# Sex differences in the relationship of biomarker change to memory decline in early Alzheimer’s disease: an observational cohort study

## TL;DR

The study finds that men and women experience different memory declines linked to Alzheimer’s biomarkers depending on the disease stage, suggesting the need to consider sex in early detection and treatment.

## Contribution

The study reveals sex-specific differences in how Alzheimer’s biomarker changes relate to memory decline across preclinical and MCI stages.

## Key findings

- In preclinical Alzheimer’s, men showed faster memory decline than women with worsening biomarkers, though not statistically significant.
- In the MCI stage, women experienced significantly steeper memory decline compared to men as biomarkers worsened.
- Results suggest a 'tipping point' in women where early resilience to memory decline shifts to greater vulnerability as the disease progresses.

## Abstract

Alzheimer’s disease (AD) exhibits sex differences in pathology and cognitive trajectories. Understanding how these differences manifest across the Alzheimer’s continuum can improve early detection, diagnostics, and interventions. We examined sex differences in the association between cerebrospinal fluid (CSF) pTau181/Aβ42 ratio changes and verbal memory decline across the preclinical and mild cognitive impairment (MCI) stages of AD.

In this retrospective, longitudinal, observational study, data were extracted from 401 participants (age range: 55-87.8, 98% non-Hispanic White) of the Alzheimer’s Disease Neuroimaging Initiative cohort study who were classified as either preclinical AD (78 females, 73 males) or MCI (104 females, 146 males) at baseline and had CSF pTau181/Aβ42 ratio and cognitive assessment data at at-least two timepoints. Using regression models, we examined the relationship between changes in CSF pTau181/Aβ42 and verbal memory across all available time points and the moderating role of sex and AD stage over a mean follow-up period of 4 years. Verbal memory was represented by a composite z-score averaging Learning and Delayed Recall z-scores of the Rey Auditory Verbal Learning Test. Covariates included baseline age, education, and apolipoprotein E genotype.

A significant sex * diagnostic group * biomarker change interaction (b=-17.47, 95%CI = 27.60 to -7.33, p = .001) indicated that sex differences in the relationship between changes in CSF pTau181/Aβ42 ratio and verbal memory differed by disease stage. While males in the preclinical AD stage showed steeper memory decline than females with increasing pTau181/Aβ42 ratios, this difference was not statistically significant. In contrast, in the MCI stage, a significant sex * biomarker change interaction (b = 10.17, 95% CI = 4.94 to 15.40, p < .001) indicated that females exhibited significantly steeper memory decline associated with increasing pTau181/Aβ42 ratios compared to males.

Sex differences in the relationship between AD biomarker levels and cognitive decline vary by disease stage. Although not statistically significant, females demonstrated resilience to memory decline in the preclinical stage, whereas, in the MCI stage, they experienced significantly steeper memory loss compared to males. Results suggest that accounting for sex in biomarker-based methods of disease detection and tracking can improve early detection and intervention in both sexes.

The online version contains supplementary material available at 10.1186/s13293-025-00820-6.

Alzheimer’s disease (AD) biomarkers in cerebrospinal fluid (pTau181/Aβ42) were linked to verbal memory decline differently in women and men, showing that sex modifies biomarker–cognition relationships across disease stages.

Despite women showing more resilience to memory decline than men as the AD biomarker advanced in the preclinical stage, this pattern significantly reversed at the MCI stage, whereby.

women showed significantly faster memory decline than men as the AD biomarker advanced.

Findings suggest a possible “tipping point” in women, where early resilience transitions to greater vulnerability as AD progresses.

Results underscore the importance of considering sex when using biomarkers to detect, track, and treat AD.

The online version contains supplementary material available at 10.1186/s13293-025-00820-6.

Alzheimer’s disease (AD) affects men and women differently, but the reasons why remain unclear. Women are more likely to develop AD and often show higher levels of tau, a protein linked to brain changes in the disease. At the same time, women tend to have better memory than men in the very early stages, which may delay diagnosis until the disease has progressed further.

In this study, we analyzed data from 401 older adults in the Alzheimer’s Disease Neuroimaging Initiative. Participants were either in the “preclinical” stage of AD (biomarker changes but no memory problems) or had mild cognitive impairment (MCI). We measured changes in spinal fluid proteins (pTau181/Aβ42 ratio) linked to AD and tracked how they related to changes in memory performance over about four years.

We found that sex differences depended on the stage of disease. In the preclinical stage, men tended to show faster memory decline than women as AD biomarkers worsened, although this was not statistically significant. In contrast, among people with MCI, women showed significantly faster memory decline than men as biomarkers increased.

These findings suggest that women may be more resilient to early Alzheimer’s-related brain changes but reach a “tipping point” at which their memory declines faster once symptoms begin. Considering sex when interpreting AD biomarkers may improve early detection, diagnosis, and treatment for both men and women.

The online version contains supplementary material available at 10.1186/s13293-025-00820-6.