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Women developed Alzheimer's disease-related brain changes earlier than men, a cross-sectional imaging study showed.

Compared with their male counterparts, cognitively normal middle-age women showed higher beta-amyloid loads, lower glucose metabolism, and lower gray and white matter volumes, said Lisa Mosconi, PhD, of Weill Cornell Medicine in New York City, and colleagues.

Menopause was the strongest predictor of Alzheimer's brain changes, they reported in .

Alzheimer's disease affects more women than men. "For every man suffering with Alzheimer's, there are two women," Mosconi said. "For a long time, the general mindset was that women live longer than men, and Alzheimer's is a disease of old age, and that's why the prevalence is higher in women."

But Alzheimer's is not a disease of the old, Mosconi emphasized. "It starts with negative changes in the brain years -- if not decades -- before clinical symptoms emerge," she told 番茄社区app.

"In this study, we show for the first time that women develop Alzheimer's-related changes in their brains earlier than men do," she said. "So, it isn't just that women live longer; we also start showing the tell-tale signs of Alzheimer's earlier on in life, specifically in midlife."

The study showed that, among many possible Alzheimer's risk factors, "menopause is the strongest predictor of brain changes in women, followed by history of hysterectomy (which makes them worse) and hormonal replacement therapy (which makes them better)," Mosconi added. "Thyroid disease was number four on the list, and that's accounting for all other risks factors, including age and family history, as well as high blood pressure, cholesterol, and so on."

Recent work has shown that healthy older women, especially those with Alzheimer's genetic risk, have higher levels of tau pathology than men, observed Rachel Buckley, PhD, of Brigham and Women's Hospital in Boston, who wasn't involved with the study.

"It's unclear when these sex differences might begin to appear," she noted. "Is the key related to the menopausal transition?"

The findings from Mosconi's group add "to a burgeoning body of evidence that is shedding new light on the menopausal transition as a harbinger of downstream repercussions for brain health," Buckley told 番茄社区app.

"Menopause is a period of massive neuroendocrine transition involving the disruption of multiple hormonally-regulated systems that affect the brain," she said. "Although all women go through menopause, not all women are destined to be diagnosed with Alzheimer's disease dementia, and so it's likely that only certain factors within this menopausal transition are triggering greater risk in some women."

In their study, Mosconi and collaborators studied 121 cognitively normal people -- 85 women and 36 men -- with a mean age of 53 and an average of 17 years of education. About 41% in each group carried an APOE4 allele, a high genetic risk factor for Alzheimer's disease. About half (49%) of women were post-menopausal and 16% used hormone replacement therapy.

Both sexes had a high percentage of never-smokers (91%). The groups were well-matched for diet adherence (35% followed a Mediterranean-style diet), exercise (44% were active), and intellectual activity (43% frequently engaged in cognitively demanding activities).

The groups had comparable cognitive measures, but women had a higher percentage of subjective memory complaints than men (P=0.017). The male group had a higher percentage of minority participants and higher levels of plasma triglyceride, cholesterol/HDL, and homocysteine than the female group (P<0.022 for all).

All participants underwent imaging for brain biomarkers: beta-amyloid load with ¹¹C-Pittsburgh compound B (PiB) PET, and neurodegeneration with ¹⁸F-fluorodeoxyglucose (FDG) PET and structural MRI.

Women showed on average 30% higher PiB uptake, 22% lower FDG uptake, 11% lower gray matter volume, and 11% lower white matter volume than men (P<0.05, corrected for multiple comparisons) in age-matched groups. Alzheimer's biomarker abnormalities were most strongly and consistently associated with menopausal status, followed by hormone therapy, hysterectomy status, and thyroid disease.

While all sex hormones likely play a role, the findings suggest estrogen declines "are involved in the Alzheimer's biomarker abnormalities in women we observed," Mosconi said. "The pattern of gray matter loss, in particular, shows anatomical overlap with the brain estrogen network."

"When we discuss Alzheimer's prevention, we talk about managing things like high cholesterol and high blood pressure," she pointed out. "We don't talk about managing menopause. Our data indicate that hormonal factors need to be a strong focus of Alzheimer's prevention strategies in women."

One study limitation is that only healthy, middle-age people without severe brain or cardiovascular disease were included, she added; larger studies that follow people over time are needed.

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