Cerebrospinal fluid tau levels are associated with abnormal neuronal plasticity markers in Alzheimer’s disease

Abstract

Background Increased total tau (t-tau) in cerebrospinal fluid (CSF) is a key characteristic of Alzheimer’s disease (AD) and is considered to result from neurodegeneration. T-tau levels, however, can be increased in very early disease stages, when neurodegeneration is limited, and can be normal in advanced disease stages. This suggests that t-tau levels may be driven by other mechanisms as well. Because tau pathophysiology is emerging as treatment target for AD, we aimed to clarify molecular processes associated with CSF t-tau levels. Methods We performed a proteomic, genomic, and imaging study in 1380 individuals with AD, in the preclinical, prodromal, and mild dementia stage, and 380 controls from the Alzheimer’s Disease Neuroimaging Initiative and EMIF-AD Multimodality Biomarker Discovery study. Results We found that, relative to controls, AD individuals with increased t-tau had increased CSF concentrations of over 400 proteins enriched for neuronal plasticity processes. In contrast, AD individuals with normal t-tau had decreased levels of these plasticity proteins and showed increased concentrations of proteins indicative of blood–brain barrier and blood-CSF barrier dysfunction, relative to controls. The distinct proteomic profiles were already present in the preclinical AD stage and persisted in prodromal and dementia stages implying that they reflect disease traits rather than disease states. Dysregulated plasticity proteins were associated with SUZ12 and REST signaling, suggesting aberrant gene repression. GWAS analyses contrasting AD individuals with and without increased t-tau highlighted several genes involved in the regulation of gene expression. Targeted analyses of SNP rs9877502 in GMNC, associated with t-tau levels previously, correlated in individuals with AD with CSF concentrations of 591 plasticity associated proteins. The number of APOE-e4 alleles, however, was not associated with the concentration of plasticity related proteins. Conclusions CSF t-tau levels in AD are associated with altered levels of proteins involved in neuronal plasticity and blood–brain and blood-CSF barrier dysfunction. Future trials may need to stratify on CSF t-tau status, as AD individuals with increased t-tau and normal t-tau are likely to respond differently to treatment, given their opposite CSF proteomic profiles.

Quantitative proteomics of cerebrospinal fluid from African Americans and Caucasians reveals shared and divergent changes in Alzheimer’s disease

“…The copyright holder for this preprint this version posted December 8, 2022. ; https://doi.org/10.1101/2022.12.07.519393 doi: bioRxiv preprint (48). A large proportion of synaptic proteins in this study mapped to M1 and M4 that positively associate with cognition and are decreased in AD.…”

“…Increased Tau in CSF is considered to result from neurodegeneration, however, it can be increased in early pre-symptomatic disease stages when neurodegeneration is limited (46,47). Recently, Tau CSF levels have been linked to enhanced synaptic plasticity (48). A large proportion of synaptic proteins in this study mapped to M1 and M4 that positively associate with cognition and are decreased in AD.…”

Cerebrospinal fluid proteomic profiling of individuals with mild cognitive impairment and suspected non‐Alzheimer's disease pathophysiology

“…Polygenic risk score analyses were available for a subset of patients of the EMIF-AD MBD study (CN = 63, MCI-SNAP = 17, MCI-AD = 61) on genome-wide single nucleotide polymorphism (SNP) genotyping data generated with the Global Screening Array (Illumina, Inc.) using PRSice (v2.3). 16 PGRS were calculated by adding the sum of each allele weighted by the strength of its association with AD risk as calculated previously by the largest genome-wide association study (GWAS) on AD. 18 Clumping was performed prior to calculating PGRS, to remove SNPs that are in linkage disequilibrium (r 2 > 0.1) within a slicing 1M bp window.…”

P-tau subgroups in AD relate to distinct amyloid production and synaptic integrity profiles

“…This framework suggests that the subgroup with normal p-tau CSF levels and abnormal amyloid (i.e., A+T−) do not have AD, but AD pathological change. However, previous studies found that up to 30% of individuals with a pathological diagnosis of AD, can show normal CSF p-tau levels [ 39 ]. Possibly, normal p-tau levels may indicate a biological subtype of AD, since individuals in this subgroup showed compared to controls a different pattern of alterations in CSF markers.…”

“…This suggests that this tau subgroup shows a distinct underlying pathophysiology that is related to lower p-tau levels in CSF. A recent CSF proteomic study suggests that A+ individuals with normal tau levels show involvement in blood-brain barrier dysfunction, and indications of decreased amyloid metabolism as well as lower levels of proteins associated with neuronal plasticity [ 39 ]. Potentially, the lowest tau subgroup could differ in additional processes, e.g., in another study, A+ individuals with normal tau levels showed reductions in immune-related proteins [ 40 ].…”