Early-onset Familial Alzheimer’s Disease With Mutations In PSEN1, PSEN2 And APP And Early-onset Sporadic Alzheimer’s Disease: Clinical Feature Comparisons

Objectives: Presenilin 1(PSEN1), presenilin 2(PSEN2) and amyloid precursor protein(APP) genes are pathogenic genes for Alzheimer’s disease(AD). Early recognition of PSEN1, PSEN2 or APP mutation carriers is pivotal for studying disease pathogenesis, genetic consulting, and early intervention. Some early-onset AD patients with PSEN1, PSEN2 or APP mutations are not recommended for mutation detection because of their unknown or unclear family history. It is difficult to recognize early-onset familial AD(EOFAD) patients with PSEN1, PSEN2 or APP mutations from such patients. This study aims to explore clinical features of EOFAD versus early-onset sporadic AD(EOSAD). This will help recognize EOFAD patients with PSEN1, PSEN2 or APP mutations via clinical features other than family history, which would further provide evidence for disease mechanism, genetic counseling and early intervention.Methods: Retrospective analysis of 20 EOFAD cases with PSEN1, PSEN2 or APP mutations and 36 EOSAD cases. Detection of PSEN1, PSEN2 and APP mutations and apolipoprotein E(APOE) genotype were performed using PCR and enzyme digestion. Demographic information, medical history, and cognitive and non-cognitive features were collected, and neuropsychological tests were conveyed. Demographic features, neuropsychological performances and clinical features were compared for differences.Results: Compared with EOFAD cases, EOSAD cases are more aged at the interview(58.47 vs 53.00 y, p=0.011), less educated(8.597 vs 11.300 y, p=0.028), and have later ages at onset(AAOs)(54.22 vs 48.25 y, p=0.005). EOSAD cases also have lower scores in long-term delayed recognition(1.93 vs 3.93, p=0.039), take longer to perform the trail making test A(128.29 vs 93.77 s, p=0.011), and have higher scores of Activity of Daily Living Scale(ADL)(40.43 vs 28.83, p=0.003). All subjects present with memory deficit as the first symptom. Disorientation and language impairment are more common for EOSAD cases than EOFAD cases(97.2% vs 75.0%, p=0.034; and 88.9% vs 60.0%, p=0.029, respectively). Linear correlation is observed between AAO and age at the interview for both groups. After adjusting for education and AAO, binary logistic regression analysis shows that the difference between groups is no more significant in long-term delayed recognition, ADL, disorientation or language impairment(p>0.05). This indicates that the differences between groups in long-term delayed recognition, ADL, disorientation and language impairment are affected by AAO and education.Conclusion: Other than the family history, features that facilitate recognizing EOFAD cases with PSEN1, PSEN2 and APP mutations include earlier AAO, higher education levels, poorer performance in long-term delayed recognition, longer time to complete the trail making test A, less frequent disorientation and language impairment, and lower ADL scores. However, differences of these manifestations between EOFAD and EOSAD might be influenced by AAO and education levels. Such findings provide clinical features other than the family history for EOFAD patients with PSEN1, PSEN2 and APP mutations, which may provide evidence for pathogenesis, genetic counseling, and early intervention for AD.