Thread by @bucklr01

After a long wait, I'd like to finally do a tweetorial about our latest paper on menopause status, amyloid and tau! #ENDALZ #ADSexGenPIA onlinelibrary.wiley.com/doi/full/10.10…

Accumulating evidence shows a sex-specific vulnerability to tau deposition. This has been found at autopsy and also in vivo with CSF and PET studies

What still isn't entirely clear is what might be driving these differences. There are some interesting findings coming out about a cardiovascular effect (academic.oup.com/braincomms/art…) from @super_brains team:

And underlying sex-specific genetic architecture differences (ncbi.nlm.nih.gov/pmc/articles/P…) by @timothyjhohman and Dr. Dumitrescu's team

Our interest was in the influence of the menopausal transition. Recent work has suggested associations between menopause status and amyloid, grey and white matter structure and glucose metabolism: ncbi.nlm.nih.gov/pmc/articles/P…
But no one had taken a look at tau specifically.

We teamed up with researchers at the Framingham Heart Study (Drs. @sudha_md & Alexa Beiser) to examine menopause as a moderator of sex diff on amyloid/tau deposition. This sample is quite unique in that they have a younger sample that has comprehensive menopause data gathered

What we saw was pretty interesting.
First, we were able to replicate our findings that there are sex differences tau deposition in many regions across the brain. Nice to see we can replicate this in a much younger cohort (by about 15-20 years) than what we've typically observed.

When we examined menopause status, we found that post-menopausal women were significantly elevated in their levels of tau than any other group, but markedly so against age-matched men. We found this to be particularly intriguing given that

age is a confounding factor for menopause status but it is not a confound when you age-match against a reference (granted, men aren't always the best controls, but it's the only easy equivalent as pre-menopausal women do not really overlap in age against post-menopausal women)

We also found that earlier age at menopause (below 50 years) was associated with higher tau deposition than later age at menopause

Take aways? Our findings signal a critical watershed period of tau vulnerability in women that occurs around the time of menopause. What about menopause might be causing this? We need to interpret these findings interpreted within the milieu of other midlife risk profiles

For instance, increased risk for metabolic syndrome and midlife vascular risk exposure. Mid-life diabetes, obesity and hypertension all become elevated post-menopause and have considerable impact on vascular-related cognitive dysfunction.

Also, these findings introduce a wider implication of what it means to be 'tau abnormal' for women relative to men. At a broad level, this has implications for how we understand tauopathies and the extent to which certain tau species propagate in a sex-specific manner.

From a pragmatic standpoint, defining individuals with ‘high tau’ in the A/T/N model may require sex adjustment. Tau therapeutic clinical trials may need to consider sex stratifications for their primary endpoints to better estimate treatment response in men and women.

There are also implications for how tau-PET composites are created across both sexes; for instance, we would recommend avoiding the rostral middle frontal, parietal, and lateral occipital regions when creating cortical tau composites as these may introduce bias.

We hope you enjoy our paper and we look forward to hearing some thoughts from #SciTwitter