AAN 2026: From Migraines to Alzheimer, How the Menopausal Transition Affects Neurological Risk in Women

In an interview with Pharmacy Times, Carolyn Fredericks, MD, assistant professor of neurology at Yale University, highlighted at the 2026 AAN annual meeting that MRI and PET studies show women in their 40s and 50s experience changes in brain connectivity—especially in memory circuits—linked to declining estrogen during menopause.

Fredericks explains that multiple neurological conditions, including migraine, epilepsy, multiple sclerosis, stroke, and Alzheimer disease, are affected by menopause and that the same tightly connected memory circuit that supports efficient memory performance in women may also serve as a pathway for more aggressive tau protein spread in those who develop Alzheimer disease.

Pharmacy Times: Can you introduce yourself and explain your current role?

Carolyn Fredericks, MD: Hi. My name is Carolyn Fredericks, and I’m an assistant professor of neurology at Yale University. I run a lab that is interested in sex differences in Alzheimer’s disease and other neurodegenerative disorders, and we typically use imaging tools like MRI and PET scans to address these questions.

Pharmacy Times: Can you give us a brief overview of what happens to brain circuitry during the menopausal transition and why this window matters neurologically?

Fredericks: Amazingly, it’s only relatively recently that we’ve been looking specifically at brain circuits. In the past, there was a lot of work trying to understand cognitive changes that might relate to menopause and trying to examine structural brain volumes, but the study of circuits is relatively recent, and the literature is, to some extent, a little conflicting in certain areas. I think the main conclusion we can draw is that if you compare women and men as women get into their 40s and 50s, we see some really significant changes in how brain circuits are wired. In particular, a brain circuit that is critically important for short-term memory and related functions seems to be more tightly connected in women than in men, especially during those decades. It seems like that may correspond to changes in estrogen and to other changes we would anticipate being part of the story in women of that age.

Pharmacy Times: Which neurological conditions are most vulnerable to the hormonal fluctuations of menopause, and what is driving that vulnerability at the circuit level?

Fredericks: This is such an important question, and I appreciate your asking it. I think I have a much better answer for the first part than the second. Many neurological disorders change significantly during menopause. In migraine, for example, people will often get considerably worse during perimenopause and then see significant improvement—or complete changes in their headache phenotype, their aura or lack thereof—after menopause. Seizures can change as well; catamenial epilepsy in particular can worsen substantially and then improve again after menopause. Multiple sclerosis can change over the course of menopause. There is some interesting, controversial data in the Parkinson’s field about whether hormone replacement after menopause can be helpful, and the jury is very much still out. In stroke, there is a suggestion that the estrogen decline in menopause might predispose women toward greater stroke risk, but whether estrogen should then be replaced gets really complicated. And in Alzheimer’s disease, which is closest to my own research, it does seem that menopause might set the stage for a higher risk of illness and for more aggressive disease in women.

Whether all of these disorders and their changes over menopause relate to changes in brain circuitry is a much harder question. To be candid, I don’t think there is a lot of literature in many of these disorders examining functional circuitry in the brain and how it shifts over that time period—and I think that is a really important area for future study. There is considerably more in areas like Alzheimer’s disease and stroke. For Alzheimer’s, for example, I mentioned earlier that there is a set of brain regions composing a circuit that seems critical for short-term memory. We know that in the very earliest stages of Alzheimer’s, that circuit can actually become more tightly connected initially and then much less connected over the course of illness, in a way that correlates with memory symptoms. It is really interesting, then, that we see this pattern of increased connectivity in healthy women of menopausal age. And one thing I find especially striking is that in those healthy women, it actually correlates with better memory performance. It is almost as though women have a kind of highway in this memory circuit that is performing very efficiently—but that may also provide a platform for pathologic proteins associated with Alzheimer’s to travel more quickly. We know that when women do develop Alzheimer’s, the tau protein seems to spread much more aggressively along circuits in the brain. So it may be that this very adaptive and effective strategy that women’s brains employ for memory performance also sets them up for greater risk.

Pharmacy Times: Estrogen has long been linked to neuroprotection. How does its decline during menopause disrupt specific brain networks, and what symptoms does that disruption produce?

Fredericks: This is another really important question, and I would add that there are also changes in other hormones during menopause. I have a graduate student, for example, who is presenting a poster at the AAN on Sunday, and she is much more interested in FSH—a hormone that actually begins to shift, rising up to six years before menopause, well before the major changes in estrogen occur—and that may also correlate with some brain changes. But the literature on estrogen in the context of menopause and human brain networks is really interesting.

Going back to that same memory network I described earlier: that is a network that tends to be active when we are thinking to ourselves about something that happened recently, but it shuts down when we are focused on a task. A number of studies have looked at women’s ability to shut down that network and switch on a more task-related network during something like a memory encoding task. It appears that lower estrogen correlates with a decreased ability to make that shift—to move from this more self-referential state to a more task-focused state. That may be part of the basis for how estrogen affects women’s memory performance after menopause.

Pharmacy Times: Are there particular phases of the menopausal transition—perimenopause versus postmenopause, for example—where brain circuitry changes are most pronounced or most clinically significant?

Fredericks: That is something we are very interested in examining in our lab right now, and I know many other labs are as well. Perimenopause in particular is such a dynamic state, and I think a lot of the shifts in brain structure and brain function seem to be happening during that phase. For example, structural connectivity in the brain can sometimes actually increase during perimenopause and then decrease again in postmenopause. What we really need—and do not yet have—are dense imaging studies in which we follow women who are actively in the menopausal transition, measuring hormone levels and brain connectivity multiple times during a cycle as they move through this transition, in order to truly understand the relationships between hormones, brain circuits, and the cognitive or other symptoms women are experiencing. That is the frontier.

Pharmacy Times: When it comes to treating menopause-specific neurological exacerbations, how should clinicians think about timing and patient selection, especially given the ongoing debate around hormone therapy?

Fredericks: That is a really important question, and one I hear frequently in my own clinic. Our official guidance right now is still that we do not have enough data to recommend hormone replacement therapy on the basis of cognitive symptoms alone, and so we typically defer to the patient’s OB-GYN with respect to other symptoms they may be experiencing. Menopause causes so many neurological symptoms in itself—vasomotor symptoms, fatigue, sleep disturbance, mood symptoms—and that remains our official platform for now. But I think this is an area that is going to evolve.

There is some literature in the Alzheimer’s field, for example, suggesting that women who receive hormone replacement close to the time of menopause fare better than women who receive it further from menopause in terms of that more aggressive tau accumulation I mentioned earlier. So it may be that there is a critical window during which estrogen therapy—or other hormone therapies—can be beneficial, and if we are able to reach people within that window, the benefit may outweigh the risk. But I think the jury is still out.