Leqembi does not help most women with Alzheimer's Disease

Lane Simonian

The latest news (actual old news that has resurfaced) is that most women with Alzheimer's disease do not benefit from Leqembi:

"Third, the most troubling aspect was no statistically significant result – let alone clinically meaningful outcome – in women on the primary outcome or any clinical secondary outcome (Supplementary Figures 1-4). In other words, the headline readout was driven by positive outcomes in men and it is beyond remarkable this was not discussed in the paper. This can not be explained by a lack of statistical power and suggests a more fundamental biological interaction at the level of therapeutic potency or mechanism of action. This will need a lot of careful analysis and further investigation to sort out. Given half the target population may be non-responsive, lecanemab is going to struggle to get to the clinic.Finally, recall these ‘meh’ results are in the face of not inconsiderable or inconsequential risk of side effects. 26% of those receiving their fortnightly IV dose experienced an infusion reaction, and a 21.5% incidence of ARIA, a form of brain imaging abnormality related to bleeding and oedema unique to those treated by anti-amyloids. Whilst most turn out to be harmless, about a quarter are clinically significant, including stroke, and in any case ARIA abnormalities need expert diagnosis and management.Altogether, lecanemab is the most potent anti-amyloid to date but like all its therapeutic cousins has not been able to show a clinically important difference compared to placebo."

https://www.skin2neuron.org/blog/lecanemab-doesnt-work-in-women

More women than men have one or two copies of the APOE4 gene which increases their risk for Alzheimer's disesae. But just as importantly, women APOE4 carriers are more likely to develop Alzheimer's disease than male APOE4 carriers. Either women have more other risk factors for Alzheimer's disease that are augmented by the APOE4 gene(s) and/or those genes increase oxidative stress in neuroinflammation in women more than men. In any case, it appears that removing amyloid (which is one of many factors that contribute to Alzheimer's disease) has less effect on women than in men.

Add to this that non-carriers who have little to no amyloid in their brain to begin with also do not benefit from treatment with Leqembi. So the drug may (or may not have) a minimally clinical significance on male APOE4 carriers which make up roughly 25 percent of the population. But in APOE4 carriers, anti-amyloid drugs can cause potentially fatal brain bleeds and swelling. To understate it, none of this is good.

mommyandme (m&m)

Interesting… thank you.

Larrytherunner

Lane, I was reading your post and was wondering why you say that APOE4 is more common in women than men, since the APOE4 gene is not located on the X or Y chromosome.

Males and females inherit an APOE gene from each parent. There are 6 combinations of APOE gene pairs, and men and women have an equal chance of getting APOE4 pairs. The APOE4 gene is not more common in women. It is the expression of the APOE4 gene that is different in women than in men.

https://www.alzdiscovery.org/cognitive-vitality/blog/apoe-and-gender

Lane Simonian

You are right, Larry. I misread a study on this.

Larrytherunner

Lane, thanks for giving us this important info and the article. I remember seeing some lines about this on Alzforum but it was so downplayed that I didn't give it much thought. It's hard to see the importance by looking at graphs and charts unless you are a researcher.

The fact that women APOE4 carriers got little or no benefit from lecanemab is not being mentioned in the popular media. The media is getting lazy and relying on info coming from Big Pharma and their allies. I am hoping that investigative journalists from the NY Times, Washington Post and others will step up and write about this.

BadMoonRising

Look at Lilly's amyloid busting drug, Donanemab. The females seemed to have benefited more than the males in terms of Tau reduction. The devil is in the details. Unfortunately, I could only scan and re-read the stats a few times before dosing off, zzzzz. ;)

https://jamanetwork.com/journals/jama/fullarticle/2807533

Lane Simonian

Well-said, Larry. I wish much more attention had been paid to this story than it was, but it not surprising that so little attention was paid to it.

Donanemab like Leqembi did not help non-ApoE4 carriers.

https://www.medpagetoday.com/neurology/alzheimersdisease/100667

Although like Biogen and Eisai, Eli Lilly tried to turn this story around later (that non-carriers benefitted most from the drug).

Women with the ApoE4 gene tend to have more amyloid than men, and in ApoE4 carriers, anti-amyloid drugs will reduce tau levels to some degree. But:

"Not everyone benefits equally from amyloid immunotherapy. Several presentations reported that people with a high tangle load clear less plaque, and their downstream biomarkers respond less robustly. Women tend to have more tangles than men at a given stage of disease, producing a sex difference in outcome in some studies...

In contrast, the one characteristic that robustly affected outcomes was sex. Women gained no benefit from gantenerumab [another anti-amyloid antibody] removal on any cognitive or functional measure, with their progression lines nearly identical to the placebo group’s. But men taking gantenerumab declined more slowly than did men on placebo—by 16 percent on the CDR-SB, 22 percent on the ADAS-Cog 13, 19 percent on the ADCS-ADL, and 16 percent on the FAQ. All four measures were statistically significant.

What is going on? Smith found no demographic differences between the male and female groups at baseline. They had the same clinical status, with around 55 percent MCI and the rest mild AD. They received the same number of gantenerumab doses and cleared about the same amount of amyloid. However, women in the study started with about 10 centiloids more plaque than men, 100 versus 90. This means they also ended the study further above the amyloid-negative threshold than did men."

So it could be that donanemab reduces tau levels even more than it does in men with the Apoe4 gene, but since women with the ApoE4 gene have higher levels of tau to begin with it does not make much difference in terms of reducing cognitive loss.