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

Abstract

Background We previously identified four Alzheimer’s disease (AD) subgroups with increasingly higher cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 181 (p-tau). These subgroups included individuals across the cognitive spectrum, suggesting p-tau subgroups could reflect distinct biological changes in AD, rather than disease severity. Therefore, in the current study, we further investigated which potential processes may be related with p-tau subgroups, by comparing individuals on CSF markers for presynaptic structure [vesicle-associated membrane protein 2 (VAMP2)], postsynaptic structure [neurogranin (NRGN)], axonal damage [neurofilament light (NfL)], and amyloid production [beta-secretase 1 (BACE1) and amyloid-beta 1–40 (Aβ40)]. Methods We selected 348 amyloid-positive (A+) individuals (53 preclinical, 102 prodromal, 193 AD dementia) and 112 amyloid-negative (A−) cognitively normal (CN) individuals from the Amsterdam Dementia Cohort (ADC). Individuals were labeled according to their p-tau subgroup (subgroup 1: p-tau ≤ 56 pg/ml; subgroup 2: 57–96 pg/ml; subgroup 3: 97–159 pg/ml; subgroup 4: > 159 pg/ml). CSF protein levels were measured with ELISA (NRGN, BACE1, Aβ40, NfL) or single-molecule array (Simoa) (VAMP2). We tested whether protein levels differed between the p-tau subgroups within A+ individuals with linear models corrected for age and sex and whether disease stage influenced these relationships. Results Among A+ individuals, higher p-tau subgroups showed a higher percentage of AD dementia [subgroup 1: n = 41/94 (44%); subgroup 2: n = 81/147 (55%); subgroup 3: n = 59/89 (66%); subgroup 4: n = 7/11 (64%)]. Relative to controls, subgroup 1 showed reduced CSF levels of BACE1, Aβ40, and VAMP2 and higher levels of NfL. Subgroups 2 to 4 showed gradually increased CSF levels of all measured proteins, either across the first three (NfL and Aβ40) or across all subgroups (VAMP2, NRGN, BACE1). The associations did not depend on the clinical stage (interaction p-values ranging between 0.19 and 0.87). Conclusions The results suggest that biological heterogeneity in p-tau levels in AD is related to amyloid metabolism and synaptic integrity independent of clinical stage. Biomarkers reflecting amyloid metabolism and synaptic integrity may be useful outcome measures in clinical trials targeting tau pathology.

Cerebrospinal fluid proteomics in patients with Alzheimer’s disease reveals five molecular subtypes with distinct genetic risk profiles

“…of controls to compare these values between subtypes. Finally, we measured BACE1, amyloid-β 40 and neurogranin with EUROIMMUN ELISA assays (Germany), NEFL with ADx NeuroSciences (Belgium) ELISA assay and VAMP2 with a prototype assay developed by ADx NeuroSciences (Belgium) with single-molecule array technology (Quanterix Corporation) as described previously 95 . These measures were not included in clustering, but used as independent markers to compare AD subtypes.…”

Large-scale cerebrospinal fluid proteomic analysis in Alzheimer’s disease patients reveals five molecular subtypes with distinct genetic risk profiles

“…We standardized continuous amyloid 1-42, t-tau and p-tau181 values within specific assays according to the mean and standard deviation of controls to compare these values between subtypes. Finally, we measured BACE1, abeta40, and neurogranin with EUROIMMUN ELISA assays (Germany), NEFL with ADx NeuroSciences (Belgium) ELISA assay, and VAMP2 with a prototype assay developed by ADx Neurosciences (Belgium) with single-molecule array (Simoa) technology (Quanterix Corp, Billerica, USA) as previously described 134 . These measures were not included in clustering, but used as independent markers to compare between AD subtypes.…”

The Role of Tau Protein on Alzheimer’s Disease

“…In cerebrospinal fluid (CSF), there are many biomarkers that can be used to measure the extent of AD, such as A-beta, p-tau, total tau (t-tau), and neurofilament light chain (NfL) [14]. CSF levels of tau are proven to be higher in AD patients than that in healthy people [15]. It was witnessed that synaptic biomarkers could significantly distinguish AD patients and non-AD neurologic disorders [14].…”

“…It was witnessed that synaptic biomarkers could significantly distinguish AD patients and non-AD neurologic disorders [14]. The possible relationships between p-tau proteins and some AD symptoms such as dementia were verified by analyzing distinct CSF p-tau levels [15]. Other symptoms that are involved in AD-like synaptic dysfunction and axonal damage can also be measured within CSF [15].…”

“…The possible relationships between p-tau proteins and some AD symptoms such as dementia were verified by analyzing distinct CSF p-tau levels [15]. Other symptoms that are involved in AD-like synaptic dysfunction and axonal damage can also be measured within CSF [15]. For example, in the preclinical stage, levels of synaptic biomarkers increased remarkably in older individuals with higher brain metabolism, indicating that the investigation through biomarkers in CSF is efficient [14].…”