Pathogenic variants in the Longitudinal Early-onset Alzheimer's Disease Study cohort

Area of Science:

• Neuroscience
• Genetics
• Medical Research

Background:

• Early-onset Alzheimer's disease (EOAD) presents before age 65 and has a significant genetic component.
• Investigating genetic factors in EOAD is crucial for understanding disease mechanisms and developing targeted therapies.
• The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) aims to uncover the genetic underpinnings of cognitive impairment in younger individuals.

Purpose of the Study:

• To investigate the genetic etiology of early-onset cognitive impairment in LEADS participants.
• To screen for known pathogenic variants in genes associated with Alzheimer's disease and related dementias.
• To identify novel genetic variants contributing to early-onset non-AD (EOnonAD) and early-onset AD (EOAD).

Main Methods:

• Whole exome sequencing was performed on 299 LEADS participants (EOAD and EOnonAD cases).
• Pathogenic variant frequency was assessed in key genes: APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72.
• Gene burden testing compared LEADS cases to cognitively normal controls from the Parkinson's Progression Markers Initiative (PPMI) study.

Main Results:

• Previously reported pathogenic variants were found in 1.35% of EOAD and 6.58% of EOnonAD cases.
• No significant enrichment of rare functional variants was observed in APP, PSEN1/2, GRN, and MAPT.
• Eight cognitively impaired pathogenic variant carriers were identified, with variants in PSEN1, GRN, MAPT, and C9ORF72.

Conclusions:

• The findings suggest that LEADS is enriched for novel genetic causative variants in early-onset cognitive impairment.
• Previously identified pathogenic variants do not explain the majority of cases in the LEADS cohort.
• LEADS serves as a valuable resource for future genetic research into early-onset Alzheimer's disease.