Women's Superior Verbal Memory Skills May Mask Alzheimer's

Deborah Brauser

October 06, 2016

When it comes to verbal memory skills women have the edge over men, yet in Alzheimer's disease (AD) this "cognitive reserve" may not confer an advantage but rather mask early signs of the disease, new research shows.

These findings, say investigators, suggest there may be a need for different cutpoints in standardized tests for men and women.

A new analysis of more than 900 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), all of whom had amnestic mild cognitive impairment (aMCI) or AD dementia, and almost 400 healthy controls showed that women in all three groups had better verbal memory scores at baseline than men.

High temporal lobe glucose metabolic rates (TLGluMR), which were measured with [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) and were higher in the full group of women than in men, were also linked to higher scores on the Rey Auditory Verbal Learning Test (RAVLT).

After stratification for diagnosis, only the women with aMCI had a significant association between high TLGluMR and high verbal memory skills, suggesting an accelerated decline in those with AD dementia.

"The female advantage in verbal memory varied by TLGluMR, such that the advantage was greater among individuals with moderate to high TLGluMR and minimal or absent among individuals with lower" rates, report the investigators, led by Erin E. Sundermann, PhD, project scientist at the University of California, San Diego.

Dr Erin E. Sundermann

Dr Sundermann, who was at the Albert Einstein College of Medicine, Bronx, New York, during the study, told Medscape Medical News that this means that diagnostic tests may need some changes.

"Right now, memory tests use norms or cutoff points that are used to determine whether someone is impaired, regardless of sex," she said. "Our results suggest that you should have two different cutoff points for men and for women. And the one for women should perhaps be more conservative in order to account for this advantage that they have."

The findings were published online October 5 in Neurology.

Sex-Specific Factors Important

The "cognitive reserve" theory proposes that persons with favorable premorbid factors, such as higher education or IQ, maintain normal cognitive function longer as AD-related brain pathology accumulates.

For these individuals, "cognitive decline is delayed until time points closer to dementia diagnosis; however, once decline begins, persons with high reserve have more rapid decline because pathology is more advanced," the authors write.

The investigators add that previous research has shown that women usually outperform men when it comes to verbal memory at time points throughout their life and "may reflect a sex-specific form of cognitive reserve."

Earlier this year, they published results showing that older women have better verbal memory skills than older men despite having similar levels of hippocampal atrophy.

"Women are the ones who are mostly affected by Alzheimer's disease, which may be because they live longer. Regardless, it's important to look at sex-specific risk factors and differences in the trajectory of the disease," said Dr Sundermann.

ADNI was started in 2004 to assess patients with early or late MCI or early AD. For the current analysis, the researchers evaluated 672 of the study's participants with aMCI and 254 with AD dementia and compared them with 390 healthy peers. In the overall group, 43.5% were women, 93% were white, and the mean age was 73.4 years.

All underwent FDG-PET brain scans at baseline and RAVLT. During RAVLT, the participants were told to recall as many of the 15 unrelated words read to them earlier as possible. Both immediate and delayed recall scores were collected.


All women, together and in each diagnostic subgroup, had significantly better adjusted immediate recall scores on the RAVLT than their male counterparts (P < .01). In addition, delayed recall scores were significantly better in the entire group of women (P < .001) and those who were in the aMCI and healthy control subgroups (P < .001 and P = .001, respectively), but not in the AD dementia group.

TLGluMR was significantly higher in the full group of women than in the full group of men (P = .004), but the diagnostic subgroups did not show any sex-based differences in amounts.

Both sexes had significant interactions between immediate recall and higher TLGluMR, but the association was stronger in the women than in the men (P < .0001 and P = .001, respectively).

And only the women showed a significant association between delayed recall and higher TLGluMR (P < .001).

After the analyses were stratified by diagnosis, the women in the aMCI group had a stronger interaction between TLGluMR and immediate (P < .0001) and delayed (P < .001) recall scores compared with men with aMCI.

This sex-based advantage was "most apparent" for the medium to high rates of metabolized glucose, "whereas performance converges for men and women with lower TGluMR," report the investigators.

If replicated in future studies, "results suggest that aMCI may be clinically detected at a more advanced disease stage in women vs men because women are better able to compensate for underlying neuropathology," they write.

"Overall, the advantage in verbal memory that women have throughout life is a good thing but, ironically, it becomes a disadvantage when they start to develop Alzheimer's," summarized Dr Sundermann.

She added that the take-home message is that clinicians need to take sex differences into account when diagnosing and treating AD.

Lack of Hard Evidence?

Commenting on the findings for Medscape Medical News, Steven T. DeKosky, MD, professor of neurology and interim director of the McKnight Brain Institute at the University of Florida in Gainesville, said that "this was a very interesting use of data" from the ADNI study.

Dr Steven T. DeKosky

"The entire issue of neuroplasticity, such as gender or people with or without education or with or without certain genetic predispositions, how do we look at those issues and how do they reflect on change in the disease? How can we trace them over time and can we use them to develop better therapies?" asked Dr DeKosky.

"I think all of that was involved in the conceptualization of the study and I thought it was very cleverly done."

That said, he isn't completely convinced that current diagnostic memory tests need to be adjusted based on these results.

"I'm not sure whether having a group study like this would have an effect at the heart of the one-on-one with patients. But it's something to consider," said Dr DeKosky.

"If we had evidence that women who come into the clinic have worse cognitive function than men do or they don't live as long after diagnosis because we didn't diagnose them until they were further along, then I would find that argument more compelling," he said.

He noted that some remarkable and simple computerized tests coming out "will probably replace some of the verbal tests. So I think we're already on the way to assessing more than just verbal skills, although all tests rely in some extent on a person's verbal abilities or they wouldn't be able to understand the instructions."

Dr DeKosky added that he found the study's finding that women's verbal memory skills were better than men's to be interesting. "But I don't know that I would change what we do on that basis, other than perhaps doing an additional test if a female patient complained of functional changes or difficulties that weren't reflected in the initial test.

"But hard evidence that we are missing people or they may go longer without being diagnosed because their verbal skills are better? I don't believe we actually have that."

ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, the Alzheimer's Association, and the Alzheimer's Drug Discovery Foundation. Additional funding participants are fully listed in the original paper. Dr Sundermann has disclosed no relevant financial relationships. Disclosures for the coauthors are in the paper.

Neurology. Published online October 5, 2016. Abstract

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