Inviting Alzheimer’s: the apoe4 gene disrupts cellular infrastructure, paving the way for cognitive decline

January 22, 2021.  Thomas Arnold

On Friday, approximately two hundred scientists from around the world met virtually to share their knowledge about apoe4, a widely known but poorly understood risk gene for Alzheimer’s disease.  They also shared their sense of urgency as they work to understand the health risks of a gene carried by a quarter of all humanity.

The co-hosts of the Massachusetts General Hospital’s Multicultural Alzheimer’s Prevention Program (MAPP) ApoE Symposium, Dr. Yakeel T. Quiroz (Harvard Medical Center) and Dr. Rik van der Kant (Vrije Universiteit Amsterdam), summarized the risks to the 25% of people who carry one copy of the apoe4 risk gene: a 3 to 4-fold increase in Alzheimer’s disease, occurring on average eight years earlier.  They also described the considerable risks for those carrying two copies of the apoe4 gene: a 9 to 15-fold increases in Alzheimer’s disease, occurring on average about sixteen years earlier.  In short, while the apoe4 gene variant is not considered “determinant” for Alzheimer’s disease, meaning not everyone with the risk gene will develop the disease, it raises the risks considerably.  For this reasons Dr. van der Kant proposed that researchers should think of apoe4-related dementia has a separate form of Alzheimer’s, one worthy of greater attention.

Throughout the event this community of researchers shared their work with patients, transgenic mice, and cultured brain cells harboring this risk gene.  The degree of collaboration was striking.  By teaming up with dozens of cooperating laboratories, the researchers used new cutting-edge technologies to probe the gene as well as its protein product, which is often toxic to brain tissues.  Some added or removed the genes from cultures of specific brain cell types, comparing the results.  Others silenced these genes or blocked the activity of the resulting apoe4 protein itself, then checked for the recovery of cultured cells or transgenic mice which serve as useful model of Alzheimer’s disease.  Others looked for clues in human populations that seem to escape some of the risks normally associated with carrying the risk gene.  This collection of established investigators and early-career researchers brought refreshing energy to this symposium reminiscent of the Alzheimer’s Afternoon seminar series from early 2020.

Together, these researchers are beginning to understand why the apoe4 protein, a component of the hollow lipoprotein particles which carry lipids and cholesterol throughout our bodies, leads to the appearance of amyloid plaques, tau tangles, and chronic brain inflammation.

The presenters emphasized several emerging trends:

  • Apoe4 has diverse effects on brain cells, including altered glucose and cholesterol metabolism, dysfunction of endosome and lysosome recycling systems, and increased inflammation.
    • Sugar hypometabolism in apoe4 brains is by now generally accepted.
    • Changes in lipid profiles are also common. Several presenters, including Dr. Lance Johnson (University of Kentucky), showed that cells carrying apoe4 genes exhibited different lipid portfolios.  For example, Dr. André Miranda (University of Minho) reported a 20-30% reduction in diacylglycerol (DAG), a common component of cell membranes and signaling pathways.  At least one presenter described this a form of “sphingolipidosis”, hinting that AD could be characterized as a type of lipid storage disorder.
    • Dysfunction in the transport of cholesterol in the brain is commonly observed when apoe4 is present, probably because of glitches in cholesterol efflux from astrocytes and uptake by other brain cell types.
  • These impacts can be observed relatively early in life but, in general, they become more pronounced with age.
  • These effects of apoe4 occur first, before the accumulations of amyloid plaques and tau tangles in the brain.
  • Apoe4 has distinct effects on in different cell types, e.g. neurons, astrocytes, glial cells, in different parts of the brain, at different times.
  • Apoe4 also causes injury to the protective blood-brain-barrier, even in younger individuals and those without obvious amyloid accumulations. Axel Mantagne (University of Edinburgh) shared his work on the cells that form this protective filter on the surface of the 400 miles of capillaries inside the human brain.  He observed leaky blood brain barriers and high markers of pericyte cell injury in some (but not all) brain regions in patients carrying the apoe4 gene.  Further he found that a drug which restores the health and integrity pericytes prevents neuronal loss and improve cognition, even without reducing the presence of amyloid plaques in the brain.
  • The connection between AD and vascular health was highlighted further by several researchers. For instance, Dr. Carolyn Kaufman (University of Kansas Medical Center), showed that there is a significant relationship between brain blood flow and amyloid burden in apoe4   Others suggested the poor vascular health was often more harmful for those carrying the risk gene.
  • Removing apoe4 from the brain can be helpful… least in mice. Chantal Ferguson (University of Massachusetts Medical School) silenced the apoe4 gene, preventing the production of the apoe4 protein, and found that this reduced the amyloid burden in mice without impacting the cholesterol levels throughout the body.  These encouraging results strongly suggest that the main problem with apoe4 is toxicity, rather than a reduced functionality.  This work suggests that a future therapy which reduces expression of the apoe4 protein might be very helpful, as long as potential side-effects could be managed.
  • The incidence of Alzheimer’s disease is higher in Blacks / African Americans but they are underrepresented in studies. In addition to raising issues of health care accessibility, representation, and fairness this underrepresentation also obscures some potentially important patterns; for example, while the apoe4 gene is more common in these populations it may be less harmful.  Dr. Elizabeth Mormino (Stanford University) shared data showing that in some populations the gene does not raise the risk of Alzheimer’s disease at all, perhaps because of the presence of other protective genes such as TOM40.
  • Dr. Kirsty Lu (University College London) presented results from a 74 year-long survey of British citizens that suggest that the apoe4 gene demonstrates antagonistic pleiotrophy – a tendency to confer a mix of positive and negative effects. She reported that despite the established risks of apoe4, healthy carriers of the gene exhibited superior working memory on particular mental tests of object identification and localization when tested at mid- or late-life ages.

In whole, the symposium made a strong case for additional study of the apoe4 risk gene.  Each presenter, in their own way, made a strong case that the direct effects of the apoe4 gene occur before the emergence of amyloid plaques and tau tangles, the traditional hallmarks of Alzheimer’s disease.  In many cases, apoe4 may trigger them.  Uncovering the mysteries of this gene variant is very likely to led to future therapies for one of the world’s leading causes of death and disability.