APOE4 Not the Only Gene Tied to Amyloid in Alzheimer's

Pauline Anderson

January 22, 2018

A comprehensive genetic study has shed new light, not only on the role of the apolipoprotein ε4 (APOE 4) allele in brain amyloid deposition but also on the importance of other genes in this process as it relates to Alzheimer's disease (AD).

Investigators found that the adenosine triphosphate–binding cassette subfamily A member 7 (ABCA7) gene has the strongest association with amyloid deposition after APOE4 and that the fermitin family homologue 2 (FERMT2) gene is linked to amyloidosis, but only in early stages of AD.

Dr Liana Apostolova

Determining the impact of the AD risk genes on amyloid deposition or other disease processes is an important step toward developing new drug targets, lead author Liana Apostolova, MD, Barbara and Peer Baekgaard Professor in Alzheimer's Disease Research, and professor of neurology radiology, medical and molecular genetics, Indiana University School of Medicine, Indianapolis, told Medscape Medical News.

"As we gain a better understanding of the genetics of Alzheimer's disease, and more studies like this are conducted, down the road we will be able to predict which patients will develop the disease and which won't. Also, knowing which variants are responsible for brain amyloidosis as opposed to other disease-associated processes will help determine which drug might be most effective in a given individual harboring a combination of these variants," she added.

Dr Apostolova and her coauthors believe this is the first comprehensive analysis of the association of the top 20 AD risk variants with brain amyloidosis.

The study was published online January 16 in JAMA Neurology.

Complex Disease

Sporadic AD is 70% to 80% heritable. The APOE gene is the strongest genetic risk factor for AD. The APOE 4 allele carries the greatest risk through the reduction of β-amyloid (Aβ) clearance.

Previous large-scale genome-wide association studies (GWAS) have identified and validated 20 novel AD genetic risk loci. Few of these loci are in or near genes associated with Aβ aggregation and clearance and are thought to influence amyloid deposition. For the remainder, the precise disease-associated mechanism remains unknown.

AD is a complicated disease that is due to many biological processes, including brain atrophy, inflammation, tau deposition, hypometabolism, and amyloidosis. It's likely that the various genes that have been linked to AD play different roles in these processes.

Dr Apostolova and colleagues are investigating the effect of the genes on these biomarkers for AD. Last year, they published an article that linked these genes with brain atrophy and hypometabolism (Alzheimers Dement (Amst). 2016;5:53-66).

The current article focuses on amyloidosis. Unlike previous studies that looked at one or just a few variants, the investigators examined all these variants described to date as relevant in AD.

"Putting them all together in the same model allowed our research team to control for the effect that other variants might have on the trait of interest at the same time," said Dr Apostolova.

Researchers used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a longitudinal study launched in 2003 that has some 50 sites across the United States and Canada.

The goal of ADNI is to track the progression of AD by using clinical and cognitive tests, MRI, fludeoxyglucose positron emission tomography (PET), amyloid PET, cerebrospinal fluid, and blood biomarkers.

The analysis included 977 participants — 322 controls, 496 with mild cognitive impairment (MCI), and 159 with AD —  who had available GWAS and florbetapir PET data. The mean age of participants was 74 years, and 54.8% were male. All participants were genotyped.

Researchers focused on the 20 well-established and validated AD risk genes in addition to all other variants that were previously associated with brain amyloidosis. The final analysis included 27 gene variants (some genes have more than one relevant variant.)

"We plugged them all into a statistical equation to see which are the most significant predictors of brain amyloidosis," said Dr Apostolova.

The study showed that APOE4 had significant associations with brain amyloidosis There was no significant difference in age, sex, educational level, Mini-Mental State Examination score, and APOE4 distribution between carriers and noncarriers for all but one of the genotypes.

The study also confirmed the association between ABCA7 and brain amyloidosis and showed that after APOE4, it had the strongest association with brain amyloidosis.

"ABCA7 seems to have a very powerful effect on amyloid deposition," said Dr Apostolova. "It means that in addition to APOE, there is this other generic risk factor that affects brain amyloidosis, so people who have both probably deposit amyloid faster," although this has yet to be determined.

The authors describe ABCA7 as encoding a 2146–amino acid ABC family transporter protein, which is responsible for transporting a variety of molecules across cellular membranes, primarily lipids.

ABCA7 is expressed in nervous tissue, with the highest expression in microglia. Research shows that loss of function of ABCA7 is associated with increased β-secretase cleavage of amyloid precursor protein, leading to higher levels of Aβ in vitro and in vivo.

The researchers also looked to see whether the genes have a sustained effect or act only in certain stages of the disease.

Results showed that the FERMT2 gene has a stage-dependent association with brain amyloidosis that is most pronounced in the MCI stage.

"We saw a huge effect of FERMT2 during that specific stage, but much less so in the cognitively normal stage or the dementia stage, indicating that when conditions are right, some of these genes — FERMT2 in this instance — might take center stage, exert their effect and then have lesser effect downstream after those conditions have passed," said Dr Apostolova.

This authors note this is the first report of such a stage-dependent association.

But it shouldn't be surprising that some AD-related genes have a stage-dependent impact, said Dr Apostolova.

"We take it for granted that the effect of a genetic variant associated with a disease is sustained throughout the course of the disease, but that's not the case," she said.

She referred to genes that are needed for critical development of an embryo or fetus that are "silenced forever afterwards, and not ever expressed again in the human life cycle."

A Comprehensive Look

Research suggests that FERMT2 encodes for a 680–amino acid scaffolding extracellular matrix protein that plays a role in cell adhesions. FERMT2 is expressed in the brain and is upregulated in atherosclerotic plaques, suggesting a possible role in inflammation and leukocyte extravasation.

In addition, research indicates that FERMT2 is a coactivator of β3-integrin, a microglial and reactive astrocyte marker that plays a role in post-stroke brain tissue recovery and has been associated with cognitive decline in AD and to modifying tau neurotoxicity.

Investigators were unable to confirm the previously reported association between complement component receptor 1 (CR1) and amyloid plaque burden, likely because previous reports used a univariable approach.

"When these other studies were staged, only a few variants were known," said Dr Apostolova.

It's important to look at all the variants together to get meaningful associations and not look at them in isolation, she added.

"To focus on a selected number of variants is very unnatural because all these genes exist and work in the human body together."

But the question of why it's important to determine the genetic contribution to amyloid when many studies suggest amyloid is not a successful therapeutic target remains.

"If we still believe in the hypothesis that the amyloid protein is at the inception of the disease, then we can't ignore it," said Dr Apostolova.

She acknowledged that antiamyloid drugs given to patients in late stages of the disease, when neurodegeneration has already occurred, have not proved effective.

"Neurodegeneration is tremendously important, and once it's on its set course, antiamyloid drugs don't seem to affect it, but we need to understand whether treating amyloid deposition early enough affects the rate and progression of downstream neurodegeneration."

This is exactly what some research projects are investigating, she added.

"Highly Relevant" Findings

Commenting on the study for Medscape Medical News, David S. Knopman, MD, a clinical neurologist at the Mayo Clinic, Rochester, Minnesota, whose research centers on AD and other late-life cognitive disorders, said it's an "excellent example of multidisciplinary investigation in combining genetic analysis with a state-of-the-art imaging-based phenotyping."

Whereas prior genetic studies included participants who were diagnosed clinically with AD dementia, this new study used amyloid imaging, a much more accurate method of defining cases, said Dr Knopman.

He stressed that the identification of ABCA7, FERMT2, and perhaps a few others uncovered by the researchers, "doesn't change anything at the clinical level."

But the findings "do support further genetic and cell biology studies of the functions represented by these genes in the pathogenesis of AD," he said.

Even if doubts persist about the relevance of Aβ in the pathogenesis of AD, "there is no question that PET β amyloid is at least a very good diagnostic marker for the AD pathway," Dr Knopman added.

"To that extent, these results are highly relevant, regardless of whether β amyloid is a target for therapeutics."

 Dr Apostolova reports serving on an advisory board for Eli Lilly and Company and on the speaker's bureau for Piramal and Eli Lilly and Company and receiving research support from GE Healthcare. Dr Knopman has disclosed no relevant financial relationships.

JAMA Neurol. Published online January 16, 2018. Abstract

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