Lewy Body pathology is detected in individuals spanning the Alzheimer's Disease spectrum
Biomarkers are used to identify pathological features of Alzheimer's disease (AD). Importantly, their measured levels are used in diagnosis, subtyping, and monitoring progress in clinical trials. In AD, imaging and fluid biomarkers are used to detect extracellular β-amyloid (Aβ) plaques and intracellular tau neurofibrillary tangles (NFTs), the two hallmarks of disease progression. Lewy bodies (LBs) are a common co-pathology of AD but are characteristic hallmarks of other neurodegenerative diseases such as dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In fact, up to half of AD autopsy cases show LBs in brain tissue.
LBs are composed of α-synuclein (α-syn) aggregates and have a different pathological spreading pattern than Aβ or tau in the brain. The presence of LBs in AD introduces heterogeneity to overall progression of disease. The co-existence of different pathological forms of proteins in the brain can complicate biomarker monitoring, and possibly affect outcomes such as those measured in clinical trials, thus lowering significance and success of potential treatments. As such, it is important to be aware of the prevalence of such proteins and their potential effects on AD pathology.
The α-synuclein seed amplification assay (SAA) is designed for testing pathogenic "seeds" of α-synuclein in cerebrospinal fluid (CSF). The assay is designed for detection of early forms of aggregated α-synuclein. Dr Tosun and colleagues tested for LB co-pathology in individuals with AD pathology in the ADNI clinical cohort. This research was presented in two papers that have been published in a special issue of Alzheimer's & Dementia recognizing the anniversary and contribution of 20 years of the ADNI.
In the first paper, SAA was performed on recent samples of CSF which included participants who were diagnosed across the AD spectrum. This study confirmed sensitivity (79%) and specificity (97%) of SAA in detecting LB pathology in comparison to gold-standard autopsy. SAA positivity (SAA+) was detected in 22% of the ADNI cohort, and increased with age and disease stage.
SAA results were compared to established AD biomarkers for Aβ burden (CSF Aβ42 and Aβ PET), tau burden (CSF p-tau181), and cognitive measures. Results showed that increased SAA+ prevalence was associated with greater Aβ burden, lower tau burden (particularly in Dementia participants), and cognitive impairment. This study expands our understanding of utilizing the α-synuclein SAA to asses LB co-pathology in AD, and broadens the clinical lens to better guide diagnostic and therapeutic approaches to AD.
The second paper focused on the longitudinal aspect of α-synuclein pathology in AD. SAA was performed on CSF samples from previous visits of individuals who were found to be SAA+ in the first study. Interestingly, 34 individuals were identified who converted from SAA- to SAA+ during their time in the ADNI. This dataset provided a unique opportunity to analyze changes in different biomarker pathologies over time, including α-synuclein.
Overall, conversion to SAA+ was associated with Aβ burden, earlier symptom onset, and greater cognitive decline. By modeling several cognitive measures as a function of estimated amyloid onset age (EAOA), the figure below illustrates that SAA+ individuals decline faster - seen as steeper slopes - across global (top panel) and regional (bottom panel) cognitive function tests.
In all, these studies highlight the potential interplay between amyloid and α-synuclein, and their impact on disease progression. This emphasizes the importance of understanding the mechanisms underpinning copathologies of AD. Moving forward, it is important to include LB pathology in diverse cohorts to enhance our understanding of AD.
Papers can be accessed here:
