"It is important to identify the reason why people are having difficulty with memory and thinking, and to ascertain that these individuals are or are not storing amyloid by doing a PET scan," he told Medscape Medical News.

"If they are storing amyloid, then they are at risk for [AD]," he said.

"These studies go towards helping us solve the old conundrum of deciding who has Alzheimer's and who has another type of dementia. Also, if you are testing drugs for efficacy in the treatment of [AD], then you want to make sure all of your study subjects are storing amyloid and are truly at risk for AD," Dr Rosenberg said.

Dr Visser reports a financial relationship with GE Healthcare to fund an amyloid PET study in nondemented subjects. Jansen and Dr Ossenkoppele have disclosed no relevant financial relationships. Dr Rosenberg reports that he is doing research to develop a DNA vaccine to prevent AD in persons at risk. Complete conflict-of-interest information is available in the individual articles.

JAMA. 2015;313:1913-1914, 1924-1949. Jansen abstract, Ossenkoppele abstract, Editorial extract

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