The biological diagnosis of Alzheimer's disease using blood-based biomarkers: A Canadian prospective.

The biological diagnosis of Alzheimer's disease using blood-based biomarkers: a Canadian prospective.

Amyloid Activates GSK-3β to Aggravate Neuronal Tauopathy in Bigenic Mice

Plasma phosphorylated tau181 (pTau181) is proving to be a useful predictor of Alzheimer's disease (AD). AD co-pathology is frequently observed across the Lewy body disease (LBD) spectrum. To determine whether pTau181 in LBD is associated with postmortem Alzheimer's disease neuropathologic changes (ADNC) and with antemortem positron emission spectrometry measurements of β-amyloid and tau deposition. We studied 53 participants with LBD who underwent plasma pTau181 assessment, contrasting them with 129 healthy control participants and 67 participants with AD. Postmortem assessments were conducted on 24 LBD cases. Spearman correlation analyses were used to assess the association between plasma pTau181 and the severity of amyloid deposits, tau accumulation, and neurodegeneration (A/T/N) measured at autopsy or via neuroimaging. Plasma pTau181 in LBD participants was higher than in healthy participants and lower than in AD participants. Plasma pTau181 in LBD was moderately correlated with Thal stage, Braak neurofibrillary tangle (NFT) stage, and CERAD (Consortium to Establish a Registry for Alzheimer's Disease) scores but not Lewy body Braak stage. Plasma pTau181 was associated with cortical PiB (Pittsburgh Compound-B) retention. Elevated plasma pTau181 levels were associated with greater cortical thinning, particularly in later Braak NFT regions. The addition of plasma pTau181 improved models that included age, sex, and APOE ε4 to detect amyloid and tau positivity. Plasma pTau181 reflects amyloid and tau pathology but not α-synuclein pathology in LBD. Plasma pTau181 is a useful indicator for neurodegeneration in cortical regions vulnerable to NFT pathology and adds value in identifying AD co-pathology. These findings support plasma pTau181 as a cost-effective screening tool for AD co-pathology in LBD. © 2025 International Parkinson and Movement Disorder Society.

The neuropathological confirmation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFT) remains the gold standard for a definitive diagnosis of Alzheimer’s disease (AD). Nowadays, the in vivo diagnosis of AD is greatly aided by both cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Although highly accurate, their broad implementation is restricted by high cost, limited accessibility and invasiveness. We recently developed a high-performance, ultrasensitive immunoassay for the quantification of tau phosphorylated at threonine-181 (p-tau181) in plasma, which identifies AD pathophysiology with high accuracy. However, it remains unclear whether plasma p-tau181, measured years before the death, can predict the eventual neuropathological confirmation of AD, and successfully discriminates AD from non-AD dementia pathologies. We studied a unique cohort of 115 individuals with longitudinal blood collections with clinical evaluation at 8, 4 and 2 years prior to neuropathological assessment at death. The results demonstrate that plasma p-tau181 associates better with AD neuropathology and Braak staging than a clinical diagnosis 8 years before post-mortem. Moreover, while all patients had a diagnosis of AD dementia during life, plasma p-tau181 proved to discriminate AD from non-AD pathologies with high accuracy (AUC = 97.4%, 95% CI = 94.1–100%) even 8 years before death. Additionally, the longitudinal trajectory of plasma p-tau181 was assessed in all patients. We found that the main increases in plasma p-tau181 occurred between 8 and 4 years prior to death in patients with AD neuropathology and later plateauing. In contrast, non-AD pathologies and controls exhibited minor, albeit significant, increases in p-tau181 up until death. Overall, our study demonstrates that plasma p-tau181 is highly predictive and specific of AD neuropathology years before post-mortem examination. These data add further support for the use of plasma p-tau181 to aid clinical management in primary care and recruitment for clinical trials.

The Synaptic Accumulation of Hyperphosphorylated Tau Oligomers in Alzheimer Disease Is Associated With Dysfunction of the Ubiquitin-Proteasome System

Most individuals with Down syndrome show early onset of Alzheimer disease (AD), resulting from the extra copy of chromosome 21. Located on this chromosome is a gene that encodes the dual specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A). One of the pathological hallmarks in AD is the presence of neurofibrillary tangles (NFTs), which are insoluble deposits that consist of abnormally hyperphosphorylated Tau. Previously it was reported that Tau at the Thr-212 residue was phosphorylated by Dyrk1A in vitro. To determine the physiological significance of this phosphorylation, an analysis was made of the amount of phospho-Thr-212-Tau (pT212) in the brains of transgenic mice that overexpress the human DYRK1A protein (DYRK1A TG mice) that we recently generated. A significant increase in the amount of pT212 was found in the brains of DYRK1A transgenic mice when compared with age-matched littermate controls. We further examined whether Dyrk1A phosphorylates other Tau residues that are implicated in NFTs. We found that Dyrk1A also phosphorylates Tau at Ser-202 and Ser-404 in vitro. Phosphorylation by Dyrk1A strongly inhibited the ability of Tau to promote microtubule assembly. Following this, using mammalian cells and DYRK1A TG mouse brains, it was demonstrated that the amounts of phospho-Ser-202-Tau and phospho-Ser-404-Tau are enhanced when DYRK1A amounts are high. These results provide the first in vivo evidence for a physiological role of DYRK1A in the hyperphosphorylation of Tau and suggest that the extra copy of the DYRK1A gene contributes to the early onset of AD.

ObjectiveThe development of non-invasive clinical diagnostics is paramount for the early detection of Alzheimer’s disease (AD). Neurofibrillary tangles in AD originate from the entorhinal cortex, a cortical memory area that mediates navigation via path integration (PI). Here, we studied correlations between PI errors and levels of a range of AD biomarkers using a 3D virtual reality navigation system to explore PI as a non-invasive surrogate marker for early detection.MethodsWe examined 111 healthy adults for PI using a head-mounted 3D VR system, AD-related plasma biomarkers (GFAP, NfL, Aβ40, Aβ42, and p-tau181), Apolipoprotein E (ApoE) genotype, and demographic and cognitive assessments. Covariance of PI and AD biomarkers was assessed statistically, including tests for multivariate linear regression, logistic regression, and predictor importance ranking using machine learning, to identify predictive relationships for PI errors.ResultsWe found significant positive correlations between PI errors with age and plasma GFAP, p-tau181, and NfL levels. Multivariate analysis identified significant correlations of plasma GFAP (t-value = 2.16, p = 0.0332) and p-tau181 (t-value = 2.53, p = 0.0128) with PI errors. Predictor importance ranking using machine learning and receiver operating characteristic curves identified plasma p-tau181 as the most significant predictor of PI. ApoE genotype and plasma p-tau181 showed positive and negative PI associations (ApoE: coefficient = 0.650, p = 0.037; p-tau181: coefficient = −0.899, p = 0.041). EC thickness exhibited negative correlations with age, mean PI errors, and GFAP, NfL, and p-tau181; however, none of these associations remained significant after adjusting for age in linear regression analyses.ConclusionThese findings suggest that PI quantified by 3D VR navigation systems may be useful as a surrogate diagnostic tool for the detection of early AD pathophysiology. The hierarchical application of 3D VR PI and plasma p-tau181, in particular, may be an effective combinatorial biomarker for early AD neurodegeneration. These findings advance the application of non-invasive diagnostic tools for early testing and monitoring of AD, paving the way for timely therapeutic interventions and improved epidemiological patient outcomes.

The microtubule-associated protein tau is hyperphosphorylated and forms neurofibrillary tangles in Alzheimer disease. Additionally caspase-cleaved tau is present in Alzheimer disease brains co-localized with fibrillar tau pathologies. To further understand the role of site-specific phosphorylation and caspase cleavage of tau in regulating its function, constructs of full-length tau (T4) or tau truncated at Asp421 (T4C3) to mimic caspase-3 cleavage with and without site-directed mutations that mimic phosphorylation at Thr231/Ser235, Ser396/Ser404, or at all four sites (Thr231/Ser235/Ser396/Ser404) were made and expressed in cells. Pseudophosphorylation of T4, but not T4C3, at either Thr231/Ser235 or Ser396/Ser404 increased its phosphorylation at Ser262 and Ser199. Pseudophosphorylation at Thr231/Ser235 impaired the microtubule binding of both T4 and T4C3. In contrast, pseudophosphorylation at Ser396/Ser404 only affected microtubule binding of T4C3 but did make T4 less soluble and more aggregated, which is consistent with the previous finding (Abraha, A., Ghoshal, N., Gamblin, T. C., Cryns, V., Berry, R. W., Kuret, J., and Binder, L. I. (2000) J. Cell Sci. 113, 3737-3745) that pseudophosphorylation at Ser396/Ser404 enhances tau polymerization in vitro. In situ T4C3 was more prevalent in the cytoskeletal and microtubule-associated fractions compared with T4, whereas purified recombinant T4 bound microtubules with higher affinity than did T4C3 in an in vitro assay. These data indicate the importance of cellular factors in regulating tau-microtubule interactions and that, in the cells, phosphorylation of T4 might impair its microtubule binding ability more than caspase cleavage. Treatment of cells with nocodazole revealed that pseudophosphorylation of T4 at both Thr231/Ser235 and Ser396/Ser404 diminished the ability of tau to protect against microtubule depolymerization, whereas with T4C3 only pseudophosphorylation at Ser396/Ser404 attenuated the ability of tau to stabilize the microtubules. These results show that site-specific phosphorylation and caspase cleavage of tau differentially affect the ability of tau to bind and stabilize microtubules and facilitate tau self-association.

BackgroundThe recent promise of disease-modifying therapies for Alzheimer’s disease (AD) has reinforced the need for accurate biomarkers for early disease detection, diagnosis and treatment monitoring. Advances in the development of novel blood-based biomarkers for AD have revealed that plasma levels of tau phosphorylated at various residues are specific and sensitive to AD dementia. However, the currently available tests have shortcomings in access, throughput, and scalability that limit widespread implementation.MethodsWe evaluated the diagnostic and prognostic performance of a high-throughput and fully-automated Lumipulse plasma p-tau181 assay for the detection of AD. Plasma from older clinically unimpaired individuals (CU, n = 463) and patients with mild cognitive impairment (MCI, n = 107) or AD dementia (n = 78) were obtained from the longitudinal Stanford University Alzheimer’s Disease Research Center (ADRC) and the Stanford Aging and Memory Study (SAMS) cohorts. We evaluated the discriminative accuracy of plasma p-tau181 for clinical AD diagnosis, association with amyloid β peptides and p-tau181 concentrations in CSF, association with amyloid positron emission tomography (PET), and ability to predict longitudinal cognitive and functional change.ResultsThe assay showed robust performance in differentiating AD from control participants (AUC 0.959, CI: 0.912 to 0.990), and was strongly associated with CSF p-tau181, CSF Aβ42/Aβ40 ratio, and amyloid-PET global SUVRs. Associations between plasma p-tau181 with CSF biomarkers were significant when examined separately in Aβ+ and Aβ− groups. Plasma p-tau181 significantly increased over time in CU and AD diagnostic groups. After controlling for clinical diagnosis, age, sex, and education, baseline plasma p-tau181 predicted change in MoCA overall and change in CDR Sum of Boxes in the AD group over follow-up of up to 5 years.ConclusionsThis fully-automated and available blood-based biomarker assay therefore may be useful for early detection, diagnosis, prognosis, and treatment monitoring of AD.

Intraneuronal accumulation of hyperphosphorylated protein tau in paired helical filaments together with amyloid-beta peptide (Abeta) deposits confirm the clinical diagnosis of Alzheimer disease. A common cellular mechanism leading to the production of these potent toxins remains elusive. Here we show that, in cultured neurons, membrane depolarization induced a calcium-mediated transient phosphorylation of both microtubule-associated protein tau and amyloid precursor protein (APP), followed by a dephosphorylation of these proteins. Phosphorylation was mediated by glycogen synthase kinase 3 and cyclin-dependent kinase 5 protein kinases, while calcineurin was responsible for dephosphorylation. Following the transient phosphorylation of APP, intraneuronal Abeta accumulated and induced neurotoxicity. Phosphorylation of APP on Thr-668 was indispensable for intraneuronal accumulation of Abeta. Our data demonstrate that an increase in cytosolic calcium concentration induces modifications of neuronal metabolism of APP and tau, similar to those found in Alzheimer disease.

BackgroundAlthough blood-based biomarkers can be used to detect early Alzheimer’s disease (AD), population differences affect their clinical value in early diagnosis of the disease spectrum.AimsTo examine the potential of plasma biomarkers to detect different stages along the AD continuum in a Chinese population.MethodsWe enrolled 113 adults from the Shenzhen community (53 cognitively unimpaired [CU], 45 with mild cognitive impairment [MCI], and 15 with AD). We used the single-molecule array technique to detect the levels of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated-tau181 (p-tau181), and performed APOE genotyping. We assessed the association between plasma biomarkers and cognitive scores, and used receiver operating characteristic curves to measure performance for early AD diagnosis.ResultsThe plasma GFAP, NfL, and p-tau181 levels increased significantly in AD and were slightly higher in MCI than in CU (GFAP p = 0.811, NfL p = 0.909, p-tau181 p = 0.696). The plasma GFAP and p-tau181 levels negatively correlated with cognitive scores. Blood markers demonstrated higher performance in identifying AD than CU or MCI. Plasma p-tau181 displayed the highest diagnostic value for AD. Predictions of cognitive impairment were more robust when blood markers were combined with clinical indicators for AD (age, sex, body mass index, years of education, and APOE ε4 carrier status).DiscussionThe expression of plasma GFAP, NfL, and p-tau181 increased in the AD continuum. Importantly, plasma p-tau181 could identify individuals with AD from the general population, with superior predictive performance when combined with age or sex.ConclusionsPlasma biomarkers are useful screening indicators for early AD in Chinese adults.

Our review summarizes the diagnostic accuracy of plasma and cerebrospinal fluid (CSF) phosphorylated tau 217 (p-tau217) in detecting amyloid and tau pathology on positron emission tomography (PET). We systematically reviewed studies that reported the diagnostic accuracy of plasma and CSF p-tau217, searching MEDLINE/PubMed, Scopus, and Web of Science through August 2024. The accuracy of p-tau217 in predicting amyloid and tau pathology on PET was evaluated in 30 studies. Both plasma and CSF p-tau217 effectively detect amyloid and tau PET deposition. Plasma p-tau217 showed 82% sensitivity for detecting amyloid and 83% for tau, with 86% and 83% specificity, respectively. CSF p-tau217 had 79% sensitivity for amyloid and 91% for tau, with 91% and 84% specificity. p-tau217 effectively identifies Alzheimer's disease (AD) pathology. Plasma p-tau217 was comparable to CSF p-tau217 in detecting amyloid deposition on PET. Despite being less sensitive for detecting tau deposition on PET, plasma p-tau217 can be an efficient screening tool for underlying AD pathology. HIGHLIGHTS: Plasma phosphorylated tau 217 (p-tau217) serves as a viable biomarker alternative to cerebrospinal fluid p-tau217 due to the strong concordance between their results. Plasma p-tau217 accurately identifies amyloid and tau positron emission tomography (PET) positivity, exhibiting a low rate of false negatives and positives, thereby establishing it as a reliable diagnostic tool for Alzheimer's disease (AD). Plasma p-tau217 demonstrates slightly higher accuracy in predicting amyloid PET positivity compared to tau PET positivity. Plasma p-tau217 demonstrates higher predictive accuracy in detecting AD pathology among cognitively impaired individuals, compared to cognitively unimpaired individuals, suggesting its enhanced utility as a diagnostic biomarker in clinical settings.

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Cerebrospinal fluid (CSF) and plasma biomarkers can detect biological evidence of Alzheimer disease (AD), but their use in low-resource environments and among minority ethnic groups is limited. To assess validated plasma biomarkers for AD among adults of Caribbean Hispanic ethnicity. In this decision analytical modeling study, adults were recruited between January 1, 2018, and April 30, 2022, and underwent detailed clinical assessments and venipuncture. A subsample of participants also consented to lumbar puncture. Established CSF cut points were used to define AD biomarker-positive status, allowing determination of optimal cut points for plasma biomarkers in the same individuals. The performance of a panel of 6 plasma biomarkers was then assessed with respect to the entire group. Data analysis was performed in January 2023. Main outcomes were the association of plasma biomarkers amyloid-β 1-42 (Aβ42), amyloid-β 1-40 (Aβ40), total tau (T-tau), phosphorylated tau181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) with AD diagnosis. These biomarkers allow assessment of amyloid (A), neurofibrillary degeneration (T), and neurodegeneration (N) aspects of AD. Statistical analyses performed included receiver operating characteristics, Pearson and Spearman correlations, t tests, and Wilcoxon rank-sum, chi-square, and Fisher exact tests. Exposures included age, sex, education, country of residence, apolipoprotein-ε4 (APOE-ε4) allele number, serum creatinine, blood urea nitrogen, and body mass index. This study included 746 adults. Participants had a mean (SD) age of 71.0 (7.8) years, 480 (64.3%) were women, and 154 (20.6%) met clinical criteria for AD. Associations were observed between CSF and plasma P-tau181 (r = .47 [95% CI, 0.32-0.60]), NfL (r = 0.57 [95% CI, 0.44-0.68]), and P-tau181/Aβ42 (r = 0.44 [95% CI, 0.29-0.58]). For AD defined by CSF biomarkers, plasma P-tau181 and P-tau181/Aβ42 provided biological evidence of AD. Among individuals judged to be clinically healthy without dementia, biomarker-positive status was determined by plasma P-tau181 for 133 (22.7%) and by plasma P-tau181/Aβ42 for 104 (17.7%). Among individuals with clinically diagnosed AD, 69 (45.4%) had plasma P-tau181 levels and 89 (58.9%) had P-tau181/Aβ42 levels that were inconsistent with AD. Individuals with biomarker-negative clinical AD status tended to have lower levels of education, were less likely to carry APOE-ε4 alleles, and had lower levels of GFAP and NfL than individuals with biomarker-positive clinical AD. In this cross-sectional study, plasma P-tau181 and P-tau181/Aβ42 measurements correctly classified Caribbean Hispanic individuals with and without AD. However, plasma biomarkers identified individuals without dementia with biological evidence of AD, and a portion of those with dementia whose AD biomarker profile was negative. These results suggest that plasma biomarkers can augment detection of preclinical AD among asymptomatic individuals and improve the specificity of AD diagnosis.

Alzheimer’s Disease (AD) is the most common single cause of dementia in our ageing society. Traditionally thought of as an untreatable degenerative condition, recent advances in drug therapy have challenged this view. The disease is characterised by an insidious decline in cognitive and non-cognitive function. Classically, short and long-term memory is impaired while language skills, concentration and attention are often affected. This results in impaired ability to learn and retain new skills as well as the loss of existing ones. Non-cognitive function is the global term used to describe problems such as depression, agitation, personality changes, delusions and hallucinations. These factors have a significant impact on patient behaviour and a very real impact on the quality of life for both patients and caregivers. Diagnosis of AD is clinically based, and using the NINCDS-ADRDA criteria (Table 1) [1], a diagnosis of probable or possible AD can be made. Definitive diagnosis relies on pathological confirmation, which in the majority of cases is rarely completed. With the development of AD specific treatments, definition of AD from other types of dementia is very important. Table 1 NINCDS-ADRDA Criteria for clinical diagnosis of Alzheimer’s disease. Pathogenesis The pathogenesis of AD has not yet been elucidated. It is widely accepted that a combination of genetic susceptibility factors and environmental triggers are responsible for late onset sporadic AD, the most common form of the disease. An understanding of the disease mechanism remains elusive, and is the key to developing a disease modifying agent. Currently, it is proposed that beta amyloid protein, abnormal tau protein or possibly both play key factors in the development of disease. It has been widely postulated that oxidative damage and a slow inflammatory process are two possible mechanisms involved. As yet, no product with proven disease modifying properties is available, and current treatments offer symptomatic benefit only. The development of acetylcholinesterase (AChe) inhibitor drugs has followed the finding that cholinergic pathways in the cerebral cortex and basal forebrain are compromised in AD [2] and the resultant cholinergic deficit contributes to the cognitive impairment of these patients [3]. Although many believe this ‘cholinergic hypothesis’ to be important, others feel it represents a less significant component of the disease process [4]. Many other neurotransmitters are affected in AD, and the relative importance of each in relation to clinical findings has not been fully elucidated. Initial work focused on the use of acetylcholine precursors, using a similar rationale to dopamine therapy in Parkinson’s disease. A series of small trials using precursors such as choline and phosphatidylcholine showed no reliable improvement in cognitive function, with only 10 out of 43 trials reporting any positive effect [5]. There has been renewed interest in muscarinic agonists drugs, which when first introduced, had major problems with adverse cholinergic effects. Better understanding of the molecular pathology of muscarinic receptors and their subtypes has led to the development of more specific agonists. Drugs such as xanomeline, milameline, and civimeline have reached clinical trials, and the improvements seen in cognitive function are reviewed by Avery et al. [6]. There are also claims that these drugs have disease modifying properties, with effects on APP processing and tau phosphorylation. Muscarinic agonists remain in trial, but have yet to fulfil their potential in AD treatment. The only group of drugs currently licensed for AD treatment is the AChe inhibitors, which act through inhibition of the enzyme acetylcholinesterase (AChe), responsible for the breakdown of ACh in the neural synapse. A meta-analysis of the early AChe inhibitor treatments was encouraging [7] and these proceeded to larger placebo controlled double-blind trials.