APOE Variant Directly Tied to Lewy Body Dementias in 2 Studies

APOE4 study

A variant of the apolipoprotein (APOE) protein, called APOE4, has been shown to directly affect Lewy body dementias, such as Parkinson’s disease.

Two separate studies, published simultaneously, found that APOE4 directly regulates levels of alpha-synuclein, which clumps  to form the nerve-damaging Lewy bodies that are the main culprits of the nerve cell death that defines Parkinson’s.

Their combined results help in understanding how APOE4 works, and how it affects disease progression. Greater insights into these mechanisms are vital for advancing research into treatments for Lewy body dementias.

Published in the peer-reviewed journal Science Translational Medicine, the two studies are “APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid,” and “APOE genotype regulates pathology and disease progression in synucleinopathy.”

“It’s nice when you do science separately … but reach similar conclusions,” Guojun Bu, PhD, senior author of one study and chair of neuroscience at the Mayo Clinic, said in a news release published in Neurology Today.

APOE4 has been the focus of research into both Alzheimer’s and Parkinson’s for some time. Studies have shown that it strongly associates with these diseases, and that it plays a strong functional role in the accumulation of amyloid-beta and tau within neurons.

Whether APOE4 directly promotes alpha-synuclein aggregation or affects disease progression as a result of these aggregates, however, is not known.

In each of these studies, scientists engineered mice to express one of three APO variants — E2, E3, or E4 — or to have no APOE at all (knockout mice). They then used different methods to examine associations between the APOE variants and disease features, or pathology.

Albert Davis, an assistant professor of neurology at Washington University School of Medicine in St. Louis and colleagues monitored one group of each type of mice, looking for the development of alpha-synuclein aggregates. His group injected groups of each of these engineered mice with alpha-synuclein fibrils to induce protein clumping, and see how its spread varied in each genetic background.

Among the first group, those expressing APOE4 (E4) showed higher amounts of insoluble and phosphorylated (pathologic) alpha-synuclein, and evidence of reactive gliosis — a type of neuroinflammation — than did mice in other groups.

Reactive gliosis refers to inflammation of glial cells, a class of protective neurons that include microglia, a cell often seen to be damaged in Parkinson’s. This inflammation typically occurs in response to damage to the central nervous system (CNS), such as the formation of Lewy bodies.

Mice carrying the E2 variant survived longer and did not show the motor difficulties seen in the other mouse groups.

Among mice injected with alpha-synuclein fibrils to monitor its spread throughout the brain, the E4 mice showed the greatest signs of pathology within the substantia nigra, the brain region most affected by alpha-synuclein aggregates in Parkinson’s.

This finding closely matched that of another recent paper, which concluded that microglia play “an integral role in the propagation and spread of alpha-synuclein pathology.”

The two papers reached different conclusions, however, regarding the order of events in inflammation and alpha-synuclein/Lewy body formation. While Davis’s group concluded that alpha-synuclein pathology leads to an inflammatory response, the other research group, lead by Jeffrey Kordower of Rush University, concluded that inflammation came first and played a driving role in alpha-synuclein aggregation.

“We and others in the field are going to look closely at that and follow up,” Davis said in the release.

Davis’ group also examined the genetic background of two groups of Parkinson’s patients, as a comparison to the mouse models. His group found people that in both cohorts, those with two copies of the E4 variant, showed the fastest cognitive declines.

“Our results demonstrate that APOE genotype directly regulates alpha-synuclein pathology independent of its established effects on [beta amyloid] and tau, corroborate the finding that APOE e4 exacerbates pathology, and suggest that APOE e2 may protect against alpha-synuclein aggregation and neurodegeneration in synucleinopathies,” these researchers concluded in their paper.

In the second study, led by Bu at the Mayo Clinic, mice were injected with viruses carrying different APOE variants.

Similar to Davis’ study, Bu’s group found that mice expressing E4, but not E2 or E3, showed more alpha-synuclein pathology and Parkinson’s-related symptoms, such as impaired behavior and the loss of neurons and synapses (the junctions between neurons where information is passed from one nerve cell to another). The E4 mice also showed deficits in their fat and energy metabolism.

Gu and his colleagues examined the brains of patients with Lewy body dementia, and discovered that those who had the APOE4 variant also showed greater alpha-synuclein pathology.

Eric Reimann, the executive director of Banner Alzheimer Institute, praised the studies, while adding that their results need to be confirmed in larger groups of both Parkinson’s patients, “including those without comorbid (simultaneously occurring) Alzheimer’s disease,” and healthy controls.

When two or more medical co-existing conditions can be common, telling the effects of one apart from the other is challenging. This is especially the case in disorders such as Parkinson’s and Alzheimer’s, which share many of the same disease features.

Reiman had also found the E4 variant to associate with higher odds for Lewy body dementia. In contrast to Davis’ study, however, Reiman found no link between the E2 variant and a lower disease risk.

Alice Chen-Plotkin, an associate professor of neurology at the University of Pennsylvania Perelman School of Medicine, commented in the release that “the data for E4 being bad is much stronger than for E2 being good.”

Although she expressed surprise at the strength of the effect Davis’s group found APOE4 to have on glial cells, she noted that researchers are coming to think much more about these nervous system support cells.

An ongoing Phase 2 clinical trial (NCT04154072), for instance, seeks to improve Parkinson’s outcomes by blocking glial activation and inflammatory signaling. At the same time, the National Institutes of Health (NIH) recently awarded a $4.8 million grant to study how APOE4 induces neurodegeneration.

The E2 variant is also the focus of an ongoing Phase 1 gene therapy trial (NCT03634007), seeking to deliver this protein to patients’ CNS as a way of treating Alzheimer’s disease.

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Immune Biomarkers May Better Classify Patients, Direct Therapy, Study Says

biomarkers, brain inflammation

Biomarkers of brain inflammation could provide a useful means for classifying Parkinson’s and Alzheimer’s patients and defining the mechanisms underpinning each person’s disease.

Testing for these biomarkers could support clinicians in providing precision medicine, by helping people with the progressive neurodegenerative disorders to choose treatments with a greater chance of benefiting them, based on their individual characteristics.

The study, “Multicenter Alzheimer’s and Parkinson’s disease immune biomarker verification study,” was published in the journal Alzheimer’s & Dementia.

Typically, diseases such as Parkinson’s are defined largely on the basis of patients’ symptoms. But while individuals share the same diagnosis, the underlying molecular and cellular causes of their illness may differ.

This also could explain why treatments do not work equally for all patients. Using these individual differences to identify patient groups may help clinicians choose more tailored treatment choices.

Many researchers propose that neurodegenerative illnesses could be defined on the basis of their molecular features, before evident symptoms occur in later stages of the disease.

To address this hypothesis, the AETIONOMY project, an European public-private partnership funded by the Innovative Medicines Initiative, is exploring potential molecular classifiers for Alzheimer’s and Parkinson’s.

Candidate markers include tracers of neuroinflammation, meaning trackers of the inflammatory reactions occurring in the brain and spinal cord, which comprise the central nervous system, or CNS.

Neuroinflammation probably begins early in neurodegenerative diseases, when the immune system senses the presence of misshaped or aggregated proteins — including beta-amyloid in Alzheimer’s, or alpha‐synuclein in Parkinson’s.

The formation of abnormal clumps of each of these proteins in the brain is believed to be at the root cause of each disease. In Parkinson’s, alpha-synuclein proteins clump together in aberrant aggregates termed protofibrils, which are toxic and thought to play an important role in the death of nerve cells (neurodegeneration).

In the first stages of the disease, these aggregates are known to activate immune cells called microglia and other supportive cells in the brain, known as astroglia. Later, immune reactivity — in which the body mistakenly attacks its own healthy cells — propagates in response to nerve cell death, with immune signals released as a consequence of the damage.

A team of researchers involved in the AETIONOMY project now sought to identify neuroinflammation-specific biomarkers. They screened 227 samples of cerebrospinal fluid or CSF, the fluid that surrounds the brain and spinal cord, collected from Alzheimer’s and Parkinson’s patients.

The goal was to look for relationships between the levels of these markers and patients’ characteristics — for example, age and sex — as well as their link with markers of neurodegeneration, such as tau, and measures of disease progression, like the Hoehn and Yahr scale for Parkinson’s.

People without dementia and patients diagnosed with mild cognitive impairment also were included for comparison.

The researchers specifically focused on 21 selected immunity markers. These included chemical messengers known as cytokines or chemokines, namely YKL‐40, TGF‐beta1, IP‐10, MCP‐1, MIF, and MIP‐1beta. The immune receptors sIl‐1RAcP, sAXL, sTyro3, sTREM2, sTNF‐RI/II, and sICAM‐1 also were targeted, as well as other complement and innate immune factors, including C-reactive protein and C1q, C3, C3b, C4, B, H, and properdin.

The findings were highly reproducible and consistent with previous findings. However, they revealed that immune markers were more tightly related to neurodegeneration — reflected by the levels of the protein tau — than having a diagnosis of Alzheimer’s, Parkinson’s, or mild cognitive impairment.

This suggests that such biomarkers may work better to discriminate the mechanisms underlying each patient’s illness.

Age was the “most striking covariate” with a “strong influence” on immunity markers. Older patients had increased levels of most immune proteins, and also tended to have more advanced disease.

The individual’s sex also influenced marker levels, as did APOE genetic variants — one of the strongest genetic risk factors for Alzheimer’s and a proposed risk factor for Parkinson’s — and center‐specific factors, or variations from the different centers from which patient data was obtained.

“These results are supportive of the use of mechanism‐based disease taxonomies [classifications] in addition to clinical features,” the researchers said.

Ageing seems to have a strong link with increased neuroinflammation; thus it should be taken into account when translating marker results to clinical practice or studies, the team said.

“Immunity biomarker levels in CSF reflect molecular and cellular pathology [disease characteristics] rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration,” the researchers concluded.

Looking ahead, the researchers reaffirm the need to characterize patients not only by symptoms but also by molecular markers that reflect their complex neurodegenerative disorders.

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