Sex specific trajectories of verbal memory decline suggest masking of Alzheimer’s Disease symptoms in females

Structured Abstract INTRODUCTION Verbal memory tests like the Rey’s Auditory Learning Test (RAVLT) are widely used in Alzheimer’s disease assessments without consideration of females’ well-known advantages in verbal memory. This study explores if this form of cognitive reserve masks symptoms and delays diagnosis in females. METHODS We employed a retrospective longitudinal cohort design (ADNI, PREVENT-AD) to model Immediate Recall subcomponents on the RAVLT over time in amyloid negative (Aβ-) cognitively normal participants versus Aβ+ participants that progressed to AD dementia. RESULTS Our Bayesian model successfully identified the inflection point where cognition deviates from normal onto the AD dementia trajectory. The timing of decline onset differed significantly across sexes, with Aβ+ females maintaining normal cognition longer than Aβ+ males. Among individuals with AD dementia, females experienced a steeper annual decline than males. DISCUSSION Delayed onset of decline suggests that females preserve cognition despite neuropathology accumulation. This masked period represents a window for earlier detection and timely intervention before irreversible neurodegeneration. Research in Context Systematic review: The authors reviewed the literature from PubMed and Elsevier to identify verbal memory as a core feature in the Alzheimer’s Disease discourse. Our critical appraisal was complemented with meetings with expert neuropsychologists and neuroinformaticians. Interpretations: We find that females have superior performance on Rey’s Auditory Learning Test (RAVLT) Immediate Recall, females maintain performance for longer than males before being diagnosed with Alzheimer’s Disease, and once diagnosed, they decline faster than males. These findings underscore the importance of conducting Alzheimer’s Disease assessments with considerations for sex differences. Future directions: We aim to continue the investigation of cognitive reserve in females in the context of the Amyloid, Tau and Neurodegeneration (ANT) framework. Considering the early stage of disease is of interest given that our results show the appearance of cognitive symptoms many years before official dementia diagnosis. Highlights - In cognitively healthy amyloid negative participants, females outperform males on the Rey’s Auditory Learning Test (RAVLT). - In the amyloid positive participants, females maintain normal verbal memory for 2.7 years longer than males. - After divergence from cognitive normality, females experience approximately a 25-50% steeper cognitive decline compared to males. - Our findings call attention to the female verbal memory advantage as an influential form of cognitive reserve that requires diagnostic consideration.

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