Clinical Manifestations.

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Autosomal dominant Alzheimer's disease (ADAD) shares similarities with sporadic AD but exhibits heterogeneity in clinical presentation and neuropathology.
• Variability exists in amyloid-β (Aβ) plaque and cerebral amyloid angiopathy (CAA) deposition, impacting disease progression.
• Investigating ADAD heterogeneity can reveal underlying mechanisms and inform therapeutic strategies.

Purpose of the Study:

• To explore the relationship between genetic mutations (APP, PSEN1) and clinical/neuropathological heterogeneity in ADAD.
• To analyze the impact of specific mutations on Aβ deposition patterns, including Aβ43, and CAA severity.
• To provide insights for developing personalized treatment approaches for ADAD.

Main Methods:

• Clinical phenotype data from over 250 individuals with ADAD mutations were analyzed.
• Post-mortem brain tissue from 50 individuals (37 PSEN1, 13 APP mutations) was examined for Aβ pathology and CAA.
• Immunohistochemistry with pan-amyloid-β antibodies and analysis of Aβ40, Aβ42, and Aβ43 binding patterns were performed.

Main Results:

• Age at onset was strongly mutation-dependent, while survival showed less influence.
• Atypical clinical presentations (non-amnestic) and features were more common in PSEN1 mutations, especially post-codon 200.
• CAA frequency and severity varied significantly; Aβ43 deposition was observed in PSEN1 but not APP mutation cases.

Conclusions:

• Phenotypic heterogeneity in ADAD is significantly influenced by the causative gene and specific mutation.
• Mutation-specific Aβ deposition patterns correlate with CAA variability and clinical manifestations.
• Understanding these genotype-phenotype-neuropathology links is crucial for personalized ADAD therapies.