# 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.

## Contribution

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

## Key findings

- In preclinical Alzheimer’s, men showed faster memory decline with rising biomarkers, though not statistically significant.
- In MCI, women experienced significantly steeper memory decline with increasing biomarkers compared to men.
- Sex differences in biomarker-memory relationships vary by disease stage, suggesting implications for personalized detection and treatment.

## 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 how cerebrospinal fluid pTau181/Aβ42 ratio changes relate to verbal memory decline across the preclinical and mild cognitive impairment (MCI) stages of AD.

In this retrospective, longitudinal, observational study, data were extracted from 404 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 (69 females, 68 males) or MCI (113 females, 151 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 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 Immediate and Delayed Recall z-scores of the Rey Auditory Verbal Learning Test. Covariates included baseline age, education, and apolipoprotein E genotype.

A significant sex x diagnostic group x biomarker change interaction (β = −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 mild cognitive impairment stage, a significant sex X biomarker change interaction (β = 10.17, 95% CI = 4.94 to 15.40, p < .001) in the MCI stage 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.

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 404 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.