Dr. Costantino Iadecola

ApoE4, a protein linked to both Alzheimer’s disease and a form of dementia caused by damage of blood vessels in the brain, increases the risk of cognitive impairment by reducing the number and responsiveness of blood vessels in the organ, a study by Weill Cornell Medicine researchers suggests. Published September 19, 2018, in Nature Communications, the study helps explain the connection between ApoE4 and vascular dementia, as well as vascular lesions that occur frequently in Alzheimer’s disease patients. “We found that the brains of mice with ApoE4 have less blood flow in the resting state and are also less able to increase blood flow when brain activity demands it, which leaves them much more vulnerable to brain damage,” says senior author Costantino Iadecola, MD, Director and Chair of the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine.

How ApoE4 promotes damage in the nerve fiber tracts has been a challenge to determine because of the technical difficulty of studying blood vessels deep in the substance of the brain. Dr. Iadecola’s team overcame this hurdle with the help of 3-photon microscopy, which enabled the investigators to image at high resolution blood vessels and nerve fiber tracts deep within the brains of living mice.

The scientists examined mice whose ApoE gene had been replaced with the gene for ApoE4, which normally occurs only in humans. Comparing these ApoE4 mice to normal mice, they found that the former, while at rest, had 14 and 19 percent less blood flow, respectively, in two brain regions, the caudate nucleus and the somatosensory cortex – representing areas affected in humans with vascular dementia. By contrast, mice engineered with ApoE3 had the same level of cerebral blood flow as normal mice. Close inspection of the ApoE4 mice’s cerebral vessels revealed the reason for the reduced blood flow: The density of vessels was lower.

Further experiments showed that the cerebral vessels of the ApoE4 mice were also less able to dilate themselves to increase their flow, as they normally do in response to increased brain activity. When the major arteries supplying blood to the brain were narrowed artificially, modeling the age-related thickening of arterial walls that happens in humans, the lower baseline flow and reduced responsiveness of the ApoE4 mice’s cerebral vessels led to much greater brain damage. The pattern of brain damage resembled that seen in human vascular dementia and in a large number of Alzheimer’s disease patients.

Initial tests suggested that ApoE4 exerts these deleterious effects by causing certain immune cells in the brain to release superoxide and other highly reactive oxygen-containing molecules. These potentially damaging molecules inhibit vessel development and interfere with vessels’ abilities to increase local blood flow as needed. “We suspect that this ‘oxidative stress’ is the driver of the vascular impairment in ApoE4-positive individuals,” says Laibaik Park, PhD, co-senior author of the study.

Dr. Iadecola and his laboratory are continuing to investigate how ApoE4 harms normal cerebral vessel function. The research could lead to future therapies that block ApoE4-induced oxidative stress to ameliorate vascular dementia and potentially other ApoE4-linked conditions such as Alzheimer’s disease.