Evolution of unawareness of memory decline in individuals with autosomal dominant Alzheimer’s disease: Neuropsychiatry and behavioral neurology: Neuropsychiatric symptoms in MCI and dementia

Background While loss of insight of cognitive deficits, anosognosia, is a common symptom in Alzheimer's disease (AD) dementia, there is a lack of consensus regarding the presence of altered awareness of memory function in the pre‐dementia stages of the disease. Here, we investigated the evolution of memory awareness in the AD‐course in a large cohort of individuals who carry mutations for autosomal dominant AD (ADAD; a population that are genetically determined to develop early‐onset dementia, and have a well‐characterized disease trajectory from pre‐symptomatic to clinical stages) and compared it with family members who do not carry the mutation. Methods Pseudo‐longitudinal analyses using linear mixed‐effect models was used to predict self‐awareness (assessed using an awareness index based on the discrepancy score between participant and study‐partner report on the Memory Complaint Scale (Spanish version),in a total of 2,379 members of a Colombian kindred including 396 ADAD (14.9% impaired) and 1,983 non‐carrier family members (Table 1). Age was entered as a fixed and random factor in the models. Results The mutation carriers complained significantly more than their study‐partner until the mean age of 35, and complained significantly less ( unawareness/anosognosia ) than their study‐partner around the age of 43 (Figure 1A), approximately 6 years prior to their estimated median age of dementia onset (49yo). Cognitively‐unimpaired non‐carriers complained significantly more than their study‐partners ( heightened awareness / hypernosognosia ) between ages 20‐60 (Figure 1B). Using the awareness index (Figure 2) we observed a decrease with age (est.=‐0.04 discrepant‐points/year,se=0.02,t=‐2.2, p =0.03) in the non‐carriers and an even steeper decline in the mutation carriers (est.=‐0.21 discrepant‐points/year,se=0.04,t=‐5.1, p =2.8*e‐7). The awareness index was significantly different between groups from age 22.5, indicating less awareness of memory in the mutation carriers as compared to the non‐carriers. Conclusion Hypernosognosia was observed in both groups, indicating that heightened awareness of memory function is common and non‐specific in this cohort. In mutation‐carriers, awareness of memory decreased in the pre‐dementia stages, reaching anosognosia 6 years before dementia onset. These findings provide further support for the usefulness of informant‐reported cognitive decline and add to the sporadic AD literature suggesting that individuals who become unaware of cognitive change in preclinical stages may represent a specific risk group to develop AD dementia.