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Cure Alzheimer’s Fund (CureAlz) researchers David Holtzman and Guojun Bu set out to identify the best time to target APOE to limit amyloid accumulation. Of the three most common APOE gene variants, APOE4 is most harmful because it not only coaxes amyloid to accumulate into plaques, but also competes with it for an efficient exit from the brain. As part of a separate research endeavor involving APOE, David Holtzman’s team also showed that it impacts the two other main players in Alzheimer’s disease—tau and inflammation. 

Given the critical nature of APOE, CureAlz is funding a total of six researchers who have formed a powerful consortium to examine how particular APOE variants influence: 1) tau, 2) inflammation, 3) blood vessel health, 4) microglia, (brain’s immune cells) and 5) gene expression in the brain regions most vulnerable to the impact of Alzheimer’s disease pathology. 

The researchers are: 

· David Holtzman, M.D. (consortium leader), Washington University, School of Medicine 

· Randall Bateman, M.D. Washington University, School of Medicine 

· Guojun Bu, Ph.D. Mayo Clinic, Jacksonville 

· Oleg Butovsky, Ph.D Brigham and Women’s Hospital, Harvard Medical School 

· Paul Greengard, Ph.D. Rockefeller University 

· Cheryl Wellington, Ph.D. University of British Columbia 

Does APOE have a Time-Limited Effect on Amyloid?
Dr. Bu and Dr. Holtzman published companion studies in the scientific journal, Neuron, that examined when APOE has the biggest effect on amyloid. They discovered that during the initial phase of Alzheimer’s disease, small amyloid aggregates form in a process called “seeding.” Over time, these aggregates grow larger following a period of rapid growth. 

The two scientists were also interested in addressing whether APOE had its greatest impact during the initial amyloid seeding phase, later when the plaques are rapidly developing, or throughout disease development. Both labs used mice engineered to produce amyloid and then increased or decreased the levels of the different variants of the APOE gene. The gene was either selectively activated or blocked at different times in development. They both found that APOE4 had the largest effect on amyloid levels during the seeding process. 

The studies also yielded another important finding: APOE4 caused swelling in the nerve connections surrounding the plaques. This occurred both during seeding and during the period of rapid plaque growth. APOE therapies may be effective throughout the disease course as a remedy for preserving neuronal health even though earlier administration would be necessary to reduce the number of amyloid plaques. Holtzman explained, “Administering APOE therapies, after seeding, can still be useful as way to protect neurons and their connections.”

Holztman and Bu agree that we still need to better understand why APOE has the power to aggravate amyloid. Bu explained, “One of the reasons APOE promotes amyloid seeds is because APOE (as well as amyloid) self-aggregates. It tangles up with amyloid, and together they get to the point of no return.” He concluded, “We need to find compounds that can reduce aggregation of amyloid, APOE, or both of them together.” 

APOE’s Role in Tangle Formation and Inflammation
Some time after amyloid plaques develop, amyloid triggers the spreading of tau tangles in the brain and an inflammatory process develops. The swollen nerve connections reported in both Holtzman’s and Bu’s studies hint that APOE4 may be involved in triggering such an inflammatory process. Stronger evidence that APOE plays such a role comes from another set of findings from Holtzman’s lab that primarily set out to test APOE’s impact on tau.

The results were published in the prestigious scientific journal, Nature, in September 2017. Mice were genetically engineered to produce a human form of tau that is particularly prone to tangle formation. The mice were then treated with one of three forms of the APOE gene. Those carrying the APOE4 variant showed the greatest quantity of tau tangles and the most shrinkage in brain regions, important for memory, compared to mice treated with the other APOE variants or to mice lacking the APOE gene altogether. 

In the next phase, Bu and Holtzman tested the impact of APOE on inflammation by combining immune cells extracted from the brain tissue of APOE4 mice with neurons containing human tau in a petri dish. The APOE4 variant unleashed a large immune response that appeared to lead to widespread neuronal damage and death. Holtzman is encouraged by the implications of his results: “Because tau tangles do not appear in substantial numbers until after amyloid plaques are already present, and because they are a good indicator of the amount of brain pathology and cognitive impairment, you can theoretically treat patients with an APOE therapy and still have a big effect after symptoms of Alzheimer’s disease symptoms emerge.” 

What does this mean for Alzheimer’s disease?
APOE plays a role in each of the three pillars of Alzheimer’s disease—amyloid, tau and inflammation. Because APOE4 amplified deleterious effects on nerve connection swelling, tau tangle formation and inflammation, and because these three pathologies all follow amyloid deposition, it means that APOE therapies could potentially be administered effectively across a wide timeframe in the disease course and still pack a powerful punch.