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Alzheimer’s May Have Different Trajectory for Women

Women developed more tau pathology than men with similar amyloid burden, an analysis of cross-sectional data found.

Across two cohorts of older cognitively normal adults, women with higher amyloid burden showed higher entorhinal cortical tau compared with men with higher amyloid burden, reported Reisa Sperling, MD, of Brigham and Women’s Hospital and Massachusetts General Hospital, both in Boston, and colleagues, in JAMA Neurology.

“This study points to a key biological difference that may explain why women are at higher risk for Alzheimer’s disease overall, and why they show faster rates of cognitive decline,” Sperling told MedPage Today. “Our previous work has suggested that women and men have similar levels of amyloid plaque, assessed with amyloid PET imaging, in the pre-symptomatic stages of Alzheimer’s disease, but women demonstrate more rapid cognitive decline for a given amount of amyloid.”

“In the current study, the sex difference was most apparent in the entorhinal cortex, where tangles are accumulating as we age and then begin to spread throughout the cortex as memory impairment becomes manifest,” she added. “These findings may be important in targeting appropriate prevention therapies for women, ideally preventing the accumulation of both amyloid and tau pathology as early as possible.”

Alzheimer’s dementia is more common in women than men, and women are more likely to show Alzheimer’s disease pathophysiology. Among apolipoprotein E (APOE) ε4 carriers — both clinically normal older adults and those with mild cognitive impairment — women exhibited higher levels of cerebrospinal fluid (CSF) tau levels than men. Last year, a meta-analysis found greater CSF total and phosphorylated tau in female APOE ε4 carriers, with findings driven by abnormal levels of amyloid-beta.

Sex differences in amyloid burden alone have not been reported in older adults. This may suggest that male-female differences appear downstream, after amyloid beta starts to accumulate, Sperling and colleagues observed.

To study this, they evaluated two cross-sectional convenience samples of clinically normal individuals who received both tau and amyloid beta PET scans from January 2016 to February 2018. The Harvard Aging Brain Study (HABS) cohort included 193 clinically normal individuals (ages 55-92; 61% women) who had carbon 11–labeled Pittsburgh Compound B (PIB) PET to assess amyloid beta. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort had 103 clinically normal individuals (ages 63-94; 51% women) who underwent florbetapir PET to assess amyloid beta.

Both groups had tau assessed with flortaucipir F18 PET. The average Mini-Mental State Examination Score (MMSE) in each group was about 29 points (30=maximum points on the scale). The HABS cohort had better logic memory delayed recall than the ADNI group, but that did not differ by age, sex, amyloid positivity, or APOE ε4 status. Women in the HABS group were younger (mean age 73.4) than women in ADNI (mean age 75.1).

Among amyloid-positive individuals, women had more tau signal in their entorhinal cortices than men (meta-analytic estimate of beta for males -0.11, 95% CI -0.21 to -0.02, P=0.02).

That gap grew wider with increased amyloid: with higher amyloid-beta burden, women showed higher entorhinal cortex tau than men in both the HABS (beta -0.17, 95% CI -0.32 to -0.01, P=0.04) and the ADNI (beta -0.23, 95% CI -0.42 to -0.04, P=0.02) cohorts.

In the HABS group, sex and APOE did not appear to interact to influence tau deposits. In the ADNI group, a sex-by-APOE ε4 interaction was found in a meta-region that included the entorhinal cortex, inferior temporal cortex, amygdala, fusiform gyrus, and the parahippocampal cortex, with the association between APOE ε4 and tau retention stronger among women than men.

This study builds on previous research “suggesting sex differences, albeit very subtle, in Alzheimer’s pathology,” noted Michelle Mielke, PhD, of the Mayo Clinic in Rochester, Minnesota, who was not involved with the study.

“In this era of precision medicine, it is critically important to study sex differences in Alzheimer’s disease in order to improve the diagnosis, prognosis and treatment for both men and women,” Mielke told MedPage Today.

The study had several limitations. The analysis was based on convenience samples; recruitment and sampling biases may result affect findings. The ADNI group was older, showed lower memory performance, and may have been further along the preclinical Alzheimer’s trajectory. The cohorts also differed in how amyloid-beta was assessed. Limitations with power and neuropsychological follow-up in this study mean results should be approached with caution, the authors stated.

“Although our findings are consistent across two large cohorts, the sex differences in tau levels are relatively small, and there are likely other factors contributing to cognitive decline that we need to study,” Sperling said. “We are also working on longitudinal tau PET imaging studies to determine if women have faster rates of tau accumulation over time that may correlate with the rates of memory decline.”

Data collection and sharing for the ADNI portion was funded by the NIH and the Department of Defense. ADNI also receives contributions from AbbVie, the Alzheimer’s Association, the Alzheimer’s Drug Discovery Foundation, Araclon Biotech, BioClinica Inc., Biogen, Bristol-Myers Squibb, CereSpir, Cogstate, Eisai, Elan Pharmaceuticals, Eli Lilly, EuroImmun, F. Hoffmann-La Roche/Genentech, Fujirebio, GE Healthcare, IXICO Ltd, Janssen Alzheimer Immunotherapy Research & Development, Johnson & Johnson Pharmaceutical Research & Development, Lumosity, Lundbeck, Merck, Meso Scale Diagnostics, NeuroRx Research, Neurotrack Technologies, Novartis Pharmaceuticals, Pfizer, Piramal Imaging, Servier, Takeda Pharmaceutical, Transition Therapeutics, and the Canadian Institutes of Health Research.

Researchers reported relationships with Eli Lilly, Biogen, Cortexyme, the European Union’s Horizon 2020 Research and Innovation Programme, Janssen Pharmaceuticals, Lundbeck Pharmaceuticals, Bayer, GE Healthcare, Siemens Medical Solutions, Sanofi Genzyme, Novartis, Roche, Ionis Pharmaceuticals, AZTherapies, Lundberg, AbbVie, Navidea, Bracket, Avid Radiopharmaceuticals, Fidelity Biosciences, Harvard NeuroDiscovery Center, and the Alzheimer’s Association.