<\/p>\n
A no-brainer confronts a brain-teaser<\/p>\n
Scientists agree that APOE4 is \u201cbad\u201d in the sense of hiking people\u2019s risk for cognitive decline in advanced age. But whether that\u2019s because ApoE4 \u2014 the protein for which APOE4 is a recipe \u2014 is an underachiever (not doing enough of some good thing it\u2019s supposed to be doing in the brain) or because ApoE4 itself is a bad actor (doing some bad thing it\u2019s not supposed to be doing there) is an open question.<\/p>\n
Knowing the answer would tell researchers and drug developers whether their goal should be to punch it up or to tone it down \u2014 a key step toward finding a drug to deal with it.<\/p>\n
That\u2019s what Greicius and his colleagues, including University of Washington professor of medicine Chang-En Yu, PhD, who was Greicius\u2019s co-senior author, set out to determine.<\/p>\n
For their study, they gained access to a giant registry of people with and without Alzheimer\u2019s whose genes had been carefully scrutinized for APOE status, then they zeroed in on people age 65 and older. Of the 56,684 people in this cohort, a fair number were APOE4 carriers \u2014 no surprises there \u2014 but precisely two carried an APOE4 copy that was so defective it couldn\u2019t direct the production of its correspondingly malfunctioning ApoE protein.<\/p>\n
Those two people turned out to be carrying, along with a nonworking copy of APOE4, a perfectly normal APOE3 copy. Neither of them, despite their advanced years (one was 90 at the age of death, the other 79 and still alive at the time), had evidenced any signs of mental decline. To the contrary.<\/p>\n
I was shocked to learn that the 90-year-old, on postmortem inspection, had no appreciable buildup of beta-amyloid plaque in his brain.\u201d<\/p>\n
\u2014 Mike Greicius\n <\/p>\n
\u201cThey were in great shape,\u201d Greicius said. \u201cI was shocked to learn that the 90-year-old, on postmortem inspection, had no appreciable buildup of beta-amyloid plaque in his brain.\u201d<\/p>\n
The cerebrospinal fluid of the younger of the two was likewise devoid of any significant A-beta changes when last checked at age 76. (By age 75, two-thirds of even asymptomatic APOE3\/APOE4 carriers \u2014 much less the ones diagnosed with cognitive symptoms of Alzheimer\u2019s disease \u2014 typically have abnormal A-beta levels in their cerebrospinal fluid.)<\/p>\n
Evidently APOE4 wasn\u2019t simply too wimpy to get the job done; it was actually bad news. If you\u2019re carrying APOE4, it seems, you\u2019re better off if this gene variant isn\u2019t making any ApoE4 than if it is.<\/p>\n
\u201cThis is the first human study to make a strong case that ApoE4 is toxic and that its loss may be protective,\u201d Greicius said.<\/p>\n
He noted that a complete absence of ApoE activity could be damaging in peripheral organs such as the heart. \u201cRare cases have been found of people with zero functioning copies of any variant,\u201d Greicius said. They had very high cholesterol levels, he said.<\/p>\n
But neither of these two broken-APOE4-carrying individuals, each of whom carried a working copy of APOE3, had sky-high cholesterol. \u201cApparently, one copy of out-of-order APOE4 doesn\u2019t hurt you,\u201d Greicius said.<\/p>\n
![\"PET](\"https:\/\/www.newsbeep.com\/uk\/wp-content\/uploads\/2025\/09\/apoe4-visual2.png\")
<\/p>\n
\n Healthy older APOE4 carriers are much more likely to be amyloid-positive on PET scans (bottom row) than non-carriers (top row), explains Mike Greicius.\n <\/p>\n
The road ahead<\/p>\n
So far, no great small molecules that could be used as drugs have been shown to safely and selectively inhibit the production or activity of the problem protein, ApoE4. Finding such a finely discriminating drug could prove daunting.<\/p>\n
But in the near term, it may not be necessary. A drug that knocks APOE down but not out, so ApoE production isn\u2019t entirely stamped out, might be safe. The robust health of the people in the new study who had only a single working copy of an APOE gene implies that, Greicius said.<\/p>\n
Nor would a drug\u2019s inability to distinguish between different APOE variants pose a problem for treating those carrying two copies of APOE4 (2-3% of all people), he observed.<\/p>\n
The new research has begun to resolve scientists\u2019 uncertainty as to whether to put more muscle into ApoE4 or put it out of commission. That should give some direction to drug-development efforts, said Greicius, who is following up in a collaboration with other Stanford Medicine scientists to learn more about ApoE\u2019s interactions with other key fat-shuttling proteins and tease out differences in how ApoE4 and its alternatively numbered counterparts select which fatty substances they take aboard.<\/p>\n
\u201cNow, we know which way to go,\u201d he said.\u00a0<\/p>\n
ApoE4 is not a wimp. It\u2019s a cutthroat. Get rid of it.<\/p>\n