Crucial Evidence About APOE4’s Role in Alzheimer’s disease

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New research indicates that the E4 variant of apolipoprotein E (APOE4)—already a known risk factor for Alzheimer’s disease—plays a role in breaking down the blood-brain barrier (BBB). This finding might explain why APOE4 carriers are at increased risk for this disease. Study results published in Nature found a link between severe damage to pericyte vascular cells and severe cognitive problems in APOE4 carriers.

APOE has three main variants: APOE2, APOE3, and APOE4. Individuals with one copy of APOE4 have about a four times greater risk of developing Alzheimer’s in comparison to those with the most common variant, APOE3. This excess risk rises to about 12 times higher in individuals with two copies of APOE4, according to study co-author Axel Montagne, PhD, associate professor of research, Zilkha Neurogenetic Institute at the Keck School of Medicine, University of Southern California. APOE4 carriers who develop Alzheimer’s are also more likely to develop neuropsychological symptoms earlier than individuals with Alzheimer’s who don’t have the variant.

In previous research, Berislav Zlokovic, MD, PhD, director of the Zilkha Neurogenetic Institute and the study’s senior author, found a link between the APOE4 gene and early vascular defects in Alzheimer’s mouse models and postmortem human brain samples. This was independent of the biomarker hallmarks of Alzheimer’s, amyloid beta (Aβ) or tau. Injured pericytes led to leakage of brain blood vessels, affecting the integrity of the BBB. Whether or not APOE4 acts alone or in conjunction with Aβ and tau in causing early BBB dysfunction in Alzheimer’s disease has been unclear.

To gain answers, investigators leveraged dynamic contrast-enhanced magnetic resonance imaging (MRI) to assess BBB permeability in healthy individuals and those with mild cognitive impairment, grouping people according to their APOE status. They also checked cognitive abilities and neuropsychological performance with standard memory tests. “The goal was to examine whether our earlier findings also applied to the living human brain. Additionally, we also wanted to investigate the cellular and molecular mechanisms by which brain vessels become injured in APOE4 carriers,” Montagne said.

Cognitively healthy individuals carrying either one or two copies of APOE4 had a leaky BBB in the hippocampus and the parahippocampal gyrus, two regions that guide cognition and memory. In APOE4 carriers with mild cognitive decline, leakage was even more prominent. “Interestingly, this was true in cognitively normal individuals and further aggravated when subtle cognitive decline kicks in,” Montagne added.

In other findings:

• Elevated levels of platelet-derived growth factor-receptor-β (sPDGFRβ), a biomarker of pericyte injury, were detected in the cerebrospinal fluid of APOE4 carriers.
• sPDGFRβ elevation was independent of Aβ and tau.
• Levels of cyclophilin A (CypA) and matrix metalloproteinase-9 (MMP9), proteins associated with BBB breakdown and pericyte damage, were highest in APOE4 carriers with mild cognitive impairment.
• APOE4-expressing pericytes secreted substantially more CypA and MMP9 than did APOE3 pericytes, suggesting that injury to pericytes and endothelial cells may contribute to BBB leakage.

Overall, the results indicated that BBB breakdown contributes to APOE4-associated cognitive degeneration separately from Alzheimer’s disease pathology. This reinforces growing evidence supporting the vascular contribution to Alzheimer’s pathogenesis, Zlokovic told CLN Stat. “Second, we also emphasize that amyloid and tau might not be the whole story; alterations of blood vessels are early markers—at least in APOE4 carriers—and can be targeted therapeutically.”

The findings by Zlokovic and colleagues run counter to previous notions that APOE4 contributes to Alzheimer’s solely through Aβ and tau accumulation, wrote Makoto Ishii, MD, PhD, and Costantino Iadecola, MD, of the Feil Family Brain and Mind Research Institute, Weill Cornell Medicine in New York City, in a related commentary.

“Instead, it seems that BBB dysfunction might explain why APOE4 carriers are susceptible to Alzheimer’s disease. The authors’ findings might also explain why APOE4 carriers have worse outcomes following stroke or traumatic brain injury than do people who carry other APOE variants,” they wrote. The variant could also slow Aβ and tau clearance as Alzheimer’s disease advances, “exacerbating declines in cognition,” Ishii and Iadecola added.

Some questions remain about whether BBB breakdown causes cognitive impairment and if certain proteins such as fibrinogen are potential culprits. Nevertheless, the study offers a new understanding of APOE4 and how it may damage cognitive function, wrote the editorialists. “A deeper appreciation of how gene variants shape Alzheimer’s disease might prove crucial for more personalized approaches to treating this prevalent and incurable disease.”

In future research, Zlokovic’s team plans to investigate which leaky brain regions are the strongest predictors of cognitive decline in relation to APOE genotype. “To address this important question, we are currently enrolling the second MRI time points. In addition, we are also currently studying the regional cerebral blood flow changes using arterial spin labeling MRI,” Zlokovic summarized.