Early Alzheimer's Can Hide in Women

Women's verbal memory skills appeared to mask Alzheimer's disease in its early stages, but accounting for sex differences in testing improved detection, an analysis of cross-sectional data showed.

Amnestic mild cognitive impairment was more prevalent in men when typical verbal learning score cutoffs were used, but adjusting for sex revealed a 10% false negative rate in women and a 10% false positive rate in men, reported Erin Sundermann, PhD, of the University of California, San Diego, and coauthors.

Biomarkers supported the hypothesis that sex-specific criteria improved diagnostic accuracy, they reported in Neurology.

"Our results suggest that the female advantage in verbal memory may hinder the ability to detect Alzheimer's in its early disease stages," Sundermann said. "This is important because our currently-available treatments and interventions are likely most effective in the early disease stages. Health care, financial, and legal planning are better implemented as well in the early stages."

"If we adjust our criteria for detection to be sex-specific and to account for the female advantage, our results suggest we would improve our diagnostic accuracy in women and also in men," Sundermann told MedPage Today.

"Normative data provide tables or formulas that adjust for age and, at times, other demographic variables to help clinicians define normal and impaired cognitive performance," said Nikki Stricker, PhD, of the Mayo Clinic in Rochester, Minnesota, who was not involved with the study.

"Many norms in use today do not consider sex differences. However, on average, women perform better on tests of verbal memory than men," she continued. This result "provides an important illustration of how crucial it is to account for this difference in performance across men and women when evaluating memory concerns."

In their study, Sundermann and colleagues looked at Rey Auditory Verbal Learning Test (RAVLT) scores from 453 women and 532 men in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. RAVLT involves learning a list of 15 unrelated words and recalling as many words as possible over five immediate-recall trials (learning score), then after learning an interference list and after a 30-minute delay period (delayed recall score). RAVLT previously has shown a strong female advantage.

Biomarker outcomes included the cerebrospinal fluid (CSF) ratio of hyperphosphorylated tau (p-tau₁₈₁) to the 42-residue form of amyloid beta (Aβ42), and cortical Aβ deposition measured by florbetapir PET. Participants were dichotomized into positive and negative groups on the basis of previously established cut-offs for CSF p-tau₁₈₁/Aβ42 and AV45 SUVR.

Using a cohort from the Mayo Clinic Study of Aging, the researchers derived two sets of normative data for RAVLT scores. Men and women had an average difference of 6 points in learning scores (scores can range from 0 to 75) and 2 points in delayed recall scores (scores can range from 0 to 15).

These two sets of scores then were used to determine who had amnestic mild cognitive impairment in the ADNI cohort. Using typical cut scores, 26% of women in ADNI were diagnosed with mild cognitive impairment. Using sex-specific cut scores, that figure jumped to 36%.

Among men, 45% were considered to have mild cognitive impairment with typical cut scores; this decreased to 35% when sex-specific cut scores were used.

False negative women had positivity rates for Alzheimer's biomarkers and APOE ε4 higher than normal participants, and nearly as high as mild cognitive impairment cases. Likewise, false positive men showed positivity rates for Alzheimer's markers lower than true positive men, and low relative to true negative men.

These findings may shed light on other reported sex differences in Alzheimer's disease, Sundermann observed. "Paradoxically, studies have reported higher incidence of Alzheimer's dementia in women, whereas some others have reported higher incidence of amnestic cognitive impairment in men," she said.

"If the female advantage in verbal memory allows women to delay verbal memory impairment until a later disease state, at which point they decline more rapidly, then the window of time for an amnestic mild cognitive impairment diagnosis will be shorter in women versus men," Sundermann pointed out.

"Our own findings and others have found that women decline more rapidly than men after the amnestic mild cognitive impairment diagnosis," she continued. "Thus, women may transition more abruptly from cognitively normal to Alzheimer's dementia. Consequently, the amnestic mild cognitive impairment stage would be less likely to be observed in women versus men in longitudinal studies with assessments occurring every 12 months or more."

This study had several limitations, the researchers noted. It used cross-sectional comparisons of Alzheimer's-associated biomarkers; longitudinal comparisons could help determine the accuracy of sex-specific mild cognitive impairment criteria more definitively. In addition, ADNI is a convenience sample of mostly white, well-educated volunteers, and results may not apply to other populations.

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