The implications of different approaches to define AT(N) in Alzheimer disease

ObjectiveTo compare different β-amyloid (Aβ), tau, and neurodegeneration (AT[N]) variants within the Swedish BioFINDER studies.MethodsA total of 490 participants were classified into AT(N) groups. These include 53 cognitively unimpaired (CU) and 48 cognitively impaired (CI) participants (14 mild cognitive impairment [MCI] and 34 Alzheimer disease [AD] dementia) from BioFINDER-1 and 389 participants from BioFINDER-2 (245 CU and 144 CI [138 MCI and 6 AD dementia]). Biomarkers for A were CSF Aβ42 and amyloid-PET ([18F]flutemetamol); for T, CSF phosphorylated tau (p-tau) and tau PET ([18F]flortaucipir); and for (N), hippocampal volume, temporal cortical thickness, and CSF neurofilament light (NfL). Binarization of biomarkers was achieved using cutoffs defined in other cohorts. The relationship between different AT(N) combinations and cognitive trajectories (longitudinal Mini-Mental State Examination scores) was examined using linear mixed modeling and coefficient of variation.ResultsAmong CU participants, A−T−(N)− or A+T−(N)− variants were most common. However, more T+ cases were seen using p-tau than tau PET. Among CI participants, A+T+(N)+ was more common; however, more (N)+ cases were seen for MRI measures relative to CSF NfL. Tau PET best predicted longitudinal cognitive decline in CI and p-tau in CU participants. Among CI participants, continuous T (especially tau PET) and (N) measures improved the prediction of cognitive decline compared to binary measures.ConclusionsOur findings show that different AT(N) variants are not interchangeable, and that optimal variants differ by clinical stage. In some cases, dichotomizing biomarkers may result in loss of important prognostic information.

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Influence of tau PET, amyloid PET, and hippocampal volume on cognition in Alzheimer disease

Neurology ◽

10.1212/wnl.0000000000006075 ◽

2018 ◽

Vol 91 (9) ◽

pp. e859-e866 ◽

Cited By ~ 58

Author(s):

Andrew J. Aschenbrenner ◽

Brian A. Gordon ◽

Tammie L.S. Benzinger ◽

John C. Morris ◽

Jason J. Hassenstab

Keyword(s):

Alzheimer Disease ◽

Executive Functioning ◽

Episodic Memory ◽

Cognitive Decline ◽

Hippocampal Volume ◽

Cognitive Change ◽

Pet Scan ◽

Cognitive Domain ◽

Amyloid Pet ◽

Tau Pet

ObjectiveTo examine the independent and interactive influences of neuroimaging biomarkers on retrospective cognitive decline.MethodsA total of 152 middle-aged and older adult participants with at least 2 clinical and cognitive assessments, a Clinical Dementia Rating score of 0 or 0.5, and a flortaucipir (18F-AV-1451) tau PET scan, a florbetapir (18F-AV-45) amyloid PET scan, and a structural MRI scan were recruited from the Knight Alzheimer Disease Research Center at Washington University in St. Louis. Cognition was assessed with standard measures reflecting episodic memory, executive functioning, semantic fluency, and processing speed.ResultsResults from retrospective longitudinal analyses showed that each biomarker had a univariate association with the global cognitive composite; however, when each marker was analyzed in a single statistical model, only tau was a significant predictor of global cognitive decline. There was an interaction between tau and amyloid such that tau-related cognitive decline was worse in individuals with high amyloid. There was also an interaction with hippocampal volume indicating that individuals with high levels of all 3 pathologies exhibited the greatest declines in cognition. Additional analyses within each cognitive domain indicated that tau had the largest negative influence on tests of episodic memory and executive functioning.ConclusionsTogether, these results suggest that increasing levels of tau most consistently relate to declines in cognition preceding biomarker collection. These findings support models of Alzheimer disease (AD) staging that suggest that elevated β-amyloid alone may be insufficient to produce cognitive change in individuals at risk for AD and support the use of multiple biomarkers to stage AD progression.

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Optimal Combinations of Biomarkers to Determine AT(N) in the Alzheimer’s Disease

10.21203/rs.3.rs-118287/v1 ◽

2020 ◽

Author(s):

Rong-Rong Lin ◽

Yan-Yan Xue ◽

Xiao-Yan Li ◽

Yi-He Chen ◽

Qing-Qing Tao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cortical Thickness ◽

Clinical Stage ◽

Youden Index ◽

Amyloid Pet ◽

Clinical Dementia Rating ◽

Cognitive Changes ◽

Neurofilament Light ◽

Tau Pet

Abstract Background: National Institute on Aging—Alzheimer’s Association (NIA-AA) proposed the AT(N) system based on β-amyloid deposition, pathologic tau, and neurodegeneration, which considered the definition of Alzheimer’s disease (AD) as a biological construct. However, the associations between different AT(N) combinations and clinical stage and progression have been poorly explored systematically. The aim of this study is to compare different AT(N) combinations using recognized biomarkers within the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.Methods: A total of 341 participants from ADNI cohort were classified into AT(N) groups, including 200 cognitively unimpaired (CU) participants and 141 cognitively impaired (CI) participants (101 mild cognitive impairment [MCI] and 40 Alzheimer’s disease [AD]). CSF Aβ42 and amyloid-PET ([18F]flutemetamol) were used as biomarkers for A; CSF phosphorylated tau (p-tau) and tau-PET ([18F]flortaucipir) were used as biomarkers for T; CSF total tau (t-tau), FDG-PET, hippocampal volume, temporal cortical thickness and plasma neurofilament light (NfL) were used as biomarkers for (N). Binarization of biomarkers was acquired from Youden index and public cutoffs. The relationship between different AT(N) biomarkers combinations and cognitive changes (longitudinal Mini-Mental State Examination scores and Clinical Dementia Rating Sum of Boxes) was examined using linear mixed modeling and coefficient of variation.Results: Among CU participants, A−T−(N)− variants were most common. More T+ cases were shown using p-tau than tau PET, and more N+ cases were shown using fluid biomarkers than neuroimaging. Among CI participants, A+T+(N)+ was more common. Tau PET combined with cortical thickness best predicted longitudinal cognitive decline in CI and MRI measurements in CU participants. Conclusion: These findings suggest that optimal combinations of biomarkers to determine AT(N) are differed by clinical stage. Different biomarkers within a specific component for defining AT(N) cannot be used identically. Furthermore, different strategies for discontinuous biomarkers will be an important area for the future studies.

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Association of CSF Aβ, amyloid PET, and cognition in cognitively unimpaired elderly adults

Neurology ◽

10.1212/wnl.0000000000010596 ◽

2020 ◽

Vol 95 (15) ◽

pp. e2075-e2085 ◽

Cited By ~ 2

Author(s):

Tengfei Guo ◽

Leslie M. Shaw ◽

John Q. Trojanowski ◽

William J. Jagust ◽

Susan M. Landau ◽

...

Keyword(s):

Cognitive Decline ◽

Amyloid Pet ◽

Elderly Adults ◽

Cognitively Normal ◽

Longitudinal Measurements ◽

Normal Individuals ◽

Aβ Amyloid ◽

Discordant Group ◽

Amyloid Aβ ◽

The Relationship

ObjectiveTo compare CSF β-amyloid (Aβ) and florbetapir PET measurements in cognitively unimpaired (CU) elderly adults in order to detect the earliest abnormalities and compare their predictive effect for cognitive decline.MethodsA total of 259 CU individuals were categorized as abnormal (+) or normal (−) on CSF Aβ1-42/Aβ1-40 analyzed with mass spectrometry and Aβ PET measured with 18F-florbetapir. Simultaneous longitudinal measurements of CSF and PET were compared for 39 individuals who were unambiguously Aβ-negative at baseline (CSF−/PET−). We also examined the relationship between baseline CSF/PET group membership and longitudinal changes in CSF Aβ, Aβ PET, and cognition.ResultsThe proportions of individuals in each discordant group were similar (8.1% CSF+/PET− and 7.7% CSF−/PET+). Among baseline Aβ-negative (CSF−/PET−) individuals with longitudinal CSF and PET measurements, a larger proportion subsequently worsened on CSF Aβ (odds ratio 4 [95% confidence interval (CI) 1.1, 22.1], p = 0.035) than Aβ PET over 3.5 ± 1.0 years. Compared to CSF−/PET− individuals, CSF+/PET− individuals had faster (estimate 0.009 [95% CI 0.005, 0.013], p < 0.001) rates of Aβ PET accumulation over 4.4 ± 1.7 years, while CSF−/PET+ individuals had faster (estimate −0.492 [95% CI −0.861, −0.123], p = 0.01) rates of cognitive decline over 4.5 ± 1.9 years.ConclusionsThe proportions of discordant PET and CSF Aβ-positive individuals were similar cross-sectionally. However, unambiguously Aβ-negative (CSF−/PET−) individuals are more likely to show subsequent worsening on CSF than PET, supporting the idea that CSF detects the earliest Aβ changes. In discordant cases, only PET abnormality predicted cognitive decline, suggesting that abnormal Aβ PET changes are a later phenomenon in cognitively normal individuals.

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Topographic Distribution of Amyloid-β, Tau, and Atrophy in Patients With Behavioral/Dysexecutive Alzheimer Disease

Neurology ◽

10.1212/wnl.0000000000011081 ◽

2020 ◽

Vol 96 (1) ◽

pp. e81-e92

Author(s):

Joseph Therriault ◽

Tharick A. Pascoal ◽

Melissa Savard ◽

Andrea L. Benedet ◽

Mira Chamoun ◽

...

Keyword(s):

Alzheimer Disease ◽

Clinical Symptoms ◽

Characteristic Curve ◽

Tertiary Care ◽

Amyloid Β ◽

Executive Dysfunction ◽

Anterior Cingulate ◽

Amyloid Pet ◽

Clinical Criteria ◽

Tau Pet

ObjectiveTo determine the associations between amyloid-PET, tau-PET, and atrophy with the behavioral/dysexecutive presentation of Alzheimer disease (AD), how these differ from amnestic AD, and how they correlate to clinical symptoms.MethodsWe assessed 15 patients with behavioral/dysexecutive AD recruited from a tertiary care memory clinic, all of whom had biologically defined AD. They were compared with 25 patients with disease severity– and age-matched amnestic AD and a group of 131 cognitively unimpaired (CU) elderly individuals. All participants were evaluated with amyloid-PET with [18F]AZD4694, tau-PET with [18F]MK6240, MRI, and neuropsychological testing.ResultsVoxelwise contrasts identified patterns of frontal cortical tau aggregation in behavioral/dysexecutive AD, with peaks in medial prefrontal, anterior cingulate, and frontal insular cortices in contrast to amnestic AD. No differences were observed in the distribution of amyloid-PET or atrophy as determined by voxel-based morphometry. Voxelwise area under the receiver operating characteristic curve analyses revealed that tau-PET uptake in the medial prefrontal, anterior cingulate, and frontal insular cortices were best able to differentiate between behavioral/dysexecutive and amnestic AD (area under the curve 0.87). Voxelwise regressions demonstrated relationships between frontal cortical tau load and degree of executive dysfunction.ConclusionsOur results provide evidence of frontal cortical involvement of tau pathology in behavioral/dysexecutive AD and highlight the need for consensus clinical criteria in this syndrome.

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Loss of white matter integrity reflects tau accumulation in Alzheimer disease defined regions

Neurology ◽

10.1212/wnl.0000000000005864 ◽

2018 ◽

Vol 91 (4) ◽

pp. e313-e318 ◽

Cited By ~ 23

Author(s):

Jeremy F. Strain ◽

Robert X. Smith ◽

Helen Beaumont ◽

Catherine M. Roe ◽

Brian A. Gordon ◽

...

Keyword(s):

White Matter ◽

Alzheimer Disease ◽

Gray Matter ◽

Structural Integrity ◽

Diffusion Tensor ◽

Mean Diffusivity ◽

Cognitively Impaired ◽

Cognitively Normal ◽

Advanced Stages ◽

Amyloid Aβ

ObjectiveWhite matter (WM) projections were assessed from Alzheimer disease (AD) gray matter regions associated with β-amyloid (Aβ), tau, or neurodegeneration to ascertain relationship between WM structural integrity with Aβ and/or tau deposition.MethodsParticipants underwent diffusion tensor imaging (DTI), PET Aβ ([18F]AV-45 [florbetapir]), and PET tau ([18F]AV-1451 [flortaucipir]) imaging. Probabilistic WM summary and individual tracts were created from either a composite or individual gray matter seed regions derived from Aβ, tau, and neurodegeneration. Linear regressions were performed for Aβ, age, tau and WM hyperintensities (WMH) to predict mean diffusivity (MD) or fractional anisotropy (FA) from the corresponding WM summaries or tracts.ResultsOur cohort was composed of 59 cognitively normal participants and 10 cognitively impaired individuals. Aβ was not associated with DTI metrics in WM summary or individual tracts. Age and WMH strongly predicted MD and FA in several WM regions, with tau a significant predictor of MD only in the anterior temporal WM.ConclusionTau, not Aβ, was associated with changes in anterior temporal WM integrity. WMH, a proxy for vascular damage, was strongly associated with axonal damage, but tau independently contributed to the model, suggesting an additional degenerative mechanism within tracts projecting from regions vulnerable to AD pathology. WM decline was associated with early tau accumulation, and further decline may reflect tau propagation in more advanced stages of AD.

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Age-accelerated cognitive decline in asymptomatic adults with CSF β-amyloid

Neurology ◽

10.1212/wnl.0000000000005291 ◽

2018 ◽

Vol 90 (15) ◽

pp. e1306-e1315 ◽

Cited By ~ 23

Author(s):

Lindsay R. Clark ◽

Sara E. Berman ◽

Derek Norton ◽

Rebecca L. Koscik ◽

Erin Jonaitis ◽

...

Keyword(s):

Cognitive Decline ◽

Characteristic Curve ◽

Hippocampal Volume ◽

Specific Pattern ◽

Preclinical Ad ◽

List Learning ◽

Amyloid Aβ ◽

Β Amyloid ◽

Neuropsychological Evaluations ◽

Stage 1

ObjectiveCompare cognitive and hippocampal volume trajectories in asymptomatic middle-aged and older adults with positive CSF markers of β-amyloid (Aβ) or tau to adults without an Alzheimer disease (AD)-associated biomarker profile.MethodsThree hundred ninety-two adults enrolled in a longitudinal cohort study (Wisconsin Registry for Alzheimer's Prevention or Wisconsin Alzheimer's Disease Research Center) completed a lumbar puncture and at least 2 biennial or annual neuropsychological evaluations. Cutoffs for Aβ42, total tau, and phosphorylated tau were developed via receiver operating characteristic curve analyses on a sample of 78 participants (38 dementia, 40 controls). These cutoffs were applied to a separate sample of 314 cognitively healthy adults (mean age at CSF collection = 61.5 years), and mixed-effects regression analyses tested linear and quadratic interactions of biomarker group × age at each visit on cognitive and hippocampal volume outcomes.ResultsTwo hundred fifteen participants (69%) were biomarker negative (preclinical AD stage 0), 46 (15%) were Aβ+ only (preclinical AD stage 1), 25 (8%) were Aβ+ and tau+ (preclinical AD stage 2), and 28 (9%) were tau+ only. Both stage 1 and stage 2 groups exhibited greater rates of linear decline on story memory and processing speed measures, and nonlinear decline on list-learning and set-shifting measures compared to stage 0. The tau+ only group did not significantly differ from stage 0 in rates of cognitive decline.ConclusionIn an asymptomatic at-risk cohort, elevated CSF Aβ (with or without elevated tau) was associated with greater rates of cognitive decline, with the specific pattern of decline varying across cognitive measures.

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Tau-PET and in vivo Braak-staging as prognostic markers of future cognitive decline in cognitively normal to demented individuals

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00880-x ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Davina Biel ◽

Matthias Brendel ◽

Anna Rubinski ◽

Katharina Buerger ◽

Daniel Janowitz ◽

...

Keyword(s):

Cognitive Impairment ◽

Cognitive Decline ◽

Prognostic Markers ◽

Patient Specific ◽

Amyloid Pet ◽

Braak Stage ◽

Cognitively Normal ◽

Braak Staging ◽

Pet Tracer ◽

Tau Pet

Abstract Background To systematically examine the clinical utility of tau-PET and Braak-staging as prognostic markers of future cognitive decline in older adults with and without cognitive impairment. Methods In this longitudinal study, we included 396 cognitively normal to dementia subjects with 18F-Florbetapir/18F-Florbetaben-amyloid-PET, 18F-Flortaucipir-tau-PET and ~ 2-year cognitive follow-up. Annual change rates in global cognition (i.e., MMSE, ADAS13) and episodic memory were calculated via linear-mixed models. We determined global amyloid-PET (Centiloid) plus global and Braak-stage-specific tau-PET SUVRs, which were stratified as positive(+)/negative(−) at pre-established cut-offs, classifying subjects as Braak0/BraakI+/BraakI–IV+/BraakI–VI+/Braakatypical+. In bootstrapped linear regression, we assessed the predictive accuracy of global tau-PET SUVRs vs. Centiloid on subsequent cognitive decline. To test for independent tau vs. amyloid effects, analyses were further controlled for the contrary PET-tracer. Using ANCOVAs, we tested whether more advanced Braak-stage predicted accelerated future cognitive decline. All models were controlled for age, sex, education, diagnosis, and baseline cognition. Lastly, we determined Braak-stage-specific conversion risk to mild cognitive impairment (MCI) or dementia. Results Baseline global tau-PET SUVRs explained more variance (partial R2) in future cognitive decline than Centiloid across all cognitive tests (Cohen’s d ~ 2, all tests p < 0.001) and diagnostic groups. Associations between tau-PET and cognitive decline remained consistent when controlling for Centiloid, while associations between amyloid-PET and cognitive decline were non-significant when controlling for tau-PET. More advanced Braak-stage was associated with gradually worsening future cognitive decline, independent of Centiloid or diagnostic group (p < 0.001), and elevated conversion risk to MCI/dementia. Conclusion Tau-PET and Braak-staging are highly predictive markers of future cognitive decline and may be promising single-modality estimates for prognostication of patient-specific progression risk in clinical settings.

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Optimal Combinations of AT(N) Biomarkers to Determine Longitudinal Cognition in the Alzheimer's Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.718959 ◽

2021 ◽

Vol 13 ◽

Author(s):

Rong-Rong Lin ◽

Yan-Yan Xue ◽

Xiao-Yan Li ◽

Yi-He Chen ◽

Qing-Qing Tao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cortical Thickness ◽

Clinical Manifestations ◽

Cognitive Status ◽

Youden Index ◽

Amyloid Pet ◽

Cognitive Changes ◽

Neurofilament Light ◽

Tau Pet

Background: National Institute on Aging—Alzheimer's Association (NIA-AA) proposed the AT(N) system based on β-amyloid deposition, pathologic tau, and neurodegeneration, which considered the definition of Alzheimer's disease (AD) as a biological construct. However, the associations between different AT(N) combinations and cognitive progression have been poorly explored systematically. The aim of this study is to compare different AT(N) combinations using recognized biomarkers within the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.Methods: A total of 341 participants were classified into cognitively unimpaired (CU; n = 200) and cognitively impaired (CI; n = 141) groups according to the clinical manifestations and neuropsychological tests. Cerebrospinal fluid (CSF) Aβ42 and amyloid-PET ([18F]flutemetamol) were used as biomarkers for A; CSF phosphorylated tau (p-tau) and tau-PET ([18F]flortaucipir) were used as biomarkers for T; CSF total tau (t-tau), hippocampal volume, temporal cortical thickness, [18F]fluorodeoxyglucose (FDG) PET, and plasma neurofilament light (NfL) were used as biomarkers for (N). Binary biomarkers were obtained from the Youden index and publicly available cutoffs. Prevalence of AT(N) categories was compared between different biomarkers within the group using related independent sample non-parametric test. The relationship between AT(N) combinations and 12-year longitudinal cognition was assessed using linear mixed-effects modeling.Results: Among the CU participants, A–T–(N)– was most common. More T+ were detected using p-tau than tau PET (p < 0.05), and more (N)+ were observed using fluid biomarkers (p < 0.001). A+T+(N)+ was more common in the CI group. Tau PET combined with cortical thickness best predicted cognitive changes in the CI group and MRI predicted changes in the CU group.Conclusions: These findings suggest that optimal AT(N) combinations to determine longitudinal cognition differ by cognitive status. Different biomarkers within a specific component for defining AT(N) cannot be used identically. Furthermore, different strategies for discontinuous biomarkers will be an important area for future studies.

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Glucose metabolism reflects local atrophy and tau pathology in symptomatic Alzheimer’s disease

10.1101/2021.03.08.21252999 ◽

2021 ◽

Author(s):

Amelia Strom ◽

Leonardo Iaccarino ◽

Lauren Edwards ◽

Orit H. Lesman-Segev ◽

David N. Soleimani-Meigooni ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Temporal Lobe ◽

Medial Temporal Lobe ◽

Cognitively Impaired ◽

Amyloid Pet ◽

Tau Pathology ◽

Ε4 Allele ◽

Tau Pet ◽

Disease Stages

AbstractPosterior cortical hypometabolism measured with [18F]-Fluorodeoxyglucose (FDG)-PET is a well-known marker of Alzheimer’s disease-associated neurodegeneration, but its associations with underlying neuropathological processes are unclear. We assessed 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 independent 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 within one year. Standard uptake value ratios (SUVR) were calculated using tracer-specific reference regions. Brain regions were defined in native space using FreeSurfer. Regression analyses were run within cohorts to identify variables associated with retrosplenial or inferior parietal FDG SUVR. On average, ADNI patients were older and had less severe cognitive impairment than UCSF patients. Regional patterns of hypometabolism were similar between cohorts, though there were cohort differences in regional gray matter atrophy. Local cortical thickness and tau-PET (but not amyloid-PET) were independently associated with both retrosplenial and inferior parietal FDG SUVR (ΔR2 = .09 to .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 ADNI (ΔR2 = .04, p = .008) but not UCSF (ΔR2 < .01, p = .52), and did not improve the inferior parietal models (ΔR2s < .01, ps > .37). Interaction analyses revealed that medial temporal volume was more strongly associated with retrosplenial FDG SUVR at earlier disease stages (p = .06 in UCSF, p = .046 in ADNI). Models including molecular pathology in functionally connected regions, defined based on task-free functional MRI data from the Neurosynth database, or APOE ε4 did not outperform local models. Overall, hypometabolism in cognitively impaired patients primarily reflected local atrophy and tau pathology, with an added contribution of medial temporal lobe degeneration at earlier disease stages. Our data did not support hypotheses of a detrimental effect of pathology in connected regions or the presence of the APOE ε4 allele in impaired participants. FDG-PET reflects structural neurodegeneration and tau, but not amyloid, pathology at symptomatic stages of Alzheimer’s disease.

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Predicting future rates of tau accumulation on PET

Brain ◽

10.1093/brain/awaa248 ◽

2020 ◽

Vol 143 (10) ◽

pp. 3136-3150

Author(s):

Clifford R Jack ◽

Heather J Wiste ◽

Stephen D Weigand ◽

Terry M Therneau ◽

Val J Lowe ◽

...

Keyword(s):

Clinical Trials ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Cognitive Performance ◽

Independent Predictor ◽

Cognitively Impaired ◽

Amyloid Pet ◽

Accumulation Rates ◽

Impaired Group ◽

Tau Pet

Abstract Clinical trials with anti-tau drugs will need to target individuals at risk of accumulating tau. Our objective was to identify variables available in a research setting that predict future rates of tau PET accumulation separately among individuals who were either cognitively unimpaired or cognitively impaired. All 337 participants had: a baseline study visit with MRI, amyloid PET, and tau PET exams, at least one follow-up tau PET exam; and met clinical criteria for membership in one of two clinical diagnostic groups: cognitively unimpaired (n = 203); or cognitively impaired (n = 134, a combined group of participants with either mild cognitive impairment or dementia with Alzheimer’s clinical syndrome). Our primary analyses were in these two clinical groups; however, we also evaluated subgroups dividing the unimpaired group by normal/abnormal amyloid PET and the impaired group by clinical phenotype (mild cognitive impairment, amnestic dementia, and non-amnestic dementia). Linear mixed effects models were used to estimate associations between age, sex, education, APOE genotype, amyloid and tau PET standardized uptake value ratio (SUVR), cognitive performance, cortical thickness, and white matter hyperintensity volume at baseline, and the rate of subsequent tau PET accumulation. Log-transformed tau PET SUVR was used as the response and rates were summarized as annual per cent change. A temporal lobe tau PET meta-region of interest was used. In the cognitively unimpaired group, only higher baseline amyloid PET was a significant independent predictor of higher tau accumulation rates (P < 0.001). Higher rates of tau accumulation were associated with faster rates of cognitive decline in the cognitively unimpaired subgroup with abnormal amyloid PET (P = 0.03), but among the subgroup with normal amyloid PET. In the cognitively impaired group, younger age (P = 0.02), higher baseline amyloid PET (P = 0.05), APOE ε4 (P = 0.05), and better cognitive performance (P = 0.05) were significant independent predictors of higher tau accumulation rates. Among impaired individuals, faster cognitive decline was associated with faster rates of tau accumulation (P = 0.01). While we examined many possible predictor variables, our results indicate that screening of unimpaired individuals for potential inclusion in anti-tau trials may be straightforward because the only independent predictor of high tau rates was amyloidosis. In cognitively impaired individuals, imaging and clinical variables consistent with early onset Alzheimer’s disease phenotype were associated with higher rates of tau PET accumulation suggesting this may be a highly advantageous group in which to conduct proof-of-concept clinical trials that target tau-related mechanisms. The nature of the dementia phenotype (amnestic versus non-amnestic) did not affect this conclusion.

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