Fluid biomarker agreement and interrelation in dementia due to Alzheimer’s disease

Abstract

The cerebrospinal fluid (CSF) levels of β-amyloid 42, total tau, and phosphorylated tau 181 are supposed to be all continuously abnormal in dementia due to Alzheimer's disease (AD), being the most advanced disease stage. The aim of the present study, which included a monocentric and a multicentric sample (N = 119 and 178, respectively), was to investigate the degree of CSF biomarker agreement and interrelation in AD dementia. Based on previously published cut-off values, biomarker values were categorized as positive or negative for AD (dichotomization strategy) and as either positive, negative, or borderline (trichotomization strategy). The statistical analyses relied on distance correlation analysis and kappa (k) statistics. Poor agreement (k < 0.4) and low interrelations between the studied biomarkers were detected in all cases with the exception of the interrelation between the markers total tau and phosphorylated tau 181, especially in the monocentric sample. Interestingly, lower interrelation and agreement degrees were observed in carriers of the Apolipoprotein E ε4 allele compared to non-carriers. The clinical phenotype currently referred to as "AD dementia" is characterized by an inhomogeneous CSF biomarker profile, possibly mirroring the complex genesis of AD-typical dementia symptoms and pointing to the necessity of shedding more light on the hypothesis of biomarker stability over time in symptomatic AD.

Validation of the Cognitive Telephone Screening Instruments COGTEL and COGTEL+ in Identifying Clinically Diagnosed Neurocognitive Disorder Due to Alzheimer’s Disease in a Naturalistic Clinical Setting

“…Finally, the clinical diagnosis, which was based on a comprehensive diagnostic procedure and on international diagnostic criteria, was used as the ultimate gold standard. Despite the high validity of the diagnostic criteria for AD, the clinical diagnoses are neither always confirmed at autopsy nor always supported by biomarker constellations typical for AD [39][40][41]. Thus, possibly erroneous clinical assessments should be also taken into account.…”

AD-Related CSF Biomarkers Across Distinct Levels of Cognitive Impairment: Correlations With Global Cognitive State

“…51 Elevation in CSF p-tau represents the hallmark of tau pathology 5 that has been documented as a good predictor of progression to dementia, 52 but its role as a proxy for cognitive status remains to be defined in AD dementia clinical phenotype. 53…”

“…All data reviewed for this study showed that correlation coefficients between cognitive parameters and any CSF biomarker revolve around 0.3 to 0.4 at best, implying that most of the variance defining cognitive impairment remains unclear and is multifactorial, such as the co-occurrence of vascular disease or Lewy body pathology, APOE status, lifestyle parameters, cognitive reserve, among others. 46,53 Hence, in a cohort of patients clinically diagnosed as AD, different factors may collaborate and interact to produce cognitive impairment, which may influence the index of correlation between CSF biomarkers level and cognition.…”

“…51 Elevation in CSF p-tau represents the hallmark of tau pathology 5 that has been documented as a good predictor of progression to dementia, 52 but its role as a proxy for cognitive status remains to be defined in AD dementia clinical phenotype. 53 The hypothetical model proposed by Sperling et al 36 describes CSF Ab 42 levels to decrease several years before the onset of cognitive symptoms to reach a plateau by the time the symptomatic threshold is reached (transition from cognitively normal to MCI). Therefore, CSF Ab 42 is expected to correlate with cognitive performance mostly in the preclinical stage or MCI 45,48,54 and may be regarded as a marker for AD development but not a proxy for disease severity.…”

Beneficial association of angiotensin-converting enzyme inhibitors and statins on the occurrence of possible Alzheimer’s disease after traumatic brain injury

“…Other studies conducted in mice have shown long-term persistence and even progression of blast-and impact-induced p-tauopathy [26-28, 33, 34]. In humans, effort has been made to search for an association (or a lack of) between cognitive decline and overlapping neurodegenerative pathologies [35,36], and possible biomarkers that reflect those changes [37]. Repetitive mild TBI was found to be associated with tau pathology and allied neurodegenerative changes in the brain [38].…”