40 Scientific American, May 2020
SOURCES: “MORTALITY IN THE UNITED STATES, 2017,” BY SHERRY L. MURPHY ET AL. NATIONAL CENTER FOR HEALTH STATISTICS DATA BRIEF,
NO. 328, NOVEMBER 2018 (leading causes of death); GLOBAL BURDEN OF DISEASE COLLABORATIVE NETWORK—GLOBAL BURDEN OF DISEASESTUDY 2017 (GBD 2017) POPULATION AND FERTILITY 1950–2017. INSTITUTE FOR HEALTH METRICS AND EVALUATION, 2018 (gender differences)Graphic by Jen Christiansen“healthy cell bias of estrogen action.” If neurons are healthy, they
are responsive to estrogen. If neurons are aged or deprived of estro-
gen for too long, they become unresponsive to the hormone
because signaling pathways deteriorate and receptors become dys-
functional. In this scenario, adding estrogen might even exacer-
bate neural degeneration. So for HT to do good and not harm, it
must be initiated in the so-called critical window, which is usual-
ly within five years of the last menstrual period, Brinton says.
Several observational studies attempted to test the critical-win-
dow hypothesis in patients who had taken HT for at least 10 years,
and their results run the gamut from a 30 percent reduction in
Alzheimer’s risk in a Utah-based study in which treatment was ini-
tiated within five years of menopause onset to a 9 to 17 percent
increase in risk in a recent Finnish study in which age at initiation
did not appear to affect risk. Which results should we believe?
Researchers do not know. Although they consider HT to be safe
and effective for many women at the start of menopause, there
remains a lack of consensus about dementia protection that is com-
plicated by a variety of factors. “More clinical trials are needed,”
Mosconi says, “especially on women who start hormone therapy
while still in perimenopause.” Women with the most severe peri-
menopausal symptoms, such as Sophie, might be unable to natu-
rally adapt well to the loss of estrogen; in them, HT may prevent
neurodegenerative damage during the transition to menopause.
“I don’t dare go off it,” Sophie says of her HT. She feels that it
saved her from a downward spiral of memory loss that would
have left her like her grandmother, a loving, strong-willed wom-
an whom Alzheimer’s rendered confused and suspicious. Sophie
has not been tested for the APOE4 gene, however, so it is unclear
if she would, in fact, have developed the disease—nor have stud-
ies confirmed whether HT does help stave it off. Even so, she urg-
es me, a woman in her 40s: “You should start as soon as you need
it.” But surely there is a better way to prevent Alzheimer’s?A WINDOW OF VULNERABILITY
menopause does not cause alzheimer’s. It is more a window of vul-
nerability—especially for women with underlying risks, Brinton
says. At first glance, its connection with Alzheimer’s is not obvi-
ous. The average age of women at menopause is 51; the average
age for a diagnosis of Alzheimer’s is 70 to 75. That is a 20-some-
thing-year gap. But the so-called prodromal phase—between ini-
tial pathology such as beta-amyloid plaques and full-blown cog-
nitive impairment—is also about 20 years. “Maybe the timing is
a coincidence,” Brinton observes. “But I don’t think so.”
Brain scans aside, is it possible to predict a woman’s Alzhei-
mer’s risk earlier on, when she is still healthy? In a study pub-
lished in 2016, Brinton and her colleagues sorted 500 healthy
postmenopausal women into three groups: metabolically opti-
mal, borderline high blood pressure and borderline metabolic
health. Only one group scored significantly lower on verbal mem-
ory tests: women with borderline-unhealthy metabolic health.
Technically these subjects’ metabolic measures were still in
the normal range. Yet there were clues that their health was going
in the wrong direction. For one, blood glucose levels in this group
were nearing the threshold of prediabetes, a condition that afflicts
about 30 percent of women and is itself linked with cognitive
impairment. After a meal the hormone insulin helps glucose enter
cells for use as energy, but in someone with prediabetes, cells in
the body start to resist insulin. When brain cells become resis-10 Leading Causes of Death in the U.S., 2017
(age-adjusted death rates)
Heart disease
Cancer
Unintentional injuries
Chronic lower respiratory disease
Stroke
Alzheimer’s disease
Diabetes
Influenza and pneumonia
Suicide
Kidney diseaseDeaths per 100,000 people0 40 80 120 160Vertical bars
represent range
of uncertainty85
Age50 55 60 65 70 75 80 85 90 95+New Cases of Alzheimer’sand Other Dementias, 2017(per 100,000 people, U.S.)Disability-Adjusted Life-Years from
Alzheimer’s and Other Dementias, 2017(per 100,000 people, U.S.)8,0006,0004,0002,0000Vertical bars
represent range
of uncertaintyAge25,00020,00015,00010,0005,0000Females
MalesVertical bars
represent range
of uncertaintyFemales
Males85
Age50 55 60 65 70 75 80 85 90 95+The Burden
of Alzheimer’s
Gender Differences
Women in the U.S. suffer from Alzheimer’s at a higher rate than men do,
according to estimates from the Institute for Health Metrics and Evalu
ation. Beginning at age 50 and continuing through age 95, there are more
and more women among newly diagnosed cases ●A. A similar growing
gap between women and men emerges when the disease is measured
by the number of years— based on average life span—lost to disability or
early death from the illness ●B.Deaths
In the U. S., Alzheimer’s disease is the six th leading cause of death, and ex
per ts note it may be underrepor ted because death cer tificates of ten list the
immediate cause, such as pneumonia, and not the underlying dementia.AB