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Alzheimer’s gene contributes to blood-brain barrier breakdown

From NIH Research Matters

Alzheimer’s disease is the most common cause of dementia in older adults. Brain changes associated with the disease include abnormal clumps (amyloid-β plaques) and tangled bundles of fibers (tau tangles). It’s thought that these changes eventually cause the death of nerve cells, leading to a progressive decline in memory and thinking skills.Man getting a brain scan

But amyloid-β and tau are likely not the only drivers of Alzheimer’s dementia. Recent studies suggest that breakdown of the blood-brain barrier may also play a role. The blood-brain barrier is a protective, tightly packed mix of cells that sits between the blood vessels that lead to the brain and the brain tissue itself.

People with a variation of the gene apolipoprotein E (APOE), called APOE4, have an increased risk of developing Alzheimer’s dementia, often at an earlier age. APOE4 is known to contribute to amyloid-β and tau accumulation. A research team led by Drs. Axel Montagne and Berislav Zlokovic from the University of Southern California wanted to know if APOE4 also affects the blood-brain barrier.

The researchers recruited 245 older adults to undergo a type of brain imaging called dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). DCE-MRI can identify leakiness in the blood-brain barrier. Study participants also underwent measurements of amyloid-β and tau, and of cognitive function over time.

The study was funded in part by NIH’s National Institute on Aging (NIA) and National Institute of Neurological Disorders and Stroke (NINDS). Results were published on May 7, 2020, in Nature.

Out of the 245 participants, 101 carried one or two copies of the high-risk APOE4 gene variation, and 144 had APOE3, a normal variation of the gene. On imaging, people with APOE4 had increased breakdown of the blood-brain barrier in two areas of the brain important for memory and cognition.

This breakdown was worse in people with APOE4 who were already experiencing mild cognitive decline. These patients had not yet experienced a loss of brain tissue. This suggests that breakdown of the blood-brain barrier may occur early in the course of the disease.

The breakdown in the blood-brain barrier also occurred apart from amyloid-β and tau levels measured in participants’ cerebrospinal fluid or brain, suggesting it may contribute independently to cognitive impairment and dementia.

Previous research suggested that cells called pericytes, which help maintain the blood-brain barrier, may become damaged in people with APOE4. The researchers measured levels of a protein that reflects pericyte damage in 146 participants at the start of the study who then had their cognitive function tracked.

The people with APOE4 and more pericyte damage were more likely to experience cognitive decline during the study (up to 4.5 years). Pericyte damage predicted cognitive decline independently of amyloid-β and tau levels in the people with APOE4. No such relationship was found in people with the APOE3 variation.

Further work identified a specific inflammatory pathway associated with pericyte injury that was more active in APOE4 carriers. Lab experiments showed that ApoE4 secreted by pericytes activated this pathway in nearby pericytes. ApoE3 did not. Blocking this pathway in mice carrying APOE4 protected the blood-brain barrier and preserved brain function.

“Our findings suggest that breakdown of the blood-brain barrier contributes to the cognitive decline associated with APOE4 and may be a target for the development of preventive or therapeutic drugs for people who carry this gene variation,” Zlokovic says.

—by Sharon Reynolds for NIH Research Matters

This research was funded in part by NIA grants R01AG023084, R01AG039452, 5P01AG052350, R01AG060049, R01AG064228, P01AG052350, P50AG016573, P01AG052350, R01AG054434, R01AG055770, P50AG05681, P01AG03991, P01AG026276, P30AG19610, R01AG031581, and 5P50AG005142.

Reference: Montagne et al. APOE4 leads to blood-brain barrier dysfunction predicting cognitive decline. Nature. 2020 May;581(7806):71-76. doi: 10.1038/s41586-020-2247-3. Epub 2020 Apr 29.