Two Alzheimer's Gene Variants Affect Brain Atrophy

Pauline Anderson

January 05, 2016

After investigating the top non-APOE4 genetic variants linked to Alzheimer's disease (AD), researchers have zeroed in on two of these variants — ABCA7 and MS4A6A — as playing an important role in cortical and hippocampal atrophy.

Their study, published in Neurobiology of Aging, sheds fresh light on how these genetic variants affect AD, according to author Liana Apostolova, MD, Barbara and Peer Baekgaard Professor in Alzheimer's Disease Research, professor in neurology, radiology, medical and molecular genetics, Indiana University School of Medicine, Indianapolis.

Dr Liana Apostolova

"We are trying to understand how these genes fit in with the complex processes involved with Alzheimer's disease," said Dr Apostolova.

To date, genome-wide association studies have uncovered several well-validated and well-replicated genes linked to AD in addition to APOE4. "But how they relate to the disease is completely unknown," said Dr Apostolova. "You have these brand new genes, and there is very limited knowledge about what their role is."

Researchers are looking for how these gene variants might be associated with disease features, such as cognitive decline, amyloidosis, and cortical atrophy.

The current study included 50 cognitively normal persons and 98 participants with mild cognitive impairment (MCI) who were assessed to meet criteria for the UCLA Imaging and Genetic Biomarkers for AD (ImaGene) study. Participants were at least 50 years of age, could independently carry out activities of daily living, and scored 24 or higher on the Mini-Mental State Examination.

An MCI diagnosis required objective cognitive decline at 1.5–standard deviation or below age- and education-adjusted neuropsychological norms, global clinical dementia rating score less than 1, preserved general cognitive function, and intact activities of daily living.

Participants underwent clinical and cognitive testing and MRI. After matching cortical and hippocampal morphology, researchers computed in three dimensions the cortical thickness and hippocampal radial distance measures for each participant.

Top 10 Genes

Dr Apostolova and her colleagues looked at the 10 genetic variants most closely linked to AD, but because APOE4 is "well studied and we know a lot about it," they concentrated on the nine non-APOE variants, she said.

Of these nine, only ABCA7 and MS4A6A had a significant association with both hippocampal and cortical atrophy, which are on the same neurodegenerative pathway, the study found.

Other researchers first described the associations of ABCA7 and MS4A6A risk variants with AD prevalence in 2011, and have since replicated them. Studies show that ABCA7 influences neuronal cholesterol efflux and amyloid β secretion and plays a role in phagocytosis of apoptotic cells. It is heavily expressed in the CA1 region of the hippocampus and in microglia.

Less is known about the function of MS4A6A. The MS4 gene locus contains several genes with unclear functional significance, although the whole family of genes is thought to have an immune-mediated function. Several common MS4A6A polymorphisms have been associated with AD.

How much cortical atrophy can be attributed to these two gene variants? Dr Apostolova estimated that 5% to 7% in the case of ABCA7 and 3% to 6% for MS4A6A.

She added that some 20% of the population has the ABCA7 variant that she studied and that carriers of this variant have a 1.23 greater chance of developing AD relative to noncarriers. As for the MS4A6A variant she studied, 42% of the population have it, and carriers have 1.11 greater chance of developing AD relative to noncarriers.

Dr Apostolova and her colleagues also looked at the expression of these genetic variants in peripheral blood to learn how active these genes are. The study found that these genes' messenger RNAs — the molecules downstream from the gene in the nucleus — are also associated with brain atrophy.

"I was able to show that the levels of these transcripts are also linked to cortical atrophy," said Dr Apostolova. "This links the activity level of the gene, if you will, to the disease processes."

The study showed that higher peripheral blood expression of ABCA7 is correlated with poorer language, memory, and executive performance. "Given the frontal predilection of cortical atrophy, the trend level associations with performance on the two most challenging executive function tests from our battery — Stroop C and Wisconsin Card Sorting test, are not surprising," write the authors.

This downstream activity might open the door to possible therapeutic targets, said Dr Apostolova. "It's very difficult to interfere with the genes in the nuclei, but what we can do is understand what these genes influence — look at the downstream disease mechanisms — and attack there."

Dr Apostolova believes this new study is the first to report an association of MS4A6A and ABCA7 and their peripheral blood expression levels with neurodegeneration in the normal and mildly impaired cognitive spectrum.

She and other researchers are learning more about how one gene can influence several disease processes. For example, in the case of ABCA7, "we know that downstream from that gene, we will be finding neurodegenerative effects on cell death, on synaptic dysfunction, and on clearance of amyloid."

And other gene variants might affect these or other disease processes, such as inflammation, said Dr Apostolova.

Igniting Disease

She surmises that in AD, certain genes may have a role only during certain stages of disease. "It could be that one gene is very important to ignite the disease early on and then is more dormant as the disease progresses while another gene could be very active when the disease is marching through the brain in full force."

Today, a typical scenario for a patient exhibiting signs of memory problems is to first be evaluated by a neurologist, who does detailed testing to document objective cognitive decline. The patient might undergo MRI of the brain to determine whether there's vascular disease, multiple strokes, a tumor, or hydrocephalus (conditions that might explain cognitive impairment) and to look for brain atrophy. The patient would also have laboratory work to help rule out other factors affecting cognition.

Only if the patient is symptomatic would he or she possibly be tested for the APOE4 genetic variant, according to Dr Apostolova. It's too early to even start thinking about screening for ABCA7 and MS4A6A, about which we know much less, she said.

Approximately 80% of AD is heritable, or encoded by genetic variants. But according to Dr Apostolova, to date, only the genes responsible for about half of this heritability have been discovered with the other half "still missing."

However, she foresees that once 100% of the heritability is mapped, clinicians will use gene panels as part of their efforts to ascertain risk for developing AD.

"In the future, if we were to have a powerful drug that can prevent disease onset, or slow down disease progression, one can easily foresee that we will be administering tests to detect risk, and give the therapy early." She calls this tailored therapy "personalized genomics medicine of the future."

Other tests that might become more routine when new therapeutics become available include amyloid positron emission tomography, which can show the presence of disease in asymptomatic individuals.

Because this new report involves only cross-sectional analyses, the authors said the term "atrophy" should be interpreted cautiously. Actual atrophy change can be accurately measured only with a longitudinal design.

The authors also noted that caution is in order for interpreting the observed cognitive associations because these were done post hoc after the pattern of imaging genetic associations were discovered, and they were not subjected to stringent multiple comparison correction.

Asked to comment, Keith Fargo, PhD, director, Scientific Programs & Outreach, Alzheimer's Association, said the study underscores the important fact that AD is a fatal disease involving degeneration of the brain, not just memory loss.

However, he added that "it's difficult to interpret a study when the number of participants is low."

The genes highlighted in the study are known to be associated with AD, and brain degeneration is part of AD, noted Dr Fargo. "So it's not too surprising that people with these gene variants may show signs of a smaller hippocampus or cortex."

What he thought was particularly interesting about the study was that participants had smaller brain regions even while they had normal cognition or MCI. "This finding deserves further research attention," he said.

The study received funding from National Institutes of Health grants and the Easton Consortium for Alzheimer's Drug Discovery and Biomarker Development.

Neurobiol Aging. Published online November 5, 2015. Abstract

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