Alzheimer’s Disease in Women: How Our Understanding Continues to Evolve

Although men and women have similar symptoms of Alzheimer’s disease (AD), evidence is mounting that many aspects of the disease differ between the sexes in important ways. In June 2020, the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas collaborated with the Women’s Alzheimer’s Movement (WAM) — a nonprofit organization founded by philanthropist Maria Shriver — to create the WAM Prevention Center at Cleveland Clinic, the first medical clinic in the nation devoted to AD prevention, research and caregiving support expressly for women.

Consult QD sat down with neuropsychologist Jessica Caldwell, PhD, Director of the WAM Prevention Center at Cleveland Clinic, to discuss how knowledge about AD in women has grown — thanks in part to WAM-supported investigations — and where research and practice in this area is headed.

Q: Why focus on women in particular?

A: There are several important reasons. Sheer numbers, for one: two-thirds of AD cases are in women. This may be partially due to genetics, as the presence of the APOE e4 allele — the most common of the known risk genes for AD — is more predictive for developing the disease in women than in men.

Another factor is menopause, which involves the rapid loss of estrogen, a hormone that is very active in the brain and supports memory. Significant changes in the brain have been documented at menopause that may explain why many women experience cognitive decline at that time of life. For instance, our group at Cleveland Clinic has published on the relationship of memory, cortical thickness and sex differences (Alzheimers Res Ther. 2022;14[1]:36), and Lisa Mosconi, PhD, led a team at Weill Cornell Medicine that showed how menopause impacts brain structure and connectivity as well as amyloid-beta deposition (Sci Rep. 2021;11[1]:10867). Men also have hormonal changes as they age, but the decline is more gradual, causing a less dramatic neurologic impact.

Interestingly, we’re also finding that our methods of diagnosis put women at a disadvantage. Most diagnostic tests for AD rely heavily on verbal task performance. Since women tend to have a baseline advantage on verbal memory compared with men, disease diagnosis in women is frequently delayed. Cognitive testing in a man and a woman with similar brain pathology might indicate that the man has AD and the woman does not, as indicated by recent investigations by our group at Cleveland Clinic (Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2020;27[1]: 18-39). And once AD is diagnosed in women, it tends to progress more rapidly than in men.

Q: What about therapeutics? Could there be something that might help women more?

A: Hormones — in a variety of forms — are a major area of interest. Although replacing estrogen at menopause might seem like an obvious way to stave off brain decline, evidence has been mixed. Some studies show that women who started taking estrogen therapy years after menopause actually had an uptick in dementia. Whether using hormone therapy around the time of menopause is cognitively beneficial is still an open question being actively investigated; a recent review by Roberta Brinton, PhD, at the University of Arizona, Tucson, describes the current state of knowledge (Climacteric. 2021;24[4]:350-358). Of course, potential AD benefits must be balanced with the known cancer and cardiovascular risks of hormone therapy.

Estrogen is not the only hormone under investigation. Other research, including work led by Sarah Banks, PhD, at the University of California, San Diego (Biol Sex Differ. 2020;11[1]:33),focuses on testosterone, which appears to reduce pathological tau biomarkers. Evidence indicates that supplementing testosterone may be more therapeutic in women than in men.

Q: What are your current research interests?

A: We are taking advantage of cutting-edge brain imaging technology combined with comprehensive neuropsychiatric testing to better understand the effects of AD. More-specific MRI biomarkers that correlate with memory impairment are needed to improve diagnostic certainty and help identify preclinical stages of the disease when intervention may be more effective [see Dr. Caldwell’s review of this area in Alzheimers & Dementia (2018:4:395-413)].

We are also working under a $1.8 million grant from the National Institute on Aging to study stress in women and its impact on AD. We are looking at possible effects of inflammation — a common response to stress — on the brain, and we’ve found that women are especially vulnerable to memory decline with inflammation (Brain Behav Immun. 2021;95:27-35).

Q: Tell us about the WAM Prevention Center.

A: The center is a place where women can have their risks for AD assessed and then be directed toward lifestyle changes we hope will reduce their risk. To participate, women must have either a family history of AD or a known genetic risk and be between ages 30 and 60, as this may be the window of opportunity for primary prevention of AD. Symptoms most commonly start around age 75, but changes in the brain may begin 20 years before then.

We work with each woman to implement sustainable lifestyle changes. The Lancet Commission (Lancet. 2020;396[10248]:413-446) identified 12 potentially modifiable factors that account for about 40% of cases of dementia: less education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, low social contact, excessive alcohol consumption, traumatic brain injury and air pollution.

We also know about other behaviors that support brain health. Sleep is important for memory consolidation, with evidence indicating that amyloid is cleared from the brain during sleep. Unfortunately, menopause often disrupts sleep, so we try to help women optimize sleep-related habits. Good nutrition is another important preventive factor that we emphasize. Recent evidence from the group at Weill Cornell Medicine (J Prev Alzheimers Dis. 2022;9:731-742) suggests that multipart clinical interventions may be particularly beneficial for women.

Q: What are your long-term goals for WAM?

A: In addition to conducting research, we would like to apply models of AD prevention practice throughout Cleveland Clinic and beyond. For some areas, we need to wait for more definitive research results, but we actually have enough data now to promote lifestyle changes that hopefully will reduce cognitive impairment 20 years in the future.

Unfortunately, such programs face limitations of insurance, which doesn’t always adequately cover prevention activities. But that challenges us to be creative and consider lower-cost interventions, such as virtual education. We are extremely grateful to partner with WAM and receive other philanthropic and grant support for research and running our clinic.