Yale Psychiatry Grand Rounds: April 1, 2022

April 01, 2022

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Sex and Gender Differences in Alzheimer's Disease: Epidemiology, Risk Factors, Genetics, Brain Structure, and Pathologies

Michelle Mielke, PhD, Chair and Professor, Wake Forest University

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00:00And welcome to the grand rounds
00:02that's sponsored by the Division of
00:04Women's Behavioral Health Research.
00:06The Department of Psychiatry.
00:08I am Carolyn Missouri.
00:09As the director of the division,
00:12it's a pleasure to welcome members
00:14of the Department of Psychiatry,
00:16some of whom we've said
00:17hello to this morning.
00:18Harvey, Heathers,
00:20and it's a pleasure to also welcome
00:23colleagues from other key departments,
00:25both across the medical school
00:26and across the university,
00:28as well as collaborators that we have in
00:29a variety of settings clinical settings.
00:32Search settings.
00:34The division is designed to bring
00:37together investigators who study the
00:39health of women and the influence
00:41of sex and gender on mental
00:44health and on the intersection.
00:46Of mental health with a wide
00:49variety of other disorders.
00:51We also have the opportunity to
00:53invite outstanding scientific
00:54leaders to speak with us about
00:57critical issues in the field.
00:58And so it's my privilege to introduce
01:01today's grand round speaker who is an
01:04outstanding and accomplished researcher.
01:06At a translational epidemiologist.
01:10She focuses on understanding the
01:12etiology and epidemiology of
01:14neurodegenerative and aging related
01:16diseases and sex specific differences
01:18as well as gender differences in the
01:21risk and progression of these diseases.
01:25In particular,
01:27Doctor Michelle Milky focuses
01:29on identifying biomarkers.
01:31For accelerated aging and for the diagnosis,
01:35prediction,
01:35and progression of Alzheimer's disease.
01:39And she does this really for the
01:41purpose of enhancing precision
01:42medicine initiatives and providing
01:44better care for both women and men.
01:47Previously,
01:48Doctor Milky was a professor at
01:50the Department of Quantitative
01:51Health Sciences in the division
01:53of Epidemiology and Professor
01:55of Neurology at the Mayo Clinic
01:57College of Medicine.
01:57Today,
01:58April 1 marks the start of her new position,
02:01which is at Wake Forest School of Medicine,
02:04where she is now the chair of the
02:07Department of Epidemiology and Prevention.
02:09As well as professor of Epidemiology,
02:11Gerontology and geriatric medicine,
02:14and neurology.
02:15So you can already tell there's a
02:19very significant interdisciplinary
02:21flavor to Michelle's work.
02:23Doctor Milky received her bachelor's
02:25degree in neuroscience from
02:27the University of Pittsburgh.
02:29She then went on to Johns Hopkins
02:31University to the Bloomberg School
02:33Public Health where she received her pH.
02:36D and she did a postdoctoral
02:38fellowship in the epidemiology of
02:40aging and then subsequently was
02:43awarded elidia against Gillespie
02:46Postdoctoral Fellowship in Psychiatry.
02:48Among her many achievements
02:50in leadership positions,
02:52she is currently,
02:53I'll just mention the current ways
02:55in which she is very involved in
02:58the broader scheme of understanding
03:00Alzheimer's disease.
03:01Doctor Melki is currently a member
03:03of the Alzheimer's Drug Discovery
03:05Foundation Scientific Review Board.
03:07The Alzheimer's Association
03:09International Society to advance
03:11Alzheimer's Research and treatment.
03:14The global Biomarker Standardization
03:16Consortium and the standardization
03:19of Alzheimer's blood biomarkers.
03:21She's also on the CDC's World Trade Center,
03:24Cognitive aging and impairment
03:27scientific working group.
03:28And finally, one other example.
03:31She's one of the members of the
03:33External Advisory Board for Brigham
03:35Harvard's NIH funded U 54 score,
03:39which studies neural processing of stress,
03:41which is strongly linked to
03:44health outcomes in aging women.
03:46She also served on many NIH as
03:48well as FDA and DoD review panels
03:50focusing on Alzheimer's disease.
03:52Research has done extensive mentoring in
03:54this area with a large number of students.
03:58And she has provided service on
04:00a variety of editorial board.
04:02She's a member of the editorial board
04:03of the journal, Neurology and senior
04:05editor of Alzheimer's and dementia,
04:08the Journal of Alzheimer's,
04:10the Alzheimer's Association.
04:12Consistently,
04:13she's been funded throughout her
04:15career with multiple oral ones.
04:17You owe one RF,
04:18one NIH grants on topics such as
04:20reproductive risk factors for
04:23Alzheimer's disease, dementia,
04:24and pathology, and sex.
04:26Specific effects of endocrine disruption
04:29on aging and Alzheimer's disease.
04:32Most notably to me, however,
04:34beyond her many achievements
04:36and contributions,
04:37is the quality of her work.
04:39As well as the strength of her
04:41commitment in informing our view
04:43on the influence of sex and gender
04:45on human health and behavior,
04:47we're thrilled to have doctor Milky
04:49here today to talk about sex and gender
04:53differences in Alzheimer's disease.
04:54Epidemiology, risk factors, genetics,
04:57brain structure and pathologies.
05:00And with that, I turn it over to you.
05:02Doctor milk.
05:04Well, thank you so much.
05:06Doctor Missouri really appreciate that.
05:09The wonderful opportunity to present
05:11with you to you today and again.
05:14I, I apologize. As you mentioned,
05:16it's my first day and so we're we're
05:18hiring out a lot of the kings.
05:20It is my background too loud.
05:23No, you're good. I'm good.
05:25OK, alright great so hopefully there won't
05:28be any more interruptions and and again,
05:31I apologize.
05:33So yes, I'm I'm really excited to
05:35talk with you today and and also
05:37talk after this as well.
05:39Focus today will be on sex and
05:41gender differences,
05:41but as Doctor Missouri had mentioned,
05:44I do do quite a bit with blood
05:46based biomarkers,
05:46which I'm not going to talk about today,
05:48but I'm happy to have a call
05:50with anybody to talk about
05:51those down the road as well.
05:58And these are my disclosures.
06:02So what I thought I would do today was
06:06to give more of a a general outline
06:08covering a variety of topics and ways
06:10in which we need to think about sex
06:12and gender differences in Alzheimer's
06:14disease and related dementias.
06:16From incidents to understanding of brain
06:20structure and neuropathology's genetics,
06:21as well as risk factors including
06:24both sex differences in the risk
06:26factors and sex specific risk factors.
06:28And as you, I'm sure all can understand.
06:32You know, once you start to
06:33dive deeper in this topic,
06:34you realize that there are a lot of areas,
06:36a lot of gaps, a lot of things that
06:38are not yet understood and, and I,
06:41I hope to put forward that the
06:44appreciation of that today and the
06:47need for much additional research.
06:50So the the first thing I'm going to start
06:52with is are women affected by a D more
06:55than men and or women are at greater risk?
06:59A lot of times we hear through the
07:02media as well as some of the top.
07:05Newspapers, New York Times,
07:07Washington Post.
07:08Variety of others that women are at greater
07:10risk and sometimes I've even heard that
07:13Alzheimer's disease is is a woman's disease.
07:16But I think when you start to look at
07:20the numbers and also how you define risk,
07:23this is a little bit questionable.
07:26So if we start to talk about
07:27the frequency of the disease,
07:28so that's the the count.
07:30The number of people with a diagnosis.
07:32It's absolutely true that more women can have
07:35a clinical diagnosis of Alzheimer's disease,
07:37and this graph here comes from the
07:40Alzheimer's Association awhile back,
07:42but it generally has maintained
07:45throughout the past ten years that
07:47about 2/3 of those with the diagnosis
07:50of Alzheimer's disease are women.
07:52However,
07:52when we think of frequency,
07:54essentially any aging related disease,
07:57there's more women than men at older ages.
08:00And so there's going to be more
08:02women than men with most chronic and
08:05conditions and aging related diseases.
08:09So what about when we think
08:11about the prevalence?
08:13So this is a graph that was published
08:17in The Lancet by the GBS 2016
08:20Dementia Consortium and I just want
08:23to highlight here that women are in
08:26blue and men are in red and this
08:29is looking at Alzheimer's disease
08:30as well as other related dementias.
08:33And there is a higher prevalence so the
08:35number of women for example with the
08:38disease divided by in a certain age
08:40group divided by the number of women.
08:43In that age group.
08:44So when we take that into account,
08:47there is slightly higher prevalence
08:49for women than men.
08:50However,
08:50there's a lot of overlap and and then
08:53it's not statistically significant.
08:57So then the next question then is,
09:00are women at greater risk?
09:01Do they have a greater incidence
09:03of developing Alzheimer's disease?
09:05And what's really interesting is that
09:08when you start to look at various
09:10countries and regions of the world,
09:12we start to see different answers.
09:15So if we look at the top of this.
09:19This is kind of covering this up
09:20it so I I think it's a stock home,
09:23the UK, Southwest France as well
09:26as the pooled eurodam data we we
09:29do see that there is a greater
09:31incidence for women compared to men,
09:33and this generally starts
09:35around the age of 85.
09:37However, when we look at some
09:39studies in the United States,
09:40including the Framingham Heart study as
09:42well as some early work that was done in the
09:45Rochester Epidemiology project in Rochester,
09:47MN, we don't see it a sex difference.
09:51Now, you'll probably notice right away
09:53that this paper was published in 2002,
09:56and there's been a lot of additional
09:58epidemiological studies in the past 20 years.
10:01I I'd like to show this because it
10:03does split it out by country and
10:06and show some of these differences.
10:09But for the vast majority
10:11of studies since 2002.
10:14Particularly in the US,
10:15we do not see sex differences in terms
10:18of the incidence of Alzheimer's disease,
10:21and these are just some of
10:23the studies listed down here.
10:25The only one that I'm aware of in
10:26the US is Cache County study of
10:28memory and aging in Cache County,
10:30Utah,
10:31which did identify a greater incidence
10:34for women after the age of 85.
10:37However,
10:37the 90 plus study recently in California
10:40had did not find that difference.
10:43When we look at systematic
10:45reviews and meta analysis,
10:47there was one that was funded by the
10:50Canadian government feast at all,
10:51which is a compilation of more
10:54than 20 different studies.
10:56The vast majority of them in
10:58North America and again for both
11:00the prevalence and incidence.
11:02They did find a trend for women,
11:04but it wasn't statistically
11:06significant and by statistically
11:08significant the P values were about .6,
11:11so it's it wasn't even that that
11:13it was necessarily close.
11:14But interestingly,
11:15roughly a year after this was funded,
11:18or this was published,
11:19there was another meta analysis
11:21completely of European studies.
11:23And again they did show that there
11:25was a higher incidence overall
11:27for women as compared to men.
11:32So what about trends overtime?
11:35Here we're showing the cognitive
11:36function and aging studies one and two.
11:39So the first incident wave was
11:41between 1989 and 19, roughly 92,
11:45and the 2nd incidence wave was
11:47between 20 or 2008 and 2011,
11:50and there's some some interesting
11:53findings in the United Kingdom.
11:56Man on the left and women on the right.
11:59And of course the first wave is in
12:01blue and the 2nd wave is in purple.
12:03And what we can see to start
12:04with was that the incidence was
12:06actually higher in men than women.
12:09During this first wave.
12:11However, interestingly,
12:12about 20 years later,
12:13during the second wave there was a
12:16a large decrease in the incidence
12:18of dementia for men and an
12:20increase or maintenance for women.
12:22And So what happened subsequently
12:24was that the incidence for women
12:26ended up being higher than men.
12:30Now when we look at the
12:33Framingham Heart study here again,
12:34we do find that the trends for
12:36dementia and this is all caused
12:38dementia have decreased overtime,
12:40but the decrease has been much sooner and
12:42much greater in women compared to men.
12:48So I I just showed you a lot of
12:50discrepancies, a lot of questions.
12:53For me. This is actually really exciting
12:56because as an epidemiologist it suggests
12:58that if we're seeing differences by
13:01countries or even by regions of countries.
13:04Potentially modifiable risk factors
13:07and possibilities to intervene,
13:09and so I get really excited about
13:11this and and thinking about what
13:13some of the causes might be,
13:15and whether there are some biases
13:17that may play a role in interpreting
13:20some of these results.
13:21So I mean, one thing we we do
13:24have to keep in mind is that from
13:26the studies that I did show that
13:28there was a sex difference in,
13:30particularly in Europe,
13:31it tends to be after the age of 80,
13:33and by that.
13:34Point in time nobody is going to have peer
13:37Alzheimer's disease dementia anymore.
13:40It's going to generally be mixed pathology,
13:42so you might have vascular dementia,
13:43Lewy bodies, Alzheimer's pathology,
13:46TDP 43 and and also general brain aging
13:50that are are being mixed together.
13:53That there is the possibility that there
13:56could be a differential diagnosis by sex,
13:59and this is something that I I will
14:01go into a little bit more depth later,
14:03but it does.
14:04It is something that worries me
14:05when we see all these headlines
14:07of women are at greater risk.
14:09Melissa Murray from Mayo Clinic,
14:11Jacksonville had published a paper
14:12where they looked in the Florida brain
14:15bank and about 3000 different brains.
14:17And they compared both the clinical
14:20diagnosis and the pathological diagnosis.
14:22And interestingly,
14:24they found for men generally
14:27between the ages of 60 and 70.
14:30There were men were more likely
14:33to have Alzheimer's pathology,
14:35but to have a different dementia
14:38diagnosis so they they weren't clinically
14:41diagnosed as Alzheimer's disease despite
14:43the theology and then at older ages,
14:45there were generally past the age of 80
14:48that tend to be is like over clinical
14:51diagnosis for women compared to men,
14:53and so women were a little bit more
14:56automatically determined to have
14:57Alzheimer's disease clinically,
14:58even though pathologically.
14:59That may have not been the case,
15:01or it was a very mixed apology.
15:05And then you know lastly,
15:07and I think a very important
15:09consideration here,
15:10as we're looking at these,
15:11is that these sex differences
15:13across the regions of the world
15:15is that there are many social,
15:17cultural,
15:17and historical events that have taken place.
15:21Certainly the women,
15:22for example in the United States,
15:24experience World War Two much
15:26differently than those in Europe
15:29did similarly to the Cold War.
15:30And I really like to discuss
15:33with Walter Rocha.
15:35Who's at mail clinic as well?
15:37His family grew up in Italy and hearing
15:39about kind of Faustus was regime and
15:42the effect and the the stress and
15:44and implications on that on disease.
15:46And certainly that plays a role
15:49for women and men right now that
15:51are at greatest risk of dementia
15:53and older age ranges.
15:55So a question is whether some
15:57of these European countries
15:58will see similar sex differences
16:00in future generation.
16:02And we also have to think about
16:03other countries and regions.
16:04There's a variety of countries.
16:05They're going through stressful situations.
16:09Wars, variety of other things as well.
16:13And in addition, there are one of
16:16the things we're thinking about.
16:18These country differences is that
16:20there are social cultural factors
16:22that the impact of gender that
16:24particularly affect risk and that
16:26differ across regions of the world,
16:29but that also differ, for example,
16:31within the United States.
16:32So we think about North versus
16:34South in terms of education.
16:38So as we're thinking about these
16:41gender differences historically.
16:42Women have had less access to
16:44education compared to men,
16:46and as I mentioned,
16:47this does vary by different or does
16:49differ by country as well as culture,
16:51but also region within the USI know
16:54some states women were able to get high
16:57school education sooner than other states.
16:59There was a nice study that was recently
17:02published in Lancet public health
17:04by Bloomberg ET al using two studies
17:06from England consisting of over 15,000
17:09participants born between 1930 and 1955
17:12who had over 19 years of follow-up,
17:16and they found that there have
17:18been significant trends in
17:20memory performance overtime.
17:22So historically,
17:24women tended to perform better
17:26on verbal memory,
17:27which is generally well known,
17:30but the performance was much
17:32better for those that were later
17:34born compared to earlier born.
17:36And the memory decline was actually
17:38faster in men versus women after
17:41considering these educational differences.
17:44So these results further suggest
17:46a role of education and secular
17:48changes in education in determining
17:50cognitive performance and women.
17:52And it, you know,
17:52as we think about in the United States,
17:54where now there are more women
17:56than men in four year colleges,
17:58it will be interesting to see how this
18:00might affect the sex differences in
18:02terms of the incidence of dementia,
18:04particularly Alzheimer's disease
18:05down the road.
18:09Another aspect that is is
18:11really important to consider,
18:12but until recently there have
18:14been a few studies on this.
18:17Is the effect of work and family
18:20experience on subsequent risk of dementia.
18:22And made it all and made a colleagues
18:25using the health Retirement Study examined
18:27the life course patterns of employment,
18:30marriage and childbearing between
18:32the ages of 16 and 50 years.
18:34And then memory decline after the age of 55.
18:38And overall what they found was that
18:40women who worked outside the home
18:43had less decline after the age of 55.
18:46Whether it's memory decline or
18:48or even global cognitive decline.
18:50Now this.
18:52It impact was regardless of whether
18:54women took time off to have their
18:56children and went back into IT workforce.
18:59Some women took up to 20 years off,
19:01went back and and still had benefits,
19:04and it was also regardless of marital status,
19:07so there there was some concern that
19:09those women who were single that were
19:11also raising families and working
19:12that would result in more stress and
19:15more negative impact on cognition.
19:16But that actually was not found
19:18to be the case.
19:19And so again,
19:20you know in terms of our
19:23culture and gender experiences,
19:25gender roles these are changing over
19:28time and the impact of those on
19:31cognitive decline and and risk of
19:33dementia still need to be examined further.
19:38So I I've given you, you know,
19:40obviously it's not a straight answer.
19:42Are women at greater risk than men?
19:44There does appear to be a lot of caveats.
19:48I have been asked multiple times
19:50that if women are not at greater risk
19:53of Alzheimer's disease than men,
19:55why do we have to look at
19:56sex and gender differences?
19:58And this you know particularly bothers
20:00me because you shouldn't have to have
20:03a greater prevalence or incidence in
20:05one sex forces another in order to
20:07look at sex and gender differences.
20:09I mean, if we take.
20:12We take cardiovascular disease,
20:14for example.
20:15Cardiovascular disease is the number
20:17one killer for both women and men,
20:19but we know that there are
20:21different risk factors.
20:22There are differences in terms
20:24of morbidity and mortality.
20:26There are differences in terms
20:28of heart attack symptoms.
20:30There are differences in terms
20:32of response to treatment,
20:33and so even if the prevalence
20:35and incidence is the same,
20:37there still are a lot of other factors
20:39that we need to think about in
20:40terms of sex and gender differences.
20:42Both for the incidence,
20:44prevalence and treatment of Alzheimer's
20:47disease and related dementias.
20:49So I'm next going to transition
20:51to talking about what some of
20:53these differences might be,
20:55and so one is potential sex differences
20:57in brain structure as well as
21:00different types of neural pathologies.
21:04So it is well known that men have a larger
21:06head size and through volume than women,
21:09and this has historically been put
21:11forth as women having a smaller brain.
21:14Therefore, they're more susceptible
21:16to Alzheimer's disease and other
21:18types of of dementia, but really,
21:21among cognitively normal individuals,
21:24men have greater age,
21:25associated brain volume decline
21:27as compared to women.
21:28There are also some differences in in
21:31Gray and white matter percentages such
21:33that women have a higher percentage
21:35of brain matter and men tend to have a
21:38higher higher percentage of white matter.
21:40However, how these differences contribute
21:42to susceptibility of dementia and
21:45dementia types are not yet clear.
21:50To further highlight some of these
21:52sex differences, I I'd like to show
21:54this particular study by Kotani ET al.
21:57Looking at language lateralization so that
22:00they brought in a group of men and women
22:04looking to understand whether language
22:07lateralization tended to be at strong,
22:11left, or bilateral, and in general,
22:14what they thought or what they
22:15found among all individuals.
22:17Was that about 2/3?
22:19Had a strong left lateral isation and then
22:22about 20% either had bilateral with left,
22:26predominant or bilateral symmetrical,
22:28both right and left lateralization.
22:31But what was interesting is when they met,
22:34then looked at sex differences so men
22:37are in blue and women are in pink.
22:40They found that men were primarily
22:42strong left lateral isation,
22:44whereas women were pretty much split equally
22:47between these three different groups.
22:49So again,
22:50how this might predispose women versus
22:52men to certain types of dementias,
22:55such as primary progressive
22:56aphasia is not understood yet,
22:58but could be a reason for some
23:00of these differences or risks.
23:04In terms of biomarkers of amyloid,
23:07there are really no consistent,
23:10consistently reported sex differences
23:12in amyloid pet CSF amyloid beta 42 or
23:16even blood amyloid beta 42 levels.
23:19However, there have recently been
23:21a couple studies that suggest,
23:23for a given CSF amyloid beta level,
23:27women have greater declines in memory
23:30and hippocampal volume that men do.
23:32It may also have a greater increase
23:35in CSFP tell now again the results
23:38are not consistent and I I can say
23:40within the Mayo Clinic study of Aging.
23:43We do not find that pattern either,
23:45but it could depend on the samples that
23:47are used and it's certainly something
23:49to consider because if that is the case,
23:52this could have an effect on cut points
23:54and there could be a need for sex
23:56specific cutpoints in terms of prognosis.
24:01Richard Buckley and and colleagues,
24:03as well as several other groups,
24:05have really been looking at sex
24:07differences in terms of Tau pathology.
24:09Of course, Tau, being associated
24:11with neurofibrillary tangles.
24:13The other homework pathology
24:15of Alzheimer's disease,
24:17and again here there are some
24:19conflicting results what?
24:21He has has suggested was that
24:23for a given level of amyloid
24:25women do have Tau in more Tau and
24:29some brain regions than men do,
24:31and these are highlighted up here in red
24:34such that female have greater levels.
24:37Now there's been another study
24:39that has not replicated this,
24:41and there's currently an
24:43ongoing meta analysis.
24:45Buckley is leading combining a
24:47variety of our studies and so
24:49hopefully by combining and increasing
24:51the sample size will be able to
24:53really understand whether there
24:54is a a sex difference or not.
24:59In addition, there are sex differences
25:02in cerebral vascular disease,
25:04and so this is a courtesy of my colleague
25:08Prashanti Burberry and has been published,
25:11and I, I believe neurology,
25:13but looking within our population,
25:15we find that women have a greater probability
25:18of having white matter intensities.
25:21Hyper intensities across ages
25:23and a greater number of white
25:25matter hyperintensities than men.
25:28Interestingly,
25:28when we look at subcortical infarcts,
25:31we don't see a sex difference.
25:33But when we look at cortical infarcts,
25:36there are more cortical infarcts
25:37among men than there are among women.
25:40Some further research that I haven't
25:42shown here is using DTI and assessing
25:46white matter integrity and we do
25:48see less white matter integrity
25:50or or more problems in that area,
25:52typically across the age for
25:54women as compared to men.
25:56But again it it does specifically
25:58depend on the region.
26:02So next time I'm going to discuss
26:04some of the genetic differences.
26:06And of course, we all know that Apple
26:09we for a Leo is the greatest risk
26:11factor for us or genetic risk factor
26:13for sporadic Alzheimer's disease.
26:15But interestingly, there are some
26:18sex differences in in terms of risk.
26:21So here, when the first papers
26:23that were published on this by
26:25far and colleagues up here,
26:27we have men and women with two E 4
26:29alleles and down here with one E 4 allele.
26:32And here in the diamonds we can see that
26:35women have a greater odds of having
26:37dementia with two E 4 Leos compared
26:40to men starting around the age of 60.
26:43And even for one E 4 allele,
26:46women have a greater odds of having
26:50Alzheimer's disease compared to men.
26:52Now there has been a lot more work
26:55on this and there you know further
26:57in terms of prognosis.
26:59So among cognitively normal individuals
27:01it's also found that women with an E4
27:04allele compared to men are at greater
27:06risk of developing mild cognitive
27:08impairment and also progressing from Mayo,
27:11cognitive impairment to dementia.
27:13Now of note,
27:14pretty much all of these studies has have
27:17been done on white Caucasian samples
27:19and the role of appellee in risk of dementia.
27:23Non African Americans and some Hispanics,
27:25depending on origin are appearing to
27:28be less so whether we would see similar
27:32sex differences and those racial and
27:34ethnic groups is not yet known.
27:39Most of the genetic work that has
27:41been done for Alzheimer's disease,
27:43if they look at sex differences,
27:46it's been primarily focused on Autozone's.
27:48There is very little work to date that
27:51have focused on the X or Y chromosomes,
27:53and obviously as you can see here,
27:55looking at some of the factors
27:58and genes on the X chromosome,
28:00there are several that affect the brain.
28:03There are also several that
28:04affect cardiovascular,
28:05endocrine and immunological
28:06function which themselves can.
28:08Also contribute to Alzheimer's disease
28:11and other types of of dementia,
28:13and so there.
28:14There's certainly a very important need to
28:17look at some of these X chromosome genes,
28:20and even more importantly,
28:22or maybe not more importantly,
28:24but to go beyond that,
28:26you know women are complex and in that way
28:29in terms of the role of X inactivation,
28:33where not all of the chromosomes will
28:36be inactivated for 1X versus the other.
28:40But many of them are,
28:41and it's that the randomization of
28:44the X chromosome that is inactivated.
28:48It is independent across a variety of
28:51of tissues as well as organs and cells.
28:55And so how this might play into
28:58susceptibility of developing
29:00cognitive impairment and dementia
29:02again is is not well understood and
29:05really has not been looked at yet.
29:08And just I'm going to put this out there.
29:10This is something that I I saw
29:12a few years back,
29:13which I've been really intrigued in and
29:15I've been encouraging my neuropathology
29:17colleagues to take a look at more.
29:19There was a this one,
29:21this study here that was done in mice
29:23looking at the laterality of X inactivation.
29:26And interestingly,
29:27the the red dots indicate paternal
29:30inheritance and the green dots
29:33indicate maternal inheritance
29:34and what was interesting,
29:36particularly about this figure,
29:37is, as you can see,
29:38is that there tend to be laterality
29:40in in terms of paternal and
29:43maternal her inheritance.
29:44And so whether this is a common aspect,
29:48whether this is unique and really
29:50how this might affect risk of
29:52cognitive decline and Alzheimer's
29:54disease is completely unknown.
29:56But something that absolutely
29:58needs to be investigated.
30:03Next thing or more lastly,
30:05I'll talk a little bit more about
30:07sex and gender differences in risk
30:09factors for Alzheimer's disease and
30:11before I dive into just talking
30:14about some of these differences,
30:16I do want to highlight that we're at a
30:19point where we need to move beyond just
30:21saying that there are sex differences
30:23or there are gender differences.
30:25But to understand what some
30:27of the overall impact is.
30:29So for example,
30:30there are four different ways that
30:33in terms of of frequency and effect,
30:35that there can be sex and gender differences.
30:38So one or risk factor could have the
30:40same frequency but a different effect.
30:43And an example of that is what I've
30:45just shown with the Apple E4 allele.
30:47The E4 allele.
30:48The frequency is exactly the
30:51same for men versus women,
30:53but it looks like women with the
30:55E 4 Leo may be at greater risk.
30:58You can also have a factor that has
31:01the effect, but a different frequency.
31:04So in terms of education.
31:07There's low education is similarly
31:09associated with risk of dementia
31:12for both men and women.
31:13However, as I mentioned,
31:15historically women have had less
31:17access to education and therefore
31:20there's more women that are
31:22affected by the risk factor.
31:24There can also be factors that have
31:27both different frequencies and effects,
31:29and one interesting example,
31:31there is brain trauma and there there's been,
31:34you know.
31:35Generally we think of TBI as being
31:38more prevalent among men than women,
31:40particularly at younger ages,
31:42although many of these studies do not
31:45take into account violence against women.
31:47But there is more research coming
31:49out of at least college athletics
31:51and soccer suggesting that women
31:53who sustained concussions actually
31:55have more long term effects on
31:57their brain than men do.
31:59And then lastly,
32:01there are those factors that
32:02are restricted to one sex.
32:04So such as pregnancy for ectomy for
32:07women and then such as prostate cancer.
32:13So we were interested in a while back.
32:15I'm trying to understand what some of
32:17the sex differences in risk factors were
32:20for the development of mild cognitive
32:22impairment in the Mayo Clinic study of 18,
32:24and this is among Olmsted County
32:26residents that were aged 70 and older,
32:29and so we looked at factors that
32:31were equally important for both
32:33women and men and then those factors
32:35that were unique for women or.
32:38And as I mentioned,
32:39what we saw solo education was a risk factor.
32:43Memory concerns stroke
32:45and atrial fibrillation.
32:47But really among women we found
32:50that midlife cardiovascular
32:52conditions had a greater risk for
32:55mild cognitive impairment in women
32:57compared to men and among men.
33:00Some Kitty risk factors were obesity,
33:04particularly with BMI greater
33:06than 30 and those.
33:08Of men that were never married
33:10or widowed or divorced.
33:14We subsequently start to look at this
33:17among earlier ages and I I I I do a lot
33:20of work with Women's Health and and.
33:23A passion of mine, but in Full disclosure,
33:26both my father in law and his
33:29father had Alzheimer's disease,
33:31and so I've also been very interested in
33:33trying to identify risk factors that might
33:36be more specific for men and in mid life.
33:39Of course, men have more cardiovascular
33:42risk factors than women,
33:44and so I had a a postdoc fellow man,
33:47Hugh, who then went on to examine, well,
33:51men have a higher prevalence of all these
33:54cardiovascular risk factors in midlife.
33:55Does that result in greater cognitive
33:58decline for them over that period of time?
34:02And as this shows, looking at the
34:04ages of 50 to 69 men had critters,
34:07factors of cardiovascular risk factors,
34:09hypertension, diabetes,
34:10dyslipidemia as well as congestive heart
34:14failure and coronary artery disease.
34:17But interestingly,
34:18we did not find a greater effect of these
34:23risk factors and conditions on men.
34:25We actually found that even though women
34:27were less likely to have these conditions,
34:29those women that did in midlife had
34:32more cognitive decline overtime.
34:34And I, I realized that this is is quite busy.
34:38Just to Orient you a little bit,
34:40the farther to the left indicates
34:42greater cognitive decline.
34:44Red is women and the blue green is.
34:48With men,
34:48we especially saw differences in terms of
34:52language such that women with hypertension,
34:55dyslipidemia,
34:56diabetes as well as coronary heart
34:59failure all had greater declines
35:01on language as well as some
35:03global cognition and attention.
35:08So in addition to looking at.
35:11At sex, differences in in factors.
35:14Of course there are also a lot of
35:16sex specific factors to consider,
35:18and so for females this will
35:20include pregnancy, whether it's
35:22hypertensive pregnancy disorders,
35:23number of pregnancies.
35:25Gestational diabetes can include menopause,
35:28so this could be early
35:30menopause due to pre menopause,
35:31bilateral for ectomy or ovarian
35:33insufficiency as well as the transition
35:36through menopause and also hormone use.
35:40So contraceptives which.
35:42Have varied in in dose of
35:44medications over the last 4050 years,
35:48menopausal hormone therapy and
35:50also breast cancer treatments and
35:52prevention manage medications.
35:54I I do want to know we have a paper
35:57that is is just going to be submitted
35:59now led by a postdoc fellow throughout
36:01car from our group looking at the
36:04effects of Raloxifene and tamoxifen
36:06on both cognition and brain structure
36:09and we did not find any differences.
36:12Or or really, any effect of those
36:15drugs on cognition in our group.
36:17For today's purposes I'm I'm not going
36:19to talk anymore about hormone use,
36:21but again,
36:22I'm happy to answer questions and
36:23and talk more about that later.
36:25I will focus more on work being
36:27done with pregnancy as well as
36:29some of our work with menopause.
36:34So historically, when you look
36:35in the literature and there have
36:37been more papers out recently,
36:39a greater number of pregnancies,
36:41with the exception of 1 paper have been
36:44associated with reduced risk of dementia.
36:46And so a question of course,
36:49is is what is the mechanism?
36:51And most often when
36:52discussing about pregnancies,
36:54the first thing that comes up is that
36:56during pregnancies women have higher
36:58estrogen levels and this must be,
36:59you know, one of the reasons for
37:02this reduced risk of dementia
37:04or other or Alzheimer's disease
37:06and other types of dementia.
37:08But really we need to move beyond.
37:11I mean, certainly hormones are important,
37:13but there are a lot of other factors
37:15that occur during pregnancy.
37:17That allow a woman to carry a baby,
37:19and so there are significant changes in
37:22inflammation in terms of blood volume.
37:24Vascular changes.
37:25There are also many stress related changes,
37:29and so it's really important going
37:32forward to understand some of these
37:34effects and how they change over
37:36the pregnancy period and how those
37:39changes might influence risk of
37:41cognitive impairment down the road.
37:42And in one case I I've worked
37:44quite a bit with Vesna Jarabeck,
37:46who is an Afro Logest at Mayo.
37:48And I I really like the way she
37:50looks at this in terms of pregnancy
37:52being a stress test and so there may
37:54be women that go in that develop
37:57hypertensive pregnancies that,
37:59because partly of this stress,
38:03that may have been predisposed,
38:05but otherwise would not have
38:07developed hypertension.
38:07This early and so in a way,
38:09it's it's a it can be seen as a
38:11positive because you can identify
38:13those women that are having these
38:15conditions under this stress as
38:16potentially greater risk down the road.
38:21We have shown, as well as others that
38:23hypertensive pregnancy disorders,
38:25both gestational hypertension.
38:26The eclampsia is associated with worse
38:29cognitive performance and low brain
38:31volume even in women in their 60s.
38:35One question that has come up though,
38:37is what the result or what
38:40the mechanism might be.
38:42Whether this is through vascular pathology,
38:45general brain aging or
38:47even Alzheimer's disease,
38:49and there have been a couple studies
38:51that have looked at the placentas
38:53of women who have had preeclampsia
38:55and they find amyloid plaques
38:57within the placentas and so that
38:59that kind of caused us to look at
39:01this a little bit further and say,
39:03well, you know is this?
39:04Indicative of maybe blacks
39:05going on in the brain?
39:06Or is there something there?
39:08Interestingly,
39:09we we are just finishing up these
39:11analysis now and we do not see
39:14associations between pre clamp C or
39:16gestational hypertension with amyloid
39:18pathology either amyloid or Tau pet.
39:21But we do with white matter hyper
39:23intensities and we also do looking
39:26at diffusion tensor imaging and
39:28white matter integrity and in
39:30several key regions as well.
39:32There is also a question about Nulliparity.
39:36Some studies suggest that women that
39:38are deliveries are at greater risk.
39:41Some studies suggest that they
39:43are at reduced risk in our data.
39:45We're finding that it it really depends
39:48on education and of course no parity
39:51can be due to inability to conceive,
39:53but then also many women that choose
39:56not to have children and so in.
39:59In our study there appeared to be a very.
40:02Significant education interaction such that.
40:07Who had a greater than a
40:09high school education?
40:10Who were nulliparous were not at
40:12any greater risk of developing
40:13cognitive impairment or dementia.
40:16But women who had less than a
40:17high school education were no.
40:19Liberals were at at greater risk,
40:21and so again it's it's much more
40:23complicated than just staying at
40:25whether somebody has children or not.
40:26Trying to understand maybe some
40:28of the reasons behind that and
40:30and some of the other societal
40:32and social factors at play.
40:36Menopause transition has has gained
40:38a lot of attention and I I think is
40:41is really important. There has been.
40:45Some announcements or or.
40:49Things that have come out suggesting
40:51that menopause may be a risk
40:52factor for Alzheimer's disease,
40:54and it's certainly true that there
40:56are many changes over the menopausal
40:58transition in terms of cardiovascular
41:00changes and fat redistribution.
41:03And it's still a bit unclear how
41:05these might affect subsequent
41:07cognitive decline down the road.
41:09There's of course a lot of reports during the
41:13menopausal transition of cognitive changes,
41:15but at least in Moscone,
41:17as as well as a lot of Pauline Mackey.
41:19Works suggest for the majority of women.
41:22This does tend to be temporary.
41:25What time I think it's important to think
41:28about menopause and the transitions,
41:30but I I don't like the idea of,
41:33say, menopause or risk factor
41:34for Alzheimer's disease or risk
41:36factor for other types of diseases,
41:38because all women go through menopause.
41:40But not all women develop
41:42Alzheimer's disease.
41:43And so again, I,
41:44I think this is a one of those advantages
41:46that we have with women similar to pregnancy,
41:49where you've got this biological and and
41:52emotional transition kind of distress.
41:55Past and someone when we'll do better
41:57over their transition than others will.
41:59And there might be clues during
42:01that transition,
42:01such as more severe hot flashes,
42:03more severe mood changes,
42:05other types of sleep abnormalities that
42:08someone might have more severe than others,
42:11but this then might indicate who
42:14may be at greater risk of certain
42:16diseases and those women that do
42:18have these more severe symptoms.
42:19Hopefully,
42:19if we can follow them up and treat them,
42:22then we can delay some of these diseases,
42:24so it is.
42:25It is also an exciting window
42:27of opportunity as well.
42:32Now Walter Rocca, my colleague,
42:35and and I and several others,
42:37have suggested that early
42:38menopause is associated with later
42:41cognitive impairment and dementia,
42:43and this is a paper that we
42:44recently published using data in
42:46the Mayo Clinic Study of Aging.
42:48So red is global cognitive decline
42:51among women who underwent bilateral
42:54reflect me less than the age of 40.
42:57Blue is 40 to 45 and orange is 46 to 49.
43:02And generally what we see is that
43:05for women who undergo bilateral for
43:07ectomy prior to natural menopause,
43:10less than the age of 45,
43:11they have about a two fold greater risk
43:14of having mild cognitive impairment.
43:16When we look at the less than 40 group we,
43:18it's actually about a threefold greater risk.
43:21And so you know, historically,
43:25women who were undergoing or had
43:27their uterus removed for fibroids
43:29or or for several other conditions,
43:31also had their ovaries taken out at the
43:34time because the general thought was that,
43:36well, you're not going
43:37through reproduction anymore.
43:38You don't need the ovaries and so if
43:40you take out the ovaries then there's
43:42no way you can develop ovarian cancer.
43:44But we're now finding that it's
43:47it's really critically important
43:48to keep these ovaries ovaries
43:50in particularly for women.
43:51That are not at great family risk,
43:54for example that have BRCA mutation
43:56mutations in their family or have
43:59strong family history and so it's
44:02it's really important going forward to
44:04highlight the need to keep ovaries in.
44:06Now.
44:06On a side note,
44:08interestingly to thinking about estrogen,
44:11we often come back to memory
44:14performance and in our studies both
44:16this study as well as a couple of
44:19other cohorts we're looking at,
44:20there really seems to be in effect.
44:22And attention as opposed to memory.
44:24And so again,
44:25this kind of gets at the question
44:28of if bilateral refractory is
44:30a risk factor for dementia.
44:32Is it through Alzheimer's pathways,
44:34vascular pathways or other
44:36aging related pathways?
44:37And that's something that again,
44:39we're trying to look at
44:40and understand right now.
44:44So I I talked a little bit about this work,
44:48but we do have a grant right now with Mayo
44:50Clinic study of Aging where we've tried to
44:53take more much more of a lifespan approach.
44:55So historically in the literature you might
44:57see a paper on hypertensive pregnancies.
45:00You might see a paper on bilateral fracta me.
45:02Maybe just on the number of pregnancies,
45:05but if you think about a 56 year
45:08old woman coming in and wine or
45:09no at risk of future disease,
45:11she is the accumulation of all the factors.
45:14That she went through and when we look at,
45:16for example, the Framingham risk score,
45:18we know that it does not.
45:19Is not as good in women as compared to men,
45:23and so our hope is that if we understand
45:26what some of these specific factors are
45:28and incorporate them into risk scores,
45:31particularly for cognitive impairment,
45:33that will be better than the
45:36current risk scores.
45:38Now it it has been very interesting.
45:40We have a a median medical
45:43records of about 45 years.
45:44It took us over four years to go through
45:47and abstract all the information from
45:49the medical records for the women.
45:52But we also realize the difficulty
45:54in terms of societal aspects.
45:56So for example,
45:57we found that tubal ligation attended to
46:00be protective for Alzheimer's disease,
46:02and we couldn't figure out what
46:04the reason for that was.
46:05Our concern was that with two ligation there,
46:07maybe.
46:07Manipulation of ovaries and
46:09that could be detrimental,
46:11but we found it to be protective.
46:13Well when we looked at it
46:15more and and what the.
46:17Medical practice was at the time
46:19at really women who had a lot of
46:21children were the only ones that
46:23were allowed to have tubal ligations
46:25in the 50s or 60s in Rochester,
46:27MN, and in fact actually if they
46:29had it at Saint Mary's Hospital,
46:31which was run by the Sisters
46:33of Saint Francis you're,
46:34you're never going to find tubal ligation or
46:37effective or prescription of contraceptives.
46:40If women were seen in that area,
46:43so again,
46:44there's a lot of societal aspects
46:46that have changed overtime that.
46:48We need to think about as
46:50we're looking at these factors.
46:52Before I go into my final slide,
46:55I I am often asked ahead of time.
46:57What about transgender men and women
46:59and and what are the effects of of
47:02hormones and and whatnot on on their
47:04risk of dementia down the road?
47:07And really,
47:08there's very little information
47:10out at this period at this time.
47:13One of the reasons when I I've
47:15talked to researchers historically,
47:17they've stated that you know hormone.
47:21Doses and things like that for
47:23transgender men or women have
47:25not been uniform overtime,
47:27and so trying to separate those doses
47:31and differences in hormone levels as
47:33well as all the stress that goes in.
47:36To get to the stage,
47:38maybe to have surgery or decide to
47:40become transgender really has a role
47:41and and it's not clear what those
47:43are yet. So there there's an absolute
47:45need to understand those factors,
47:47and I've been working with a group the
47:50diversity and disparities professional
47:51interest area on sex and gender differences,
47:54and have also been trying to put
47:56forward to think about sex and gender
47:58is not just being a binary construct,
48:01and so we certainly need to move
48:04forward there from a continuous aspect.
48:06And then also not just think about
48:08it from a US centric standpoint,
48:10because clearly these many cultures
48:13around the world are different.
48:14There are some that are more accepting
48:16some that are less accepting and
48:17it's going to be important to look
48:19at this from a global perspective.
48:24So in conclusion, as I first talked
48:26about in terms of the epidemiology,
48:28more women than men have a
48:31diagnosis of Alzheimer's disease.
48:32However, the prevalence and incidence
48:34is a little bit more equivocal and
48:37may depend on area of the country
48:39as well as area of the world.
48:42As a field I I do get concerned
48:44in terms of how we present this,
48:47because as an epidemiologist to and with
48:49the blood based biomarker work I do,
48:51I tend to think more from a primary
48:54care perspective and so if primary care
48:56providers who are the ones that are are
48:59going to see these dementia patients first.
49:01If they automatically think oh,
49:03a woman memory impairment,
49:05it's probably Alzheimer's disease may
49:08be losing out on some other factors
49:11or treatments that could potentially.
49:13Help sustain their their cognitive decline.
49:16Similarly,
49:16we don't want men to be misdiagnosed either.
49:21Overall,
49:21there still are two few studies that
49:24examine sex and gender differences,
49:26and the vast majority of studies
49:28still typically adjust for it instead,
49:30and so it's it's not.
49:32It would be difficult to do a
49:34meta analysis until we would have,
49:36for example, uniform reporting,
49:37and so it's possible that some of
49:39the papers that are being reported
49:41on with sex differences are that
49:42they just happen to find it,
49:44and many other papers they didn't
49:46look or or they they didn't see
49:49anything and so they didn't report it.
49:51So it really in need for whole
49:53studies to report whether there
49:55are sex or gender differences.
49:57And there's also a need for
49:58more diverse cohorts.
49:59As I mentioned,
50:00most of this work has been done on White,
50:03Caucasian,
50:04European background cohorts,
50:06and I've been working with Nila
50:08major wall at Rush University in
50:10the Chicago Healthy Aging project.
50:12Looking at pre menopausal bilateral
50:14reflect me on both white and black
50:17women and the average age of bilateral
50:19for ectomy for white women was 49.
50:22And the average age for black women was 40,
50:25and so there are some.
50:26You know,
50:27definite key differences that we need
50:30to consider by race ethnicity as well.
50:34As I mentioned,
50:35even if there the prevalence of the
50:38disease is the same for men and women,
50:40the mechanisms and factors can differ by sex,
50:43and so we we shouldn't have to
50:44say men are at greater risk.
50:46But women are at greater risk to really
50:48look at sex differences and hone in
50:51that we should be doing it regardless.
50:53As I mentioned there,
50:54there is a need to examine more of
50:57these sex and gender differences from
50:59a diversity and disparities culture
51:01and social determinants of health.
51:04And as Doctor Missouri had mentioned earlier,
51:08really important to look at these
51:10sex differences from a precision
51:11medicine standpoint.
51:12But I I also want to argue that it's
51:15also important to look at it from a
51:17socio cultural standpoint as well.
51:18Because as we look at some of these.
51:22Look at dementia around the
51:24world and some of these
51:25countries where women have
51:27significantly less education and
51:28their family roles are different.
51:30There are opportunities to change
51:33and lower their risk for more
51:35of a sociocultural perspective,
51:36so both precision medicine and
51:39social medicine is is important.
51:42So again, I'm I.
51:43I'm sorry I don't know
51:45what the time frame is.
51:46I hope I didn't go over too much,
51:48but I'm I'm very,
51:49very happy to be here and and have
51:51to answer questions I I don't
51:52have a Wake Forest email address,
51:54but you can get ahold of
51:56me by my Gmail account.
51:58Thank you.