Pathophysiological subtypes of Alzheimer’s disease based on cerebrospinal fluid proteomics

Abstract

Alzheimer's 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.

The Innovative Medicines Initiative neurodegeneration portfolio: From individual projects to collaborative networks

“…Our findings show that the IMI NDD portfolio has contributed to the development of tools, standards and approaches to address the high unmet medical need for effective disease-modifying as well as symptomatic interventions in NDDs in general, and Alzheimer's disease in particular. For example, IMI projects such as EMIF and EPAD have developed platforms and infrastructures to speed up clinical development, also generating cohort datasets which have been widely used by researchers to advance the development of novel, non-invasive biomarkers for the diagnosis and monitoring of Alzheimer's disease from its very earliest stages (6,7). The EQIPD Quality System, which includes a series of tools, guidance and requirements to support preclinical researchers ensure their work is robust and reliable, is being incorporated into the global Partnership for Assessment and Accreditation of Scientific Practice (PAASP) network (https://paasp.net).…”

Decorin is an early CSF biomarker of Alzheimer’s Aβ amyloidosis

“…In an attempt to further understand how changes in the mouse CSF proteomes of the AD mouse models re ect those observed in patients, we next compared them to MS-characterized CSF proteomes of a large human cohort European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) (33). According to the speci c criteria, individuals with abnormal CSF Aβ42 were classi ed into three clinical stages; preclinical AD (normal cognition, i.e., NC), prodromal AD (mild cognitive impairment, i.e., MCI) and mild to moderate AD-type dementia, based on their cognitive performance (34).…”

“…Mass spectrometry analysis of human CSF CSF proteomic results reported in a previous study were included in the present research (33). Brie y, we selected individuals with AD pathology de ned as abnormal CSF Aβ42, and we subdivided this group into abnormal (a+t+, n = 151) and normal CSF t-tau groups (a+t-, n = 77).…”

“…Based on their cognitive performance, AD individuals were classi ed in 3 clinical stages as preclinical AD (normal cognition, i.e., NC), prodromal AD (mild cognitive impairment, i.e., MCI) and mild to moderate AD-type dementia according to study speci c criteria (34). MS was performed using tandem mass tag technique with 10+1 plexing as previously described, using high-pH reverse phase HPLC for peptide prefractionation (33,61). The EMIF-AD MS proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identi er 10.6019/PXD019910 (61).…”

Potential multiple disease progression pathways in female patients with Alzheimer's disease inferred from transcriptome and epigenome data of the dorsolateral prefrontal cortex

“…One reason for this is the variations in technical factors among studies. However, the diversity of molecular conditions in the brain among patients with AD could also be a major contributor (Tijms et al, 2020;Neff et al, 2021;Tijms et al, 2021;Bellenguez et al, 2022;Johnson et al, 2022). Additionally, such diversity in molecular conditions may be related to the diversity in symptoms and clinical manifestations (Komarova et al, 2011;Younas et al, 2020;Duara et al, 2021;Younas et al, 2024).…”