Basic Science and Pathogenesis

Area of Science:

• Neuroscience
• Genetics
• Cognitive Psychology

Background:

• Autosomal dominant Alzheimer's disease (ADAD) offers insights into early Alzheimer's disease (AD) cognitive changes.
• The role of APOE ε4 in sporadic AD is established, but its impact on ADAD cognitive phenotypes is unclear.

Purpose of the Study:

• Investigate the effect of APOE ε4 co-occurrence with APP_V717I or PSEN1_A431E mutations on preclinical ADAD cognitive function.
• Determine if specific mutations and APOE ε4 influence cognitive performance in individuals at risk for ADAD.

Main Methods:

• Genetic analysis (APP_V717I/PSEN1_A431E mutations, APOE genotyping) and neuropsychological evaluation (CERAD-MX) were performed on 81 Mexican-mestizo individuals.
• Participants were categorized into mutation carriers (C) and non-carriers (NC), and further stratified by APOE ε4 status (ε4+/ε4-).
• Cognitive performance was assessed using normalized z-scores across 12 CERAD-MX tasks, with group differences analyzed using non-parametric tests.

Main Results:

• Mutation carriers (C) demonstrated significantly lower performance in visual memory tasks (Constructional Praxis-Recall, Rey-Osterrieth Complex Figure-Recall) compared to non-carriers (NC).
• Within mutation carriers, those without the APOE ε4 allele (Cε4-) showed poorer Rey-Osterrieth Complex Figure-Recall performance compared to non-carriers without the APOE ε4 allele (NCε4-).

Conclusions:

• Early visual memory impairment is detectable in the preclinical stage of ADAD.
• The APOE ε4 allele did not show a detrimental effect on memory performance in this ADAD cohort.
• Further research with larger sample sizes is needed to confirm findings and explore other cognitive domains and influencing factors like APOE ancestry.