Alzheimer’s Patients and Low Tau Burden Outcomes
Overview
The study focuses on individuals within the Alzheimer’s Disease (AD) pathway exhibiting abnormal amyloid-beta (Aβ) and tau deposition. Specifically, it investigates a subgroup characterized by low tau levels (A+T−) and compares them to their counterparts with higher tau levels (A+T+).
The research involves 397 individuals classified as Aβ+ (indicating the presence of abnormal amyloid-beta) and explores the distinctions between those with low tau (A+T−) and those with elevated tau (A+T+). Results reveal that a significant proportion, 71% of Aβ+ unimpaired individuals and 42% of impaired Aβ+ individuals, fall into the A+T− category based on global tau levels. Notably, among impaired individuals, A+T− status correlates with older age, male sex, and increased cardiovascular risk.
The study identifies a connection between α-synuclein and cognitive decline, especially in cases where tau levels are low. Interestingly, tau burden tends to be elevated in specific temporal regions, irrespective of the tau status (T+/T−).
The findings emphasize the prevalence of low tau in individuals on the AD pathway and its association with comorbidities contributing to cognitive impairment. The research carries implications for the selection of individuals suitable for Aβ- and tau-modifying therapies. Recognizing the demographic and risk factor associations with A+T− status provides valuable insights into the complex interplay of biomarkers in Alzheimer’s Disease, informing potential therapeutic strategies.
Introduction
The study investigates individuals within the Alzheimer’s Disease (AD) pathway characterized by abnormal amyloid-beta (Aβ) deposition but with low tau levels (A+T−), comparing them to counterparts with higher tau levels (A+T+). The research aims to discern demographic, health, and biomarker characteristics associated with low tau in individuals on the AD pathway, a subgroup that remains poorly understood.
Utilizing data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the study examines A+T− unimpaired and impaired participants, employing global tau as the primary measure. The study aligns with the Alzheimer’s Disease National Institute on Aging–Alzheimer’s Association Research Framework, emphasizing the significance of Aβ and tau biomarkers in defining disease stages.
Key findings indicate that A+T− status is relatively common, especially among impaired individuals. This subgroup is identified as experiencing “Alzheimer’s pathologic change,” considered an early stage of the disease. The study recognizes the challenge of measuring the full spectrum of age-related neuropathologies in vivo but highlights autopsy studies linking TDP-43, vascular pathology, and α-synuclein to cognitive symptoms in AD.
The research delves into demographic factors, health/cardiovascular risk, biomarkers, and cognitive measurements associated with A+T− individuals. Notably, male sex, older age, and elevated cardiovascular risk are more prevalent in impaired A+T− individuals. The presence of α-synuclein, a marker of age-related neuropathology, significantly affects cognition, particularly when tau is low.
The study emphasizes the importance of understanding A+T− individuals, as Aβ- and tau-modifying therapy trials increasingly use A+/− and T+/− criteria for participant selection. The exclusion of impaired patients with low tau from recent trials prompts questions about their prevalence and potential treatment responses compared to their higher tau counterparts.
The research contributes to informing the selection of individuals likely to benefit from anti-Aβ and tau therapies by identifying characteristics and comorbidities common to those with low tau on the AD pathway.
Method
The research involved participants enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI), focusing on those with available Aβ PET, tau PET, and MRI scans. The study included 890 individuals, with a primary focus on the 397 Aβ PET+ participants for analyses. The participants, aged 55 to 90 at baseline, met specific criteria such as completing at least 6 years of education, fluency in English or Spanish, and being free of significant neurological diseases.
Aβ PET imaging utilized tracers like [18F] florbetapir (FBP) and [18F] florbetaben (FBB). Longitudinal Aβ PET data were available for 64% of the sample. Hippocampal volumes were determined, and glucose metabolism was assessed using fluorodeoxyglucose PET. Tau PET scans employed [18F]Flortaucipir (FTP) and were analyzed in specific regions, with thresholds based on the 90th percentile of ADNI Aβ− cognitively unimpaired individuals.
Biomarkers, including cerebrospinal fluid (CSF) and plasma ptau181, as well as plasma neurofilament light, were analyzed. Cognitive assessments, such as the Mini-Mental State Examination and Preclinical Alzheimer Cognitive Composite scores, were conducted. Comorbidities, including cardiovascular and cerebrovascular risk, were evaluated using the Framingham Risk Score and clinical interview records. White matter hyperintensities and α-synuclein status were also assessed.
The study aimed to comprehensively understand the demographic, health, and biomarker characteristics associated with low tau in individuals on the Alzheimer’s disease pathway. By integrating data from various imaging modalities, cognitive assessments, and evaluations of comorbidities, the researchers sought to provide a detailed analysis of the factors influencing tau levels in the studied population. This multifaceted approach allows for a nuanced exploration of the complex interplay between different variables in the context of Alzheimer’s disease progression.
Statistical Analysis
The available data for the study varied across measures, and non-missing data for each variable are detailed in the study.
In comparing the unimpaired and impaired groups with low tau (A+T−) to those with elevated tau (A+T+), various analyses were conducted. Independent-samples t-tests and chi-square tests at a significance level of 0.05 were utilized to compare demographic factors, comorbid diseases, AD biomarkers (Aβ, tau, neurodegeneration), and cognitive measurements between these groups. Longitudinal measurements were assessed by calculating annualized slopes using all available time points.
To predict cognitive performance, regression models were implemented for unimpaired and impaired Aβ+ groups. Baseline cognitive outcomes (PACC, MMSE) were associated with predictors such as comorbidities (FRS, α-synuclein+/− status), tau (global tau SUVr), interactions between tau and comorbidities (global tau × FRS, global tau × α-synuclein), as well as demographic variables like age at baseline PET, sex, underrepresented racial group (URG) status (+/−), APOE ε4 status (+/−), and education.
In the final analysis, regionwise baseline FTP SUVrs and SUVr slopes were examined for A+T− and A+T+ groups. This involved averaging across 70 FreeSurfer-defined regions. Regional tau SUVrs were ranked for each individual, and the median rank for each region was determined within each A+T− and A+T+ unimpaired and impaired group. The same procedure was applied to rank regional SUVr slopes. This comprehensive approach allowed for a detailed exploration of the differences and trends within these groups across various variables and measurements.
Result
The study included 890 participants with available Aβ and tau PET scans, of which 397 were identified as Aβ+ individuals. Within this Aβ+ group, a substantial proportion exhibited normal tau levels in specific brain regions: 64% of unimpaired and 20% of impaired individuals had entorhinal tau within the normal range, 65% of unimpaired and 24% of impaired individuals had normal temporal tau, and 71% of unimpaired and 42% of impaired individuals had normal global tau.
Concordance analysis revealed that a majority (87-88%) of the sample exhibited consistency in tau status across various brain regions.
To explore the differences between individuals with low tau (A+T−) and elevated tau (A+T+), the global tau region was employed to define these groups. Unimpaired A+T− individuals showed fewer overall health conditions, higher cognitive scores, and were less likely to report subjective memory complaints compared to A+T+ counterparts. Impaired A+T− individuals were older, more likely to be male, and had higher education. Cardiovascular health conditions were more prevalent in the A+T− group, which also displayed less tau accumulation and cognitive impairment.
Longitudinal analysis indicated that a portion of A+T− individuals converted to A+T+ status over time, emphasizing the dynamic nature of tau pathology. Predictive models suggested that in impaired individuals, low tau was consistently associated with better cognitive performance. The interaction between tau and α-synuclein indicated that α-synuclein+ status was linked to poorer cognition only when tau levels were low.
Furthermore, regional tau rankings highlighted consistent patterns across A+T+ and A+T− groups, with medial and lateral temporal regions consistently exhibiting the highest tau levels. This finding held true for both baseline tau and longitudinal tau accumulation.
In summary, this study sheds light on the prevalence and characteristics of individuals with abnormal Aβ but low tau, emphasizing the need to understand the dynamics and implications of tau pathology in Alzheimer’s disease. The findings have significant implications for therapeutic interventions targeting Aβ and tau in Alzheimer’s disease.
Conclusion
The study reveals that a significant proportion (20% to 42%) of cognitively impaired individuals on the Alzheimer’s disease (AD) pathway, identified by abnormal amyloid-beta (Aβ) but normal tau PET, exhibit an atypical biomarker profile (A+T−) not meeting NIA-AA criteria for AD. This phenomenon challenges the conventional understanding that tau burden is a key predictor of cognitive decline in AD. While lower tau levels in A+T− individuals may suggest an earlier disease stage, other characteristics contradict this hypothesis.
Impaired A+T− individuals, compared to their A+T+ counterparts, demonstrated unique features such as being more likely to be male, older, highly educated, and having increased cardiovascular disease risk factors. The impaired A+T− group also exhibited a greater prevalence of cardiovascular conditions, higher Framingham Risk Score (FRS), modified Hachinski scores, and white matter hyperintensities. Interestingly, A+T− individuals were less likely to identify as belonging to a non-White racial group.
Moreover, in the impaired group, α-synuclein was linked to poorer cognition specifically when tau levels were low, providing in vivo biomarker support for the role of mixed pathologies in cognitive performance. Although tau and α-synuclein independently influenced cognition, the main effect of tau was more consistent and explained more variance, especially in temporal and global regions, suggesting a primary role for cortical tau burden in disease progression.
The findings emphasize that variability in tau burden may impact the efficacy of Aβ- and tau-modifying therapies. Individuals with lower tau may progress slowly or possess different characteristics that affect treatment response. This has implications for clinical trial design and participant selection.
The study, while offering valuable insights, has limitations, including potential biases from survival effects and the need for more comprehensive biomarker characterization, especially with fluid biomarkers. The observed characteristics associated with low tau in impaired Aβ+ individuals suggest a complex and heterogeneous profile, with α-synuclein playing a significant role in cognitive impairment in individuals on the AD pathway.
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