Alpha-synuclein deposition patterns in Alzheimer’s disease: association with cortical amyloid beta and variable tau load

Alpha-synuclein (α-syn) deposits are common in around half of the Alzheimer’s disease (AD) cases. While direct and indirect protein interactions are suggested, the relationships between different protein aggregates remain poorly understood. Here, we aimed to characterize α-syn, amyloid beta (Aβ), and tau load distributions of AD patients. Protein deposits were automatically quantified with random forest pixel classifiers in immunohistochemical stainings of up to 28 brain regions in 72 brains with advanced AD neuropathological change. α-syn negative cases were distinguished from amygdala predominant, brainstem predominant, and cortical α-syn positive cases. Relationships with age, sex, and ApoE genotype were examined. α-syn co-pathology was detected in 60% of AD cases, more frequently in women. Half of these positive cases presented α-syn deposits in the cortex, around one third predominantly in the amygdala, and the remaining cases primarily in the brainstem. A high α-syn load in the amygdala was associated with an increased cortical Aβ load. The cortical tau load was increased in the amygdala predominant α-syn group but decreased in the brainstem predominant and cortical α-syn cases in comparison with α-syn negative cases. ApoE4 was associated with higher hippocampal α-syn and cortical Aβ deposition. Younger age at death was associated with a focally higher Aβ and tau load. AD cases with cortical α-syn deposition tended to have a younger age at death. Here we show that next to age, sex, and ApoE genotype, the α-syn distribution in AD is related to different Aβ and tau loads. This may have therapeutic relevance for identifying patients who respond to Aβ immunotherapy related to tau burden and underpin the need to define α-syn pathology and distribution in early disease stages.