Objective: To examine the ability to detect concurrent Lewy Body Disease via Lew Body pathology (LBP) in Autosomal Dominant Alzheimer’s Disease (ADAD) through detection of misfolded alpha-synuclein (aSyn) in CSF using a seed amplification assay (SAA).

Background: Neuropathological studies have shown that LBP is present in about 50% of cases of sporadic AD and 30% of ADAD. Clinical recognition of concurrent LB and AD pathologies in patients is crucial as the presence of both predicts a faster rate of cognitive decline, need to treat additional parkinsonian motor and non-motor symptoms, and a less predictable response to symptomatic and disease modifying treatments.

Method: We collected clinical, CSF, and post-mortem neuropathological data from 31 subjects within families with confirmed ADAD due to mutations in either PSEN1 or APP. 22 individuals were mutation carriers and 9 were non-carriers. We examined the prevalence of aSyn-SAA positivity in CSF from these subjects. We correlated this data with their clinical presentation and post-mortem neuropathological data.

Results: Of the 22 mutation carriers, 4 (18%) showed positive aSyn-SAA. Of the 9 non-carriers, none showed aSyn-SAA. Of the 4 mutation carriers with positive SAA, 2 were asymptomatic, 1 was mildly symptomatic (Mild Cognitive Impairment, CDR 0.5), and 1 had mild dementia (CDR 1). Among the 22 mutation carriers, we found no association between aSyn-SAA and UPDRS III score nor dream enactment behavior.

Conclusion: We found that the presence of LBP in AD, specifically ADAD, can be detected via the presence of aSyn-SAA in CSF. This can occur during both the pre-symptomatic and symptomatic stages of the disease, a novel finding. Our data also shows that like LBP on autopsy, the presence of aSyn-SAA in CSF varies from person-to-person within a family with the same ADAD mutation. These differences within a mutation and even within the same families who share the mutation argues that environment and exposures must also influence the presence of LBP in ADAD. This would not be unexpected, as Parkinson’s Disease, Dementia with Lewy Bodies, and Alzheimer’s Disease have long been suspected of having many environmental risk factors. Our findings demonstrate that LBP is not just a late feature of ADAD pathology. With the advent of SAA technology, we can now assess for LBP early in the disease course before symptoms begin.

Table 1. Demographics

Table 2. Comparison of aSyn Positivity with ADA m

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