Introduction: The Genetic Landscape of Early-Onset Alzheimer’s Disease
Alzheimer’s disease (AD) is a heterogeneous neurodegenerative disorder traditionally classified by the age of symptom onset. While late-onset Alzheimer’s disease (LOAD), occurring after age 65, is the most prevalent form, early-onset Alzheimer’s disease (EOAD) presents a unique clinical challenge. While rare autosomal dominant mutations in APP, PSEN1, and PSEN2 account for a small fraction of EOAD cases, the genetic architecture of sporadic EOAD—which accounts for the majority of cases—remains largely elusive.
Recent advances in genomic medicine have shifted focus toward polygenic risk scores (PGS), which aggregate the cumulative effects of thousands of common genetic variants. While the utility of PGS in predicting LOAD is well-documented, its relevance to the distinct clinical and biological profile of EOAD has been less clear. A landmark study recently published in Alzheimer’s & Dementia, titled Alzheimer’s disease polygenic risk in early- and late-onset Alzheimer’s disease, sought to bridge this gap by evaluating how genetic risk factors identified in LOAD populations translate to the EOAD phenotype.
Study Design and Methodology
To investigate these genetic associations, researchers utilized data from two major longitudinal cohorts: the Longitudinal Early-onset Alzheimer’s Disease Study (LEADS) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The LEADS cohort provided a critical window into EOAD, while ADNI served as the primary reference for LOAD.
The research team calculated a LOAD-based polygenic score (PGS) for participants in both studies. This score was then analyzed for its association with several key clinical and biological variables:
Clinical Predictors
Association with the overall risk of developing AD, the specific age of symptom onset, and longitudinal cognitive performance as measured by standardized neuropsychological assessments.
Imaging Biomarkers
Amyloid deposition quantified via PET imaging using the Centiloid scale, providing a standardized measure of plaque burden.
Fluid Biomarkers
Cerebrospinal fluid (CSF) levels of amyloid-beta (Aβ42), tau, and markers of synaptic integrity, specifically synaptosomal-associated protein 25 (SNAP-25).
A critical component of the statistical analysis was the adjustment for APOE ε4 carrier status. Given that the APOE ε4 allele is the strongest individual genetic risk factor for AD, the researchers aimed to determine if the broader polygenic score provided incremental predictive value beyond this single locus.
Key Findings: Polygenic Risk and Clinical Phenotypes
The results of the study provide a nuanced view of the genetic overlap between LOAD and EOAD. While the LOAD-derived PGS was significantly elevated in both LOAD and EOAD patients compared to healthy controls, its predictive power in the EOAD cohort was limited.
Predicting Disease Risk and Onset
Perhaps the most significant finding was that after adjusting for APOE ε4 status, the LOAD PGS was not a significant independent predictor of EOAD risk. Furthermore, the PGS did not show a statistically significant association with the age of onset within the EOAD group (p = 0.106). This suggests that while LOAD and EOAD share some genetic commonalities, the drivers of early disease manifestation may involve distinct genetic pathways or a higher burden of rare variants not captured by standard polygenic scores.
Cognitive Performance
The study also found no significant correlation between a higher LOAD PGS and the rate of cognitive decline or baseline cognitive performance in EOAD patients (p = 0.417). This decoupling of polygenic risk from clinical progression in younger patients highlights the potential influence of cognitive reserve or different pathological velocities in EOAD compared to the more protracted course often seen in LOAD.
Biomarker Insights: SNAP-25 and the Amyloid Paradox
While the clinical correlations were modest, the associations between the LOAD PGS and biological markers in the LEADS cohort were striking, offering new insights into the pathophysiology of early-onset disease.
Synaptic Dysfunction: The SNAP-25 Connection
A major highlight of the study was the association between higher LOAD PGS and elevated levels of CSF SNAP-25 (p = 2.3 × 10^-5). SNAP-25 is a critical component of the SNARE complex, essential for synaptic vesicle exocytosis and neurotransmitter release. Elevated CSF levels of SNAP-25 are widely regarded as markers of synaptic degeneration or increased synaptic turnover. The finding that LOAD genetic risk factors are linked to SNAP-25 levels in EOAD patients suggests that common genetic variants may converge on pathways governing synaptic integrity, potentially accelerating the neurodegenerative process even if they do not dictate the exact timing of symptom onset.
The Amyloid Discrepancy
The researchers observed a complex and somewhat contradictory relationship regarding amyloid markers. Higher LOAD PGS was associated with lower amyloid PET Centiloids, which typically suggests less brain amyloid deposition. However, the same higher PGS was associated with lower CSF Aβ42 levels, a proxy marker usually indicating higher amyloid sequestration in the brain.
These divergent findings reflect the biological complexity of EOAD. The researchers noted that these results support the need for larger, more powered studies to determine whether LOAD genetic factors truly drive increased amyloid deposition in EOAD or if they influence the solubility and clearance of amyloid in ways that differ from LOAD.
Expert Commentary: Mechanistic Implications and Clinical Utility
The findings from the LEADS and ADNI comparison underscore a fundamental principle in modern neurogenetics: the risk of developing a disease is not always synonymous with the drivers of its progression or its specific clinical presentation.
From a clinical perspective, the fact that LOAD PGS does not independently predict EOAD onset after adjusting for APOE ε4 suggests that, for now, broad polygenic testing may have limited utility in the diagnostic workup of sporadic EOAD in the clinic. However, the strong association with SNAP-25 is of high interest for drug development. If polygenic risk influences synaptic transmission and protein aggregation, then therapies targeting synaptic preservation might be particularly relevant for individuals with high polygenic burdens.
Furthermore, the study highlights the ‘APOE ε4 shadow.’ In many genetic studies of AD, the massive effect size of the APOE locus can mask the contributions of other variants. By adjusting for this, the researchers have shown that while the ‘polygenic tail’ of LOAD risk factors is present in EOAD, it does not carry the same weight in determining the clinical timeline for younger patients as it might in older populations.
Conclusion and Summary
In summary, the study by Pentchev et al. clarifies the role of LOAD-derived polygenic risk in the context of early-onset Alzheimer’s disease. While these genetic scores contribute minimally to the timing of EOAD onset and cognitive dysfunction, their significant association with fluid biomarkers—particularly SNAP-25—points toward a shared role in the underlying pathophysiology of synaptic failure.
For clinicians and researchers, these results emphasize that EOAD remains a distinct entity with genetic drivers that are only partially explained by LOAD risk factors. Future research must continue to explore the role of rare variants, structural genomic changes, and environmental interactions that specifically trigger the early manifestation of AD. The LEADS study continues to be a vital resource in unravelling these mysteries, paving the way for more personalized approaches to diagnosis and treatment in this vulnerable patient population.
References
1. Pentchev JV, et al. Alzheimer’s disease polygenic risk in early- and late-onset Alzheimer’s disease. Alzheimers Dement. 2026 Jan;22(1):e71066. doi: 10.1002/alz.71066.
2. Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS) Consortium Data.
3. Alzheimer’s Disease Neuroimaging Initiative (ADNI) Database.
