β-Amyloid and tau biomarkers and clinical phenotype in dementia with Lewy bodies

Abstract

ObjectiveIn a multi-center cohort of probable dementia with Lewy bodies (DLB), we tested the hypothesis that amyloid-β and tau biomarker positivity increases with age, which is modified by APOE genotype and sex, and that there are isolated and synergistic associations with the clinical phenotype.MethodsWe included 417 DLB patients (45–93 years, 31% women). Positivity on amyloid-β (A+) and tau (T+) biomarkers was determined by cerebrospinal fluid amyloid-β 1-42 and phosphorylated tau in the European cohort, and Pittsburgh compound-B and AV-1451 positron emission tomography in the Mayo Clinic cohort. Patients were stratified into 4 groups: A-T-, A+T-, A-T+, A+T+.ResultsA-T- was the largest group (39%), followed by A+T- (32%), A+T+ (15%), and A-T+ (13%). The percentage of A-T- decreased with age and A+ and T+ increased with age both in women and men. A+ increased more in APOE ε4 carriers with age than in non-carriers. A+ was the main predictor of lower cognitive performance when considered together with T+. T+ was associated with a lower frequency of parkinsonism and probable rapid eye movement sleep behavior disorder. There were no significant interactions between A+ and T+ in relation to the clinical phenotype.ConclusionsAlzheimer's disease pathologic changes are common in DLB and are associated with the clinical phenotype. Amyloid-β is associated with cognitive impairment and tau pathology is associated with lower frequency of clinical features of DLB. These findings have important implications for diagnosis, prognosis, and disease monitoring, as well as for clinical trials targeting disease-specific proteins in DLB.Classification of evidenceThis study provides Class II evidence that in patients with probable DLB, amyloid-β is associated with lower cognitive performance and tau pathology is associated with lower frequency of clinical features of DLB.

Genetic Architecture and Molecular, Imaging and Prodromic Markers in Dementia with Lewy Bodies: State of the Art, Opportunities and Challenges

“…The influence of comorbid tau on DLB clinical phenotypes, cognitive functions and brain imaging is well-documented. A key contribution to the tau-imaging has been obtained with radioligand [18F] AV-1451 based on its high affinity, selectivity and favorable kinetics [215,216]. Recent postmortem evidences have confirmed that this tracer is able to bind strongly to tau in neurofibrillary tangles and neurites without binding Aβ and, above all, it does not bind α-synuclein aggregates or Lewy bodies [214,217].…”

“…They found that AD-tau related pathologic changes are common in DLB and were selectively associated with the clinical phenotype. Indeed, while amyloid-β was associated with cognitive impairment, tau pathology was associated with a lower frequency of clinical features of DLB [216]. Additionally, two multimodal PET-imaging studies should be cited [224,225].…”

Fluid and Tissue Biomarkers of Lewy Body Dementia: Report of an LBDA Symposium

“…Evidence suggests that these Alzheimer markers likely reflect concomitant Alzheimer pathological process along with the Lewy body disease. Specifically, AD biomarkers in DLB (DLB-AD) are associated with increased age, female sex, increased APOE ε4 genotype, decreased memory, increased delusions and hallucinations, less REM-behavior sleep disorder and parkinsonism, worse language performance, faster progression, increased temporal thinning and tau pathology, and greater risk of institutionalization and mortality (2)(3)(4)(24)(25)(26)(27)(28). These findings are corroborated by post-mortem clinicopathologic studies showing that AD pathologic features (neuritic plaques and also tangles) in cases clinically defined as "probable DLB" are associated with an atypical "Alzheimerized" clinical presentation (e.g.…”

“…Panelists agreed with the potential importance of stratifying therapeutic trial inclusions and/or outcomes based on AD biomarker profiles in LBD due to the strong association of these biomarkers with clinical outcomes, exemplified by the prospective data in the European DLB (E-DLB) consortium. Frequency of AD pathology in DLB (DLB-AD) varies between 25-89% depending on biomarker cutoffs and diagnostic criteria (2)(3)(4)(5). Distinct lines of evidence have shown that DLB-AD may represent a biological interaction of these mixed amyloid-beta, tau and alpha-synuclein pathologies.…”

“…The discussion was confined to biomarkers in body fluids and tissues and did not extend to other modalities such as neuroimaging. Given that the majority of people with LBD harbor both Lewy body and Alzheimer Disease (AD) pathology (2)(3)(4)(5), options for identifying and quantifying the presence of each of these types of pathology were reviewed. Novel biomarkers for related disease processes such as endolysosomal processing were also evaluated.…”