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Alzheimers disease (AD) is biologically heterogeneous, and detailed understanding of the processes involved in patients is critical for development of treatments. Cerebrospinal fluid (CSF) contains hundreds of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. We studied whether AD biological subtypes can be detected in cerebrospinal fluid (CSF) proteomics using the dual clustering technique non-negative matrix factorization. In two independent cohorts (EMIF-AD MBD and ADNI) we found that 705 (77% of 913 tested) proteins differed between AD (defined as having abnormal amyloid, n=425) and controls (defined as having normal CSF amyloid and tau and intact cognition, n=127). Using these proteins for data-driven clustering, we identified within each cohorts three robust pathophysiological AD subtypes showing 1) hyperplasticity and increased BACE1 levels; 2) innate immune activation; and 3) blood-brain barrier dysfunction with low BACE1 levels. In both cohorts, the majority of individuals was labelled as having subtype 1 (80, 36% in EMIF-AD MBD; 117, 59% in ADNI), 71 (32%) in EMIF-AD MBD and 41 (21%) in ADNI were labelled as subtype 2, 72 (32%) in EMIF-AD MBD and 39 (20%) individuals in ADNI were labelled as subtype 3. Genetic analyses showed that all subtypes had an excess of genetic risk for AD (all p>0.01). Additional pathological comparisons that were available for a subset in ADNI only further showed that subtypes showed similar severity of AD pathology, and did not differ in the frequencies of co-pathologies, providing further support that these differences truly reflect AD heterogeneity. Compared to controls all non-demented AD individuals had increased risk to show clinical progression, and compared to subtype 1, subtype 2 showed faster progression to after correcting for age, sex, level of education and tau levels (HR (95%CI) subtype 2 vs 1 = 2.5 (1.2, 5.1), p = 0.01), and subtype 3 at trend level (HR (95%CI) = 2.1 (1.0, 4.4)). Together, these results demonstrate the value of CSF proteomics to study biological heterogeneity in AD patients, and suggest that subtypes may require tailored therapy.

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