α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden

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INTRODUCTIONAmyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in approximate to 50% of AD and ADAD brains.METHODSUsing an alpha-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo.RESULTSNo asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed alpha-synuclein seeding activity in CSF in vivo.DISCUSSIONResults suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF alpha-synuclein SAA has low sensitivity.Highlights Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded alpha-synuclein in approximate to 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect alpha-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF alpha-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.

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