Regional Tau Deposition Reflects Different Pathways of Subsequent Neurodegeneration and Memory Decline in Cognitively Normal Older Adults.

OBJECTIVE: Tau pathology is recognized as a primary contributor to neurodegeneration and clinical symptoms in Alzheimer's disease (AD). This study aims to localize the early tau pathology in cognitively normal older people that is predictive of subsequent neurodegeneration and memory decline, and delineate factors underlying tau-related memory decline in individuals with and without ß-amyloid (Aß). METHODS: A total of 138 cognitively normal older individuals from the Berkeley Aging Cohort Study underwent 11 C-Pittsburgh Compound-B (PiB) positron emission tomography (PET) to determine Aß positivity and 18 F-Flortaucipir (FTP) PET to measure tau deposition, with prospective cognitive assessments and structural magnetic resonance imaging. Voxel-wise FTP analyses examined associations between baseline tau deposition and longitudinal memory decline, longitudinal hippocampal atrophy, and longitudinal cortical thinning in AD signature regions. We also examined whether hippocampal atrophy and cortical thinning mediate tau effects on future memory decline. RESULTS: We found Aß-dependent tau associations with memory decline in the entorhinal and temporoparietal regions, Aß-independent tau associations with hippocampal atrophy within the medial temporal lobe (MTL), and that widespread tau was associated with mean cortical thinning in AD signature regions. Tau-related memory decline was mediated by hippocampal atrophy in Aß- individuals and by mean cortical thinning in Aß+ individuals. INTERPRETATION: Our results suggest that tau may affect memory through different mechanisms in normal aging and AD. Early tau deposition independent of Aß predicts subsequent hippocampal atrophy that may lead to memory deficits in normal older individuals, whereas elevated cortical tau deposition is associated with cortical thinning that may lead to more severe memory decline in AD. ANN NEUROL 2024;95:249-259.

Tau accumulation and atrophy predict amyloid independent cognitive decline in aging.

INTRODUCTION: Amyloid beta (Aß) and tau pathology are cross-sectionally associated with atrophy and cognitive decline in aging and Alzheimer's disease (AD). METHODS: We investigated relationships between concurrent longitudinal measures of Aß (Pittsburgh compound B [PiB] positron emission tomography [PET]), tau (flortaucipir [FTP] PET), atrophy (structural magnetic resonance imaging), episodic memory (EM), and non-memory (NM) in 78 cognitively healthy older adults (OA). RESULTS: Entorhinal FTP change was correlated with EM decline regardless of Aß, but meta-temporal FTP and global PiB change were only associated with EM and NM decline in Aß+ OA. Voxel-wise analyses revealed significant associations between temporal lobe FTP change and EM decline in all groups. PiB and FTP change were not associated with structural change, suggesting a functional or microstructural mechanism linking these measures to cognitive decline. DISCUSSION: Our results show that longitudinal Aß is linked to cognitive decline only in the presence of elevated Aß, but longitudinal temporal lobe tau is associated with memory decline regardless of Aß status. HIGHLIGHTS: Entorhinal tau change was associated with memory decline in older adults (OA), regardless of amyloid beta (Aß). Greater meta-region of interest (ROI) tau change correlated with memory decline in Aß+ OA. Voxel-wise temporal tau change correlated with memory decline, regardless of Aß. Meta-ROI tau and global amyloid change correlated with non-memory change in Aß+ OA. Tau and amyloid accumulation were not associated with structural change in OA.

Individuals with Alzheimer's disease and low tau burden: Characteristics and implications.

INTRODUCTION: Abnormal amyloid-beta (Aß) and tau deposition define Alzheimer's Disease (AD), but non-elevated tau is relatively frequent in patients on the AD pathway. METHODS: We examined characteristics and regional patterns of 397 Aß+ unimpaired and impaired individuals with low tau (A+T-) in relation to their higher tau counterparts (A+T+). RESULTS: Seventy-one percent of Aß+ unimpaired and 42% of impaired Aß+ individuals were categorized as A+T- based on global tau. In impaired individuals only, A+T- status was associated with older age, male sex, and greater cardiovascular risk. α-synuclein was linked to poorer cognition, particularly when tau was low. Tau burden was most frequently elevated in a common set of temporal regions regardless of T+/T- status. DISCUSSION: Low tau is relatively common in patients on the AD pathway and is linked to comorbidities that contribute to impairment. These findings have implications for the selection of individuals for Aß- and tau-modifying therapies.

Distinct Factors Drive the Spatiotemporal Progression of Tau Pathology in Older Adults.

Mechanisms underlying the initial accumulation of tau pathology across the human brain are largely unknown. We examined whether baseline factors including age, amyloid-ß (Aß), and neural activity predicted longitudinal tau accumulation in temporal lobe regions that reflect distinct stages of tau pathogenesis. Seventy cognitively normal human older adults (77 ± 6 years, 59% female) received two or more 18F-flortaucipir (FTP) and 11C-Pittsburgh Compound B (PiB) PET scans (mean follow-up, 2.5 ± 1.1 years) to quantify tau and (Aß). Linear mixed-effects models were used to calculate the slopes of FTP change in entorhinal cortex (EC), parahippocampal cortex (PHC), and inferior temporal gyrus (IT), and slopes of global PiB change. Thirty-seven participants underwent functional MRI to measure baseline activation. Older age predicted EC tau accumulation, and baseline EC tau levels predicted subsequent tau accumulation in EC and PHC. In IT, however, baseline EC tau interacted with Aß to predict IT tau accumulation. Higher baseline local activation predicted tau accumulation within EC and PHC, and higher baseline hippocampal activation predicted EC tau accumulation. Our findings indicate that factors predicting tau accumulation vary as tau progresses through the temporal lobe. Older age is associated with initial tau accumulation in EC, while baseline EC tau and neural activity drive tau accumulation within medial temporal lobe. Aß subsequently facilitates tau spread from medial to lateral temporal lobe. Our findings elucidate potential drivers of tau accumulation and spread in aging, which are critical for understanding Alzheimer's disease pathogenesis.SIGNIFICANCE STATEMENT To further understand the mechanisms leading to tau pathogenesis and spread, we tested whether baseline factors such as age, amyloid-ß pathology, and activation predicted longitudinal tau accumulation in cognitively normal older adults. We found that distinct mechanisms contribute to tau accumulation as tau progresses across the temporal lobe, with initial tau accumulation in entorhinal cortex driven by age and subsequent spread driven by neural activity and amyloid-ß. We demonstrate that higher baseline activation predicts increased longitudinal tau accumulation, providing novel evidence that activation-dependent tau production may occur in the human brain. Our findings support major hypotheses generated from preclinical research, and have important translational implications, suggesting that the reduction of hyperactivation may help prevent the development of tau pathology.

Optimizing quantification of MK6240 tau PET in unimpaired older adults.

Accurate measurement of Alzheimer's disease (AD) pathology in older adults without significant clinical impairment is critical to assessing intervention strategies aimed at slowing AD-related cognitive decline. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (POINTER) is a 2-year randomized controlled trial to evaluate the effect of multicomponent risk reduction strategies in older adults (60-79 years) who are cognitively unimpaired but at increased risk for cognitive decline/dementia due to factors such as cardiovascular disease and family history. The POINTER Imaging ancillary study is collecting tau-PET ([18F]MK6240), beta-amyloid (Aß)-PET ([18F]florbetaben [FBB]) and MRI data to evaluate neuroimaging biomarkers of AD and cerebrovascular pathophysiology in this at-risk sample. Here 481 participants (70.0±5.0; 66% F) with baseline MK6240, FBB and structural MRI scans were included. PET scans were coregistered to the structural MRI which was used to create FreeSurfer-defined reference regions and target regions of interest (ROIs). We also created off-target signal (OTS) ROIs to examine the magnitude and distribution of MK6240 OTS across the brain as well as relationships between OTS and age, sex, and race. OTS was unimodally distributed, highly correlated across OTS ROIs and related to younger age and sex but not race. Aiming to identify an optimal processing approach for MK6240 that would reduce the influence of OTS, we compared our previously validated MRI-guided standard PET processing and 6 alternative approaches. The alternate approaches included combinations of reference region erosion and meningeal OTS masking before spatial smoothing as well as partial volume correction. To compare processing approaches we examined relationships between target ROIs (entorhinal cortex (ERC), hippocampus or a temporal meta-ROI (MetaROI)) SUVR and age, sex, race, Aß and a general cognitive status measure, the Modified Telephone Interview for Cognitive Status (TICSm). Overall, the processing approaches performed similarly, and none showed a meaningful improvement over standard processing. Across processing approaches we observed previously reported relationships with MK6240 target ROIs including positive associations with age, an Aß+> Aß- effect and negative associations with cognition. In sum, we demonstrated that different methods for minimizing effects of OTS, which is highly correlated across the brain within subject, produced no substantive change in our performance metrics. This is likely because OTS contaminates both reference and target regions and this contamination largely cancels out in SUVR data. Caution should be used when efforts to reduce OTS focus on target or reference regions in isolation as this may exacerbate OTS contamination in SUVR data.

Plasma p-tau231, p-tau181, PET Biomarkers, and Cognitive Change in Older Adults.

OBJECTIVE: The objective of this study was to evaluate novel plasma p-tau231 and p-tau181, as well as Aß40 and Aß42 assays as indicators of tau and Aß pathologies measured with positron emission tomography (PET), and their association with cognitive change, in cognitively unimpaired older adults. METHODS: In a cohort of 244 older adults at risk of Alzheimer's disease (AD) owing to a family history of AD dementia, we measured single molecule array (Simoa)-based plasma tau biomarkers (p-tau231 and p-tau181), Aß40 and Aß42 with immunoprecipitation mass spectrometry, and Simoa neurofilament light (NfL). A subset of 129 participants underwent amyloid-ß (18 F-NAV4694) and tau (18 F-flortaucipir) PET assessments. We investigated plasma biomarker associations with Aß and tau PET at the global and voxel level and tested plasma biomarker combinations for improved detection of Aß-PET positivity. We also investigated associations with 8-year cognitive change. RESULTS: Plasma p-tau biomarkers correlated with flortaucipir binding in medial temporal, parietal, and inferior temporal regions. P-tau231 showed further associations in lateral parietal and occipital cortices. Plasma Aß42/40 explained more variance in global Aß-PET binding than Aß42 alone. P-tau231 also showed strong and widespread associations with cortical Aß-PET binding. Combining Aß42/40 with p-tau231 or p-tau181 allowed for good distinction between Aß-negative and -positive participants (area under the receiver operating characteristic curve [AUC] range = 0.81-0.86). Individuals with low plasma Aß42/40 and high p-tau experienced faster cognitive decline. INTERPRETATION: Plasma p-tau231 showed more robust associations with PET biomarkers than p-tau181 in presymptomatic individuals. The combination of p-tau and Aß42/40 biomarkers detected early AD pathology and cognitive decline. Such markers could be used as prescreening tools to reduce the cost of prevention trials. ANN NEUROL 2022;91:548-560.

Cortical hypometabolism reflects local atrophy and tau pathology in symptomatic Alzheimer's disease.

Posterior cortical hypometabolism measured with 18F-fluorodeoxyglucose (FDG)-PET is a well-known marker of Alzheimer's disease-related neurodegeneration, but its associations with underlying neuropathological processes are unclear. We assessed cross-sectionally the relative contributions of three potential mechanisms causing hypometabolism in the retrosplenial and inferior parietal cortices: local molecular (amyloid and tau) pathology and atrophy, distant factors including contributions from the degenerating medial temporal lobe or molecular pathology in functionally connected regions, and the presence of the apolipoprotein E (APOE) ε4 allele. Two hundred and thirty-two amyloid-positive cognitively impaired patients from two cohorts [University of California, San Francisco (UCSF), and Alzheimer's Disease Neuroimaging Initiative (ADNI)] underwent MRI and PET with FDG, amyloid-PET using 11C-Pittsburgh Compound-B, 18F-florbetapir or 18F-florbetaben, and 18F-flortaucipir tau-PET in 1 year. Standard uptake value ratios (SUVRs) were calculated using tracer-specific reference regions. Regression analyses were run within cohorts to identify variables associated with retrosplenial or inferior parietal FDG standard uptake value ratios. On average, ADNI patients were older and were less impaired than the UCSF patients. Regional patterns of hypometabolism were similar between cohorts, although there were cohort differences in regional grey matter atrophy. Local cortical thickness and tau-PET (but not amyloid-PET) were independently associated with both retrosplenial and inferior parietal FDG SUVRs (ΔR2 = 0.09 to 0.21) across cohorts in models that also included age and disease severity (local model). Including medial temporal lobe volume improved the retrosplenial FDG model in the ADNI cohort (ΔR2 = 0.04, P = 0.008) but not for the UCSF (ΔR2 < 0.01, P = 0.52), and did not improve the inferior parietal models (ΔR2 < 0.01, P > 0.37). Interaction analyses revealed that medial temporal volume was more strongly associated with retrosplenial FDG SUVRs at earlier disease stages (P = 0.06 in UCSF, P = 0.046 in ADNI). Exploratory analyses across the cortex confirmed overall associations between hypometabolism and local tau pathology and thickness and revealed associations between medial temporal degeneration and hypometabolism in retrosplenial, orbitofrontal and anterior cingulate cortices. Finally, our data did not support hypotheses of a detrimental effect of pathology in connected regions or of an effect of the APOE ε4 allele in impaired participants. Overall, in two independent groups of patients at symptomatic stages of Alzheimer's disease, cortical hypometabolism mainly reflected structural neurodegeneration and tau, but not amyloid, pathology.

Regional Tau Effects on Prospective Cognitive Change in Cognitively Normal Older Adults.

Studies suggest that tau deposition starts in the anterolateral entorhinal cortex (EC) with normal aging, and that the presence of ß-amyloid (Aß) facilitates its spread to neocortex, which may reflect the beginning of Alzheimer's disease (AD). Functional connectivity between the anterolateral EC and the anterior-temporal (AT) memory network appears to drive higher tau deposition in AT than in the posterior-medial (PM) memory network. Here, we investigated whether this differential vulnerability to tau deposition may predict different cognitive consequences of EC, AT, and PM tau. Using 18F-flortaucipir (FTP) and 11C-Pittsburgh compound-B (PiB) positron emission tomography (PET) imaging, we measured tau and Aß in 124 cognitively normal human older adults (74 females, 50 males) followed for an average of 2.8 years for prospective cognition. We found that higher FTP in all three regions was individually related to faster memory decline, and that the effects of AT and PM FTP, but not EC, were driven by Aß+ individuals. Moreover, when we included all three FTP measures competitively in the same model, only AT FTP significantly predicted memory decline. Our data support a model whereby tau, facilitated by Aß, transits from EC to cortical regions that are most closely associated with the anterolateral EC, which specifically affects memory in the initial stage of AD. Memory also appears to be affected by EC tau in the absence of Aß, which may be less clinically consequential. These findings may provide clarification of differences between normal aging and AD, and elucidate the transition between the two stages.SIGNIFICANCE STATEMENT Tau and ß-amyloid (Aß) are hallmarks of Alzheimer's disease (AD) but are also found in cognitively normal people. It is unclear whether, and how, this early deposition of tau and Aß may affect cognition in normal aging and the asymptomatic stage of AD. We show that tau deposition in the entorhinal cortex (EC), which is common in advanced age, predicts memory decline in older adults independent of Aß, likely reflecting normal, age-related memory loss. In contrast, tau in anterior-temporal (AT) regions is most predictive of memory decline in Aß+ individuals. These data support the idea that tau preferentially spreads to specific cortical regions, likely through functional connections, which plays a primary role in memory decline in the early stage of AD.

Hippocampal Connectivity with Retrosplenial Cortex is Linked to Neocortical Tau Accumulation and Memory Function.

The mechanisms underlying accumulation of Alzheimer's disease (AD)-related tau pathology outside of the medial temporal lobe (MTL) in older adults are unknown but crucial to understanding cognitive decline. A growing body of evidence from human and animal studies strongly implicates neural connectivity in the propagation of tau in humans, but the pathways of neocortical tau spread and its consequences for cognitive function are not well understood. Using resting state functional magnetic resonance imaging (fMRI) and tau PET imaging from a sample of 97 male and female cognitively normal older adults, we examined MTL structures involved in medial parietal tau accumulation and associations with memory function. Functional connectivity between hippocampus (HC) and retrosplenial cortex (RsC), a key region of the medial parietal lobe, was associated with tau in medial parietal lobe. By contrast, connectivity between entorhinal cortex (EC) and RsC did not correlate with medial parietal lobe tau. Further, greater hippocampal-retrosplenial (HC-RsC) connectivity was associated with a stronger correlation between MTL and medial parietal lobe tau. Finally, an interaction between connectivity strength and medial parietal tau was associated with episodic memory performance, particularly in the visuospatial domain. This pattern of tau accumulation thus appears to reflect pathways of neural connectivity, and propagation of tau from EC to medial parietal lobe via the HC may represent a critical process in the evolution of cognitive dysfunction in aging and AD.SIGNIFICANCE STATEMENT The accumulation of tau pathology in the neocortex is a fundamental process underlying Alzheimer's disease (AD). Here, we use functional connectivity in cognitively normal older adults to track the accumulation of tau in the medial parietal lobe, a key region for memory processing that is affected early in the progression of AD. We show that the strength of connectivity between the hippocampus (HC) and retrosplenial cortex (RsC) is related to medial parietal tau burden, and that these tau and connectivity measures interact to associate with episodic memory performance. These findings establish the HC as the origin of medial parietal tau and implicate tau pathology in this region as a crucial marker of the beginnings of AD.

Reduced Repetition Suppression in Aging is Driven by Tau-Related Hyperactivity in Medial Temporal Lobe.

Tau deposition begins in the medial temporal lobe (MTL) in aging and Alzheimer's disease (AD), and MTL neural dysfunction is commonly observed in these groups. However, the association between tau and MTL neural activity has not been fully characterized. We investigated the effects of tau on repetition suppression, the reduction of activity for repeated stimulus presentations compared to novel stimuli. We used task-based functional MRI (fMRI) to assess MTL subregional activity in 21 young adults (YA) and 45 cognitively normal human older adults (OA; total sample: 37 females, 29 males). AD pathology was measured with position emission tomography (PET), using 18F-Flortaucipir for tau and 11C-Pittsburgh compound B (PiB) for amyloid-ß (Aß). The MTL was segmented into six subregions using high-resolution structural images. We compared the effects of low tau pathology, restricted to entorhinal cortex and hippocampus (Tau- OA), to high tau pathology, also occurring in temporal and limbic regions (Tau+ OA). Low levels of tau (Tau- OA vs YA) were associated with reduced repetition suppression activity specifically in anterolateral entorhinal cortex (alEC) and hippocampus, the first regions to accumulate tau. High tau pathology (Tau+ vs Tau- OA) was associated with widespread reductions in repetition suppression across MTL. Further analyses indicated that reduced repetition suppression was driven by hyperactivity to repeated stimuli, rather than decreased activity to novel stimuli. Increased activation was associated with entorhinal tau, but not Aß. These findings reveal a link between tau deposition and neural dysfunction in MTL, in which tau-related hyperactivity prevents deactivation to repeated stimuli, leading to reduced repetition suppression.SIGNIFICANCE STATEMENT Abnormal neural activity occurs in the medial temporal lobe (MTL) in aging and Alzheimer's disease (AD). Because tau pathology first deposits in the MTL in aging, this altered activity may be due to local tau pathology, and distinct MTL subregions may be differentially vulnerable. We demonstrate that in older adults (OAs) with low tau pathology, there are focal alterations in activity in MTL subregions that first develop tau pathology, while OAs with high tau pathology have aberrant activity throughout MTL. Tau was associated with hyperactivity to repeated stimulus presentations, leading to reduced repetition suppression, the discrimination between novel and repeated stimuli. Our data suggest that tau deposition is related to abnormal activity in MTL before the onset of cognitive decline.

Tau and ß-Amyloid Burden Predict Actigraphy-Measured and Self-Reported Impairment and Misperception of Human Sleep.

Alzheimer's disease is associated with poor sleep, but the impact of tau and ß-amyloid (Aß) pathology on sleep remains largely unknown. Here, we test the hypothesis that tau and Aß predict unique impairments in objective and self-perceived human sleep under real-life, free-living conditions. Eighty-nine male and female cognitively healthy older adults received 18F-FTP-tau and 11C-PIB-Aß PET imaging, 7 nights of sleep actigraphy and questionnaire measures, and neurocognitive assessment. Tau burden, but not Aß, was associated with markedly worse objective sleep. In contrast, Aß and tau were associated with worse self-reported sleep quality. Of clinical relevance, Aß burden predicted a unique perceptual mismatch between objective and subject sleep evaluation, with individuals underestimating their sleep. The magnitude of this mismatch was further predicted by worse executive function. Thus, early-stage tau and Aß deposition are linked with distinct phenotypes of real-world sleep impairment, one that includes a cognitive misperception of their own sleep health.SIGNIFICANCE STATEMENT Alzheimer's disease is associated with sleep disruption, often before significant memory decline. Thus, real-life patterns of sleep behavior have the potential to serve as a window into early disease progression. In 89 cognitive healthy older adults, we found that tau burden was associated with worse wristwatch actigraphy-measured sleep quality, and that both tau and ß-amyloid were independently predictive of self-reported sleep quality. Furthermore, individuals with greater ß-amyloid deposition were more likely to underestimate their sleep quality, and sleep quality underestimation was associated with worse executive function. These data support the role of sleep impairment as a key marker of early Alzheimer's disease, and offer the possibility that actigraphy may be an affordable and scalable tool in quantifying Alzheimer's disease-related behavioral changes.

Diagnostic Accuracy of Amyloid versus 18 F-Fluorodeoxyglucose Positron Emission Tomography in Autopsy-Confirmed Dementia.

OBJECTIVE: The purpose of this study was to compare the diagnostic accuracy of antemortem 11 C-Pittsburgh compound B (PIB) and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) versus autopsy diagnosis in a heterogenous sample of patients. METHODS: One hundred one participants underwent PIB and FDG PET during life and neuropathological assessment. PET scans were visually interpreted by 3 raters blinded to clinical information. PIB PET was rated as positive or negative for cortical retention, whereas FDG scans were read as showing an Alzheimer disease (AD) or non-AD pattern. Neuropathological diagnoses were assigned using research criteria. Majority visual reads were compared to intermediate-high AD neuropathological change (ADNC). RESULTS: One hundred one participants were included (mean age = 67.2 years, 41 females, Mini-Mental State Examination = 21.9, PET-to-autopsy interval = 4.4 years). At autopsy, 32 patients showed primary AD, 56 showed non-AD neuropathology (primarily frontotemporal lobar degeneration [FTLD]), and 13 showed mixed AD/FTLD pathology. PIB showed higher sensitivity than FDG for detecting intermediate-high ADNC (96%, 95% confidence interval [CI] = 89-100% vs 80%, 95% CI = 68-92%, p = 0.02), but equivalent specificity (86%, 95% CI = 76-95% vs 84%, 95% CI = 74-93%, p = 0.80). In patients with congruent PIB and FDG reads (77/101), combined sensitivity was 97% (95% CI = 92-100%) and specificity was 98% (95% CI = 93-100%). Nine of 24 patients with incongruent reads were found to have co-occurrence of AD and non-AD pathologies. INTERPRETATION: In our sample enriched for younger onset cognitive impairment, PIB-PET had higher sensitivity than FDG-PET for intermediate-high ADNC, with similar specificity. When both modalities are congruent, sensitivity and specificity approach 100%, whereas mixed pathology should be considered when PIB and FDG are incongruent. ANN NEUROL 2021;89:389-401.

Spatial Relationships between Molecular Pathology and Neurodegeneration in the Alzheimer's Disease Continuum.

A deeper understanding of the spatial relationships of ß-amyloid (Aß), tau, and neurodegeneration in Alzheimer's disease (AD) could provide insight into pathogenesis and clinical trial design. We included 81 amyloid-positive patients (age 64.4 ± 9.5) diagnosed with AD dementia or mild cognitive impairment due to AD and available 11C-PiB (PIB), 18F-Flortaucipir (FTP),18F-FDG-PET, and 3T-MRI, and 31 amyloid-positive, cognitively normal participants (age 77.3 ± 6.5, no FDG-PET). W-score voxel-wise deviation maps were created and binarized for each imaging-modality (W > 1.64, P < 0.05) adjusting for age, sex, and total intracranial volume (sMRI-only) using amyloid-negative cognitively normal adults. For symptomatic patients, FDG-PET and atrophy W-maps were combined into neurodegeneration maps (ND). Aß-pathology showed the greatest proportion of cortical gray matter suprathreshold voxels (spatial extent) for both symptomatic and asymptomatic participants (median 94-55%, respectively), followed by tau (79-11%) and neurodegeneration (41-3%). Amyloid > tau > neurodegeneration was the most frequent hierarchy for both groups (79-77%, respectively), followed by tau > amyloid > neurodegeneration (13-10%) and amyloid > neurodegeneration > tau (6-13%). For symptomatic participants, most abnormal voxels were PIB+/FTP+/ND- (median 35%), and the great majority of ND+ voxels (91%) colocalized with molecular pathology. Amyloid spatially exceeded tau and neurodegeneration, with individual heterogeneities. Molecular pathology and neurodegeneration showed a progressive overlap along AD course, indicating shared vulnerabilities or synergistic toxic mechanisms.

Distinct effects of beta-amyloid and tau on cortical thickness in cognitively healthy older adults.

INTRODUCTION: Published reports of associations between ß-amyloid (Aß) and cortical integrity conflict. Tau biomarkers may help elucidate the complex relationship between pathology and neurodegeneration in aging. METHODS: We measured cortical thickness using magnetic resonance imaging, Aß using Pittsburgh compound B positron emission tomography (PiB-PET), and tau using flortaucipir (FTP)-PET in 125 cognitively normal older adults. We examined relationships among PET measures, cortical thickness, and cognition. RESULTS: Cortical thickness was reduced in PiB+/FTP+ participants compared to the PiB+/FTP- and PiB-/FTP- groups. Continuous PiB associations with cortical thickness were weak but positive in FTP- participants and negative in FTP+. FTP strongly negatively predicted thickness regardless of PiB status. FTP was associated with memory and cortical thickness, and mediated the association of PiB with memory. DISCUSSION: Past findings linking Aß and cortical thickness are likely weak due to opposing effects of Aß on cortical thickness relative to tau burden. Tau, in contrast to Aß, is strongly related to cortical thickness and memory.

Sleep as a Potential Biomarker of Tau and ß-Amyloid Burden in the Human Brain.

Recent proposals suggest that sleep may be a factor associated with accumulation of two core pathological features of Alzheimer's disease (AD): tau and ß-amyloid (Aß). Here we combined PET measures of Aß and tau, electroencephalogram sleep recordings, and retrospective sleep evaluations to investigate the potential utility of sleep measures in predicting in vivo AD pathology in male and female older adults. Regression analyses revealed that the severity of impaired slow oscillation-sleep spindle coupling predicted greater medial temporal lobe tau burden. Aß burden was not associated with coupling impairment but instead predicted the diminished amplitude of <1 Hz slow-wave-activity, results that were statistically dissociable from each other. Additionally, comparisons of AD pathology and retrospective, self-reported changes in sleep duration demonstrated that changes in sleep across the lifespan can predict late-life Aß and tau burden. Thus, quantitative and qualitative features of human sleep represent potential noninvasive, cost-effective, and scalable biomarkers (current and future forecasting) of AD pathology, and carry both therapeutic and public health implications.SIGNIFICANCE STATEMENT Several studies have linked sleep disruption to the progression of Alzheimer's disease (AD). Tau and ß-amyloid (Aß), the primary pathological features of AD, are associated with both objective and subjective changes in sleep. However, it remains unknown whether late life tau and Aß burden are associated with distinct impairments in sleep physiology or changes in sleep across the lifespan. Using polysomnography, retrospective questionnaires, and tau- and Aß-specific PET, the present study reveals human sleep signatures that dissociably predict levels of brain tau and Aß in older adults. These results suggest that a night of polysomnography may aid in evaluating tau and Aß burden, and that treating sleep deficiencies within decade-specific time windows may serve in delaying AD progression.

Longitudinal tau accumulation and atrophy in aging and alzheimer disease.

OBJECTIVE: To determine the rate of tau accumulation in healthy older adults (OA) and patients with Alzheimer disease (AD), as well as the relationship of tau accumulation to cortical atrophy. METHODS: Two longitudinal flortaucipir (FTP) positron emission tomography (PET) and magnetic resonance imaging (MRI) scans were acquired from 42 OA (21 Pittsburg compound B [PiB]+ , age = 77.6 ± 4.6 years, 25 female [F]/17 male [M]) and 19 PiB+ patients with AD (age = 63.1 ± 10.3 years, 12 F/7 M) over 1 to 3 years of follow-up. FTP change, structural MRI measures of atrophy, and cross-modal correlations were examined on a voxelwise level. Regional annual percentage change in FTP was also calculated. RESULTS: Voxelwise FTP change in AD showed the greatest increases in lateral and medial frontal lobes. Atrophy over the same interval was more widespread and included posteromedial cortical areas, where tau accumulation rates were lower. In OA, FTP binding increased in bilateral temporal lobe and retrosplenial cortex, accompanied by atrophy in the same regions. There were no associations between voxelwise change in FTP and sex, PiB, or APOE. Regional FTP significantly increased at follow-up in OA and patients with AD. Mixed effects models showed greater FTP increases in AD compared to OA, and no differences within OA based on PiB status. INTERPRETATION: Our findings indicate that tau accumulates even in amyloid-negative healthy OA and this process can be measured with in vivo tau-PET. In OA, tau accumulation and atrophy share a similar topography. In AD, tau increases more rapidly and accumulation occurs in frontal regions that are not yet undergoing significant atrophy. Ann Neurol 2019; 1-12 ANN NEUROL 2019;85:229-240.

Spatial patterns of tau deposition are associated with amyloid, ApoE, sex, and cognitive decline in older adults.

PURPOSE: The abnormal deposition of tau begins before the onset of clinical symptoms and seems to target specific brain networks. The aim of this study is to identify the spatial patterns of tau deposition in cognitively normal older adults and assess whether they are related to amyloid-ß (Aß), APOE, sex, and longitudinal cognitive decline. METHODS: We included 114 older adults with cross-sectional flortaucipir (FTP) and Pittsburgh Compound-B PET in addition to longitudinal cognitive testing. A voxel-wise independent component analysis was applied to FTP images to identify the spatial patterns of tau deposition. We then assessed whether tau within these patterns differed by Aß status, APOE genotype, and sex. Linear mixed effects models were built to test whether tau in each component predicted cognitive decline. Finally, we ordered the spatial components based on the frequency of high tau deposition to model tau spread. RESULTS: We found 10 biologically plausible tau patterns in the whole sample. There was greater tau in medial temporal, occipital, and orbitofrontal components in Aß-positive compared with Aß-negative individuals; in the parahippocampal component in ε3ε3 compared with ε2ε3 carriers; and in temporo-parietal and anterior frontal components in women compared with men. Higher tau in temporal and frontal components predicted longitudinal cognitive decline in memory and executive functions, respectively. Tau deposition was most frequently observed in medial temporal and ventral cortical areas, followed by lateral and primary areas. CONCLUSIONS: These findings suggest that the spatial patterns of tau in asymptomatic individuals are clinically meaningful and are associated with Aß, APOE ε2ε3, sex and cognitive decline. These patterns could be used to predict the regional spread of tau and perform in vivo tau staging in older adults.

Correction to: A new Centiloid method for 18F-florbetaben and 18F-flutemetamol PET without conversion to PiB.

Funding information from the original version of this article was incomplete. Complete information is presented here.

A new Centiloid method for 18F-florbetaben and 18F-flutemetamol PET without conversion to PiB.

PURPOSE: We developed a new method to directly calculate Centiloid (CL) units of 18F-florbetaben (FBB) and 18F-flutemetamol (FMM) without conversion to the PiB standardized uptake value ratio (SUVR). METHODS: Paired FBB and FMM PET scans were obtained from 20 Alzheimer's disease-related cognitive impairment patients, 16 old controls, and 20 young controls. We investigated the correlations between the FBB and FMM CL units using the direct comparison of FBB-FMM CL (dcCL) method and the standard CL method and compare differences in FBB and FMM CL units between dcCL method and the standard method. RESULTS: Following the conversion of FBB or FMM SUVRs into CL units, a direct relationship was formed between the FBB or FMM SUVRs and the CL units using dcCL method (FBB dcCL = 151.42 × FBB dcSUVR - 142.24 and FMM dcCL = 148.52 × FMM dcSUVR - 137.09). The FBB and FMM CL units were highly correlated in both our method (R2 = 0.97, FMM dcCL = 0.97 × FBB dcCL + 1.64) and the standard method (R2 = 0.97, FMM CLstandard = 0.79 × FBB CLstandard + 1.36). However, the CL variations between FBB and FMM were smaller when calculated by dcCL method (6.15) than when calculated by the previous method (10.22; P = 0.01). CONCLUSIONS: Our findings suggest that our direct comparison of FBB-FMM method, rather than the standard method, is a reasonable way to convert FBB or FMM SUVRs into CL units, at least in environments where FBB or FMM ligands are used frequently.

Entorhinal Tau Pathology, Episodic Memory Decline, and Neurodegeneration in Aging.

The medial temporal lobe (MTL) is an early site of tau accumulation and MTL dysfunction may underlie episodic-memory decline in aging and dementia. Postmortem data indicate that tau pathology in the transentorhinal cortex is common by age 60, whereas spread to neocortical regions and worsening of cognition is associated with ß-amyloid (Aß). We used [18F]AV-1451 and [11C]PiB positron emission tomography, structural MRI, and neuropsychological assessment to investigate how in vivo tau accumulation in temporal lobe regions, Aß, and MTL atrophy contribute to episodic memory in cognitively normal older adults (n = 83; age, 77 ± 6 years; 58% female). Stepwise regressions identified tau in MTL regions known to be affected in old age as the best predictor of episodic-memory performance independent of Aß status. There was no interactive effect of MTL tau with Aß on memory. Higher MTL tau was related to higher age in the subjects without evidence of Aß. Among temporal lobe subregions, episodic memory was most strongly related to tau-tracer uptake in the parahippocampal gyrus, particularly the posterior entorhinal cortex, which in our parcellation includes the transentorhinal cortex. In subjects with longitudinal MRI and cognitive data (n = 57), entorhinal atrophy mirrored patterns of tau pathology and their relationship with memory decline. Our data are consistent with neuropathological studies and further suggest that entorhinal tau pathology underlies memory decline in old age even without Aß.SIGNIFICANCE STATEMENT Tau tangles and ß-amyloid (Aß) plaques are key lesions in Alzheimer's disease (AD) but both pathologies also occur in cognitively normal older people. Neuropathological data indicate that tau tangles in the medial temporal lobe (MTL) underlie episodic-memory impairments in AD dementia. However, it remains unclear whether MTL tau pathology also accounts for memory impairments often seen in elderly people and how Aß affects this relationship. Using tau-specific and Aß-specific positron emission tomography tracers, we show that in vivo MTL tau pathology is associated with episodic-memory performance and MTL atrophy in cognitively normal adults, independent of Aß. Our data point to MTL tau pathology, particularly in the entorhinal cortex, as a substrate of age-related episodic-memory loss.