Working memory in preclinical autosomal dominant Alzheimer’s disease
Embargo Date
2025-10-02
OA Version
Citation
Abstract
The hallmark cognitive symptom that presents early in Alzheimer’s disease (AD), episodic memory difficulties, is well studied relative to cognitive processes that may support episodic memory, including working memory. In this project, I examined working memory and its relation to disease biomarkers in a unique Colombian cohort of carriers of the Presenilin-1 E280A mutation that causes autosomal dominant AD (ADAD) by mid-life.
Study 1 examined cognition in ADAD mutation-carrying children (ages 6-16 years) and non-carrier children, with the hypothesis that carrier children would exhibit poorer performance across cognitive tests than non-carriers. 1354 children participated, including 265 with the ADAD mutation. Across the tests, the overall groups did not differ on cognitive abilities, but subgroup analysis revealed sex differences in working memory in the carriers, with boys exhibiting worse performance than girls, as well as performing more poorly than boys and girls without the mutation.
Study 2 assessed working memory and its relation to AD biomarkers, including resting-state functional connectivity and in-vivo AD pathology (amyloid-beta and tau), in 31 adult carriers of the ADAD mutation and 34 non-carrier family members. My first hypothesis, that carriers would be more impaired on working memory than non-carriers, was not supported. By contrast, supporting my second hypothesis, in carriers relative to non-carriers, working memory was more strongly correlated with greater age, neocortical amyloid-beta and precuneus tau; it was not, however, related to network functional connectivity.
In Studies 3-5, I developed a new digital working memory measure, the Memory for Semantically Related Objects (MESERO) test, and piloted it in healthy adults and the Colombian ADAD cohort. The results indicated that the MESERO is likely a reliable cognitive test. Further, performance on the MESERO differentiated cognitively unimpaired ADAD mutation carriers from non-carriers, suggesting that the MESERO is sensitive to early clinical changes associated with AD.
Together, these studies illustrate the following: (1) working memory performance is related to AD biomarkers in preclinical ADAD; (2) there were sex differences in working memory, at least in child carriers; and (3) a new test of working memory may be helpful at identifying individuals at increased risk for AD.