Plasma levels of phosphorylated tau 181 are associated with cerebral metabolic dysfunction in cognitively impaired and amyloid-positive individuals

Abstract Alzheimer’s disease biomarkers are primarily evaluated through MRI, PET and CSF methods in order to diagnose and monitor disease. Recently, advances in the assessment of blood-based biomarkers have shown promise for simple, inexpensive, accessible and minimally invasive tools with diagnostic and prognostic value for Alzheimer’s disease. Most recently, plasma phosphorylated tau181 has shown excellent performance. The relationship between plasma phosphorylated tau181 and cerebral metabolic dysfunction assessed by [18F]fluorodeoxyglucose PET in Alzheimer’s disease is still unknown. This study was performed on 892 older individuals (297 cognitively unimpaired; 595 cognitively impaired) from the Alzheimer’s Disease Neuroimaging Initiative cohort. Plasma phosphorylated tau181 was assessed using single molecular array technology and metabolic dysfunction was indexed by [18F]fluorodeoxyglucose PET. Cross-sectional associations between plasma and CSF phosphorylated tau181 and [18F]fluorodeoxyglucose were assessed using voxelwise linear regression models, with individuals stratified by diagnostic group and by β-amyloid status. Associations between baseline plasma phosphorylated tau181 and longitudinal (24 months) rate of brain metabolic decline were also assessed in 389 individuals with available data using correlations and voxelwise regression models. Plasma phosphorylated tau181 was elevated in β-amyloid positive and cognitively impaired individuals as well as in apolipoprotein E ε4 carriers and was significantly associated with age, worse cognitive performance and CSF phosphorylated tau181. Cross-sectional analyses showed strong associations between plasma phosphorylated tau181 and [18F]fluorodeoxyglucose PET in cognitively impaired and β-amyloid positive individuals. Voxelwise longitudinal analyses showed that baseline plasma phosphorylated tau181 concentrations were significantly associated with annual rates of metabolic decline in cognitively impaired individuals, bilaterally in the medial and lateral temporal lobes. The associations between plasma phosphorylated tau181 and reduced brain metabolism, primarily in cognitively impaired and in β-amyloid positive individuals, supports the use of plasma phosphorylated tau181 as a simple, low-cost, minimally invasive and accessible tool to both assess current and predict future metabolic dysfunction associated with Alzheimer’s disease, comparatively to PET, MRI and CSF methods.


Introduction
The pathognomonic signs of Alzheimer's disease are the accumulation of b-amyloid (Ab) and the aggregation of hyperphosphorylated tau into intraneuronal tangles. 1 Alzheimer's disease is also importantly characterized by brain glucose metabolism dysfunction and cerebral atrophy. 2 As these pathological changes precede the appearance of clinical symptoms by many years, 3 these pathologies may play an important role in both research and clinical trials for the screening, diagnosis and progression monitoring of Alzheimer's disease. 4 Currently, these biomarkers, i.e. Ab, tau, glucose metabolism and brain atrophy, are primarily assessed through PET, MRI and CSF measures. 3,5 However, the excessive cost, relative invasiveness and time-consuming nature of these methods obstruct their use in clinical practice. 6 As such, given the need for more accessible Alzheimer's disease biomarkers, blood-based biomarkers, such as measures of phosphorylated tau, Ab42/40 ratio and neurofilament light protein, 7 constitute a viable promise and warrant thorough investigation with regards to their specificity to Alzheimer's disease. 8 Phosphorylated tau is the principal component of neurofibrillary tangles and dystrophic neurites in Alzheimer's disease. Tau protein phosphorylated at threonine-181 (p-tau181) has been examined in CSF, 9 and it has been demonstrated that p-tau181 is highly specific for Alzheimer's disease-related tau aggregation. 2 Importantly, recent technological advancements have led to ultrasensitive assays of p-tau181 in blood samples (i.e. plasma and serum) using ultrasensitive immunoassays [10][11][12][13][14] and mass spectrometry methods. 15 Plasma p-tau181 levels have been shown to be strongly associated with brain tau pathology, significantly elevated in Alzheimer's disease and differentiate the disease from other neurodegenerative disorders. [10][11][12][13][14] However, to date the associations between plasma p-tau181 and Alzheimer's disease-related brain metabolic dysfunction, a well-recognized pathophysiological process underlying Alzheimer's disease, remains unknown.
In order to address this knowledge gap, the current study was designed to measure plasma p-tau181 levels and brain glucose metabolism as assessed by [ 18 F]fluorodeoxyglucose (FDG) PET in participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI). The goal of the study is to examine (i) how the plasma biomarker compares to the CSF biomarker in terms of its association to [ 18 F]FDG PET crosssectionally and (ii) how baseline levels of plasma p-tau181 relate to longitudinal change in brain metabolic decline. We hypothesize that plasma p-tau181 performs similarly to CSF p-tau181 with regards to its relationship to brain metabolic dysfunction and that baseline plasma p-tau181 is able to predict reduction of brain metabolism over time.

Study participants
The current study was based on data from the ADNI database. ADNI is a multicentre study launched in 2003 as a public-private partnership, led by Principal Investigator Michael W. Weiner, MD. ADNI's primary goal is to test whether the combination of neuroimaging and biochemical biomarkers and clinical and neuropsychological assessments can be used for early detection and monitoring of Alzheimer's disease dementia. 16 The ADNI study was approved by local Institutional Review Boards of participating institutions, and informed written consent was provided by enrolled participants at each site. Full information regarding the ADNI inclusion/exclusion criteria is described elsewhere (http://adni.loni.usc. edu/, last accessed 15 February 2021). ADNI is a prospective cohort study that continues to recruit participants; this study was based on participants with available plasma p-tau181 data (data downloaded in June 2020).
The study population was classified into two diagnostic groups: cognitively unimpaired (CU) and cognitively impaired (CI) individuals. The CU classification was based on a CDR of 0; participants who had no cognitive dysfunction but reported subjective cognitive decline were analyzed together with CU, as per the National Institute of Aging-Alzheimer's Association's biological Alzheimer's disease research framework. 2 The CI group consisted of individuals that were clinically defined as having a mild cognitive impairment or Alzheimer's disease dementia. Mild cognitive impairment and Alzheimer's disease dementia classification followed the criteria described elsewhere. 16 Supplementary Fig. 1. The first available plasma p-tau181 measurement was used as the baseline time point for longitudinal analyses, as well as for age and diagnostic classification for cross-sectional and longitudinal analyses.

Patient consent
The ADNI study was approved by the local Institutional Review Boards of all of the participating institutions. Informed written consent was provided by enrolled participants at each site.

Plasma p-tau181 measurement
Blood samples were collected, shipped and stored as described by the ADNI Biomarker Core Laboratory (http://adni.loni.usc.edu/methods/, last accessed 15 February 2021). Plasma p-tau181 was analyzed with the Single Molecule Array (Simoa) technique, using a clinically validated in-house assay described previously. 10 Plasma p-tau181 was measured on Simoa HD-X instruments (Quanterix, Billerica, MA, USA) in April 2020 at the Clinical Neurochemistry Laboratory, University of Gothenburg, Mö lndal, Sweden. Plasma p-tau181 data were collected over 47 analytical runs. The assay precision was assessed by measuring two different quality control samples at the start and end of each run, resulting in within-run and between-run coefficients of variation of 3.3-11.6% and 6.4-12.7%, respectively. Out of 3762 ADNI samples, four were removed due to inadequate volumes. The remaining 3758 all measured above the assay's lower limit of detection (0.25 pg/ml), with only six below the lower limit of quantification (1.0 pg/ ml). Plasma p-tau181 measurements were downloaded from the ADNI database (accessed 2020-06-20).
CSF p-tau181 measurement CSF samples were collected by lumbar puncture, shipped and stored as described by the ADNI Biomarker Core Laboratory (http://adni.loni.usc.edu/methods/, last accessed 15 February 2021). CSF concentrations of p-tau181 were quantified using fully automated Elecsys immunoassays (Roche Diagnostics) at the ADNI Biomarker Laboratory at the University of Pennsylvania. The lower and upper technical limits for CSF p-tau181 were 8 and 120 pg/ml. Procedures have been described in detail previously. 18,19 MRI acquisition and processing Pre-processed 3 T MRI T1-weighted magnetization-prepared rapid acquisition gradient-echo images were downloaded from the ADNI database; full information regarding ADNI acquisition and pre-processing protocols of MRI data can be found elsewhere (http://adni.loni.usc. edu/methods/mri-tool/mri-analysis/, last accessed 15 February 2021). 20 Images underwent linear and non-linear registration to the ADNI template space, and all images were visually inspected to ensure proper alignment to the ADNI template.

PET acquisition and processing
Pre-processed [ 18 F]FDG and [ 18 F]Florbetapir PET images were downloaded from the ADNI database; full information regarding ADNI acquisition and pre-processing protocols of PET data can be found elsewhere (http://adni.loni. usc.edu/methods/pet-analysis-method/pet-analysis/, l a s t accessed 15 February 2021). Images underwent spatial normalization to the ADNI standardized space using the automatic registration of PET images to their corresponding T1-weighted image space as well as the linear and non-linear transformations from the T1-weighted image space to the ADNI template space. PET images were spatially smoothed to achieve a final resolution of 8 mm full width at half maximum and were visually inspected to ensure proper alignment to the ADNI template.
[ 18 F]FDG and [ 18 F]Florbetapir standardized uptake value ratio (SUVR) maps were generated using the pons and the full cerebellum as the reference region, respectively. For each participant, a global [ 18 F]FDG SUVR value was estimated by averaging the SUVR from the angular gyrus, posterior cingulate and inferior temporal cortices. 21 A global [ 18 F]Florbetapir SUVR value was similarly estimated using the precuneus, prefrontal, orbitofrontal, parietal, temporal, anterior and posterior cingulate cortices. 21 Amyloid-b (Ab) positivity was determined for each participant by a global [ 18 F]Florbetapir SUVR exceeding 1.11. 22

Statistical analyses
All non-imaging statistical analyses were performed using R v4.0.0. Voxelwise imaging statistical analyses were executed using the VoxelStats toolbox 23 in MATLAB version 9.4. Subjects were considered outliers if their baseline plasma p-tau181 value was three standard deviations above the population mean, and their data were excluded. Comparing demographic and clinical characteristics between diagnostic groups was done using v 2 test with continuity correction for categorical variables, Mann-Whitney U test for non-normal continuous variables and one-way ANOVA for normal continuous variables. Correlations between plasma p-tau181 levels and demographic and clinical characteristics used Pearson's correlation coefficient (r). All P values were two-tailed and P values <0.05 were considered significant.
Cross-sectional data were evaluated with correlations between log-transformed CSF and plasma p-tau181 concentrations using Pearson's correlation coefficient, with subjects stratified by diagnostic group and Ab status. Voxelwise linear regression models tested the cross-sectional associations between [ 18 F]FDG PET uptake and both CSF and plasma p-tau181 concentrations, adjusting for age and sex, in diagnostic groups (with and without Ab status stratification).
Longitudinal analyses investigated the associations between baseline plasma p-tau181 levels and longitudinal metabolic decline. Annual rates of change were calculated both for global [ 18 F]FDG SUVR and voxelwise for [ 18 F]FDG images by subtracting the baseline value from the 24-month follow-up value and normalizing by the time difference between time points, in years. Correlations and voxelwise linear regression models then tested the associations between the annual rate of change in metabolic decline (using [ 18 F]FDG SUVR and images, respectively) and log-transformed baseline concentration of plasma p-tau181 and, adjusting for age and sex. Logtransformation of CSF and plasma p-tau181 measurements in pg/ml was used in all voxelwise analyses in order to reduce the skew of the distribution. Random field theory with a cluster threshold of P < 0.001 was used to correct voxelwise analyses for multiple comparisons. 24

Data availability
The dataset supporting the conclusions of this article is available in full on the ADNI site, at http://adni.loni.usc. edu/data-samples/access-data/ (last accessed 15 February 2021).

Demographic characteristics
A total of 823 participants was included in the cross-sectional dataset, while 389 participants were included in the longitudinal dataset. In total, we studied unique 892 participants across both datasets, as we included individuals in the longitudinal dataset who did not have an available CSF p-tau181 assessment. From the unique participants, 297 were classified into the CU group and 595 into the CI group. Demographic and clinical characteristics are summarized for both datasets stratified by diagnostic group in Table 1.
Of the 892 unique individuals, 476 (53.4%) were male and median age at baseline plasma collection was 73.0 years (interquartile range 67.9-78.1). CI individuals were significantly younger (P < 0.001) than CU participants only in the longitudinal dataset, whereas significantly more CI individuals were male (P ¼ 0.005) only in the cross-sectional dataset. CU individuals had more years of education (p cross ¼ 0.016, p long ¼ 0.027) than CI individuals in both datasets. As expected, in both datasets, CI individuals had significantly worse performance in cognitive tests (mini-mental state examination and CDR; p cross < 0.001, p long < 0.001 for both tests), higher amyloid load indexed by [ 18 F]Florbetapir SUVR (p cross < 0.001, p long < 0.001), lower brain metabolism indexed by [ 18 F]FDG SUVR (p cross < 0.001, p long ¼ 0.011), and significantly more CI individuals were APOE e4 carriers (p cross < 0.001, p long < 0.001) and Ab-positive (p cross < 0.001, p long < 0.001).
CI individuals had significantly elevated (P < 0.001) levels of CSF p-tau181 compared with CU individuals in the cross-sectional dataset. Plasma p-tau181 concentrations were significantly higher (P < 0.001) in CI individuals in both crosssectional and longitudinal datasets. Considering the 892 unique participants at baseline, plasma p-tau181 levels were significantly higher in males (P ¼ 0.007), irrespective of diagnosis. Plasma p-tau181 was also highly significantly elevated in APOE e4 carriers (P < 0.0001) and in Abþ individuals (P < 0.0001). Furthermore, plasma p-tau181 was positively associated with age (r ¼ 0.17, P ¼ 3.7eÀ07), CDR sum of boxes score (r ¼ 0.28, P < 2.2eÀ16) and [ 18 F]Florbetapir SUVR (r ¼ 0.36, P < 2.2eÀ16), and negatively associated with education (r ¼ À0.09, P ¼ 0.006) and mini-mental state examination score (r ¼ À0.26, P ¼ 6.6eÀ15). When stratifying CU and CI individuals of the cross-sectional dataset by Ab status, we observed significant differences in CSF and plasma p-tau181 levels between CU AbÀ and CU Abþ groups, CI AbÀ and CI Abþ groups and CU Abþ and CI Abþ groups (P < 0.001), but not CU AbÀ and CI AbÀ groups ( Fig. 1A and B). Similarly, in the longitudinal dataset, we observed significant differences in baseline plasma p-tau181 levels between CU AbÀ and CU Abþ groups (P < 0.01) and CI AbÀ and CI Abþ groups (P < 0.001; Fig. 2A).
Plasma p-tau181 associates crosssectionally with CSF p-tau181 and brain metabolism In the cross-sectional dataset, increased concentrations of plasma p-tau181 were correlated with greater CSF p-tau181 levels in CU Abþ (r ¼ 0.233, P ¼ 8.45eÀ05), CI  p-tau181 levels in pg/ml were compared in individuals in the cross-sectional dataset, stratified by both their cognitive status cognitively unimpaired (CU) or impaired (CI)] and Ab status (þ or À), using Mann-Whitney U test. Significant differences in CSF p-tau181 were found between the CU-and CUþ groups (P < 0.001), the CUþ and CIþ groups (P < 0.001), and the CIÀ and CIþ groups (P < 0.001). (B) Similarly, plasma p-tau181 levels in pg/ml were compared cross-sectionally in individuals stratified by both cognitive and Ab status. Significant differences in plasma p-tau181 were found between the CUÀ and CUþ groups (P < 0.001), the CUþ and CIþ groups (P < 0.001), and the CIÀ and CIþ groups (P < 0.001). (C) Pearson's correlation coefficient (r) was computed for associations between log-transformed CSF levels and logtransformed plasma p-tau181 levels in individuals in the cross-sectional dataset stratified by cognitive and Ab status. These measures were significantly positively correlated in the CUþ (r ¼ 0.233, P ¼ 8.45eÀ05), CIÀ (r ¼ 0.346, P ¼ 0.012), and CIþ groups (r ¼ 0.233, P ¼ 7.6eÀ05), but not in the CUÀ group (r ¼ 0.084, P ¼ 0.224). (D) Voxelwise linear regressions were performed to assess associations between log-transformed CSF p-tau181 and plasma p-tau181 in CI individuals stratified by Ab status, adjusting for age and sex. Negative associations between CSF p-tau181 and [ 18 F]FDG SUVR were observed bilaterally in CI Abþ individuals in the inferior temporal, posterior cingulate and precuneus (peak tvalue of À5.78). Negative associations were found in similar brain regions between [ 18 F]FDG uptake and plasma p-tau181 levels among CI Abþ participants (peak t-value of À6.03). Voxelwise results were corrected for multiple comparisons.
AbÀ (r ¼ 0.346, P ¼ 0.012) and CI Abþ (r ¼ 0.233, P ¼ 7.6eÀ05), but not in CU AbÀ individuals (r ¼ 0.084, P ¼ 0.224; Fig. 1C). At the voxel level, linear regression models found no significant associations in CU individuals between [ 18 F]FDG uptake and CSF p-tau181 whereas for plasma p-tau181, negative associations were observed in very small clusters in the anterior cingulate and left temporal and parietal lobes (results not pictured, peak t-value of À4.82). Within CI individuals, stratified by Ab status, significant negative associations between CSF p-tau181 and [ 18 F]FDG retention were observed in CI Abþ individuals bilaterally in the inferior temporal, posterior cingulate and precuneus ( Fig. 1D; peak t-value of À5.78). Significant negative associations were also found between [ 18 F]FDG uptake and plasma p-tau181 levels among CI Abþ participants in more widespread temporal lobe clusters, and in the anterior and posterior cingulate, precuneus and orbitofrontal cortices (peak t-value of À6.03). Associations between both CSF and plasma p-tau181 and [ 18 F]FDG uptake in all CI participants without stratification are shown in Supplementary  Fig. 2.
Baseline plasma p-tau181 is associated with longitudinal decrease in brain metabolism  Supplementary Fig. 3 and is highest (i.e. more negative values representing more pronounced metabolic decline) in the posterior cingulate, precuneus, temporal, and medial and lateral prefrontal cortices. Correlations between baseline concentration of plasma p-tau181 and annual rate of change in [ 18 F]FDG SUVR was statistically significant and negative within CI individuals (r ¼ À0.17, P ¼ 0.007), but not significant in CU individuals (Fig. 2B). When stratifying individuals by both diagnostic group and Ab status, correlations were statistically significant only in the CU Abþ group (r ¼ À0.4, P ¼ 0.035) (Supplementary Fig. 4). Voxelwise associations between baseline plasma p-tau181 and rate of change in [ 18 F]FDG SUVR did not survive correction for multiple comparisons in CU individuals. In CI individuals, baseline plasma p-tau181 predicted rate of change of [ 18 F]FDG SUVR in the bilateral medial and lateral temporal lobes (Fig. 2C, peak t-value of À5.01).

Discussion
In this study, we provide not yet reported evidence for associations between plasma measures of p-tau181 and cerebral hypometabolism as assessed by [ 18 F]FDG PET. Our main findings were that cross-sectionally, plasma p-tau181 is associated with the metabolic signatures of Alzheimer's disease. Moreover, in cognitively impaired individuals, levels of plasma p-tau181 at baseline are associated with longitudinal metabolic decline. Taken together, our study suggests that plasma p-tau181 may provide a cost-effective and minimally invasive method to assess existing disease pathophysiology highly associated with metabolic dysfunction.
We found that plasma p-tau181 was higher in males and APOE e4 carriers, which to our knowledge is a finding that has not yet been described. We also observed plasma p-tau181 to be significantly associated with older age, fewer years of education, an elevated global cortical composite measure of Ab-PET, and worse performance on cognitive scores, which, with the exception of education, concur with earlier studies on plasma p-tau181. [10][11][12][13]25 As previously described, in our cross-sectional analyses, plasma p-tau181 was correlated with CSF p-tau181. [10][11][12] Moreover, in agreement with previous research, plasma levels of p-tau181 in our sample were significantly elevated in cognitively impaired individuals, as well as in Abþ individuals independent of their cognitive status. [10][11][12][13] Our cross-sectional analyses indicated that plasma p-tau181 levels and metabolic dysfunction were associated in the temporal, anterior and posterior cingulate, precuneus and orbitofrontal cortices in CI Abþ individuals. Interestingly, one can speculate that the small clusters in the anterior corpus callosum present in CU individuals may indicate a link between white matter energetic abnormalities in early states of the disease. 26 Importantly, in both CU and CI groups, higher plasma p-tau181 levels were linked to Ab status. Furthermore, baseline plasma and CSF p-tau181 had highly similar associations with [ 18 F]FDG PET, with higher correlations in individuals on the Alzheimer continuum (i.e. cognitively impaired amyloid-positive individuals) and in similar brain regions. This indicates that glucose metabolism associates with abnormal tau phosphorylation at threonine-181 measured in either blood or CSF.
Longitudinally, we found that baseline concentrations of plasma p-tau181 were significantly associated with annual rate of metabolic decline assessed by a decrease in global [ 18 F]FDG SUVR, within CI and CU Abþ individuals, although the correlation coefficient was low for the CI group (r ¼ À0.17, P ¼ 0.007). Voxelwise analysis, which provides additional regional information, conducted in the CI group revealed that plasma p-tau181 was significantly associated with annual rate of change in [ 18 F]FDG uptake in the medial and lateral lobes after multiple comparison correction. Together, these results support the concept that elevated plasma p-tau181 implies the presence of worsening neurodegeneration.
In our results, the topography of hypometabolism was consistent with brain regions that are known to be affected by Alzheimer's disease. Specifically, metabolic dysfunction in the posterior cingulate gyrus, precuneus, and medial and lateral temporal lobes are commonly observed in amnestic mild cognitive impairment and Alzheimer's disease dementia. [27][28][29] Moreover, the posterior cingulate gyrus, precuneus and medial and lateral temporal lobes are brain regions that are affected by significant tau aggregation in Alzheimer's disease. 30,31 Metabolic dysfunction in these regions is further associated with cognitive decline as well as increased risk of progression to dementia. 32 Because tau aggregation as measured by PET 33 and by CSF 34 is tightly associated with brain metabolism, the results of our study suggest that plasma p-tau181 can serve as a less invasive and more accessible measure of Alzheimer's disease-related cerebral metabolic dysfunction.
Neurodegeneration biomarkers in isolation are neither sensitive nor specific to Alzheimer's disease. 2 In both cross-sectional and longitudinal analyses, we found little associations between plasma p-tau181 and [ 18 F]FDG PET in CU individuals. This finding is consistent with the observation that metabolic dysfunction is tightly related to cognitive decline 35 and thus significant metabolic decline is more commonly observed in individuals with cognitive impairment. Furthermore, we conducted stratified analyses of relationships between plasma p-tau181 and [ 18 F]FDG PET in Abþ and AbÀ individuals. In individuals on the Alzheimer's disease continuum (Abþ), we observed significantly more pronounced cross-sectional associations between plasma p-tau181 and [ 18 F]FDG PET in regions vulnerable to hypometabolism in Alzheimer's disease. However, in individuals who were not on the Alzheimer's disease continuum (AbÀ), we did not observe associations between plasma measures of p-tau181 and brain metabolic dysfunction. This was observed for both CU and CI AbÀ individuals. These results are consistent with accepted disease models in which (detectable) Ab aggregation occurs upstream of (detectable) tau aggregation. 3,36 Taken together, these results suggest that the specificity of plasma p-tau181 for AD-type pathology 10,11,37 provides important information about the aetiology of neurodegeneration and corresponding cognitive decline.
Associations between plasma measures of p-tau181 and [ 18 35 and reduced brain metabolism constitutes an important risk for clinical progression to dementia. 39 [ 18 F]FDG PET abnormalities are also observed before MRI atrophy, 40 suggesting that [ 18 F]FDG PET is a sensitive marker of neurodegeneration. Previous studies have investigated the relationship between available plasma markers of neurodegeneration (such as plasma neurofilament light) and FDG PET, both cross-sectionally and longitudinally. 7 As tau hyperphosphorylation is believed to precede the changes in cerebral metabolism according to the b-amyloid pathology, tau pathology, and neurodegeneration (ATN) framework, 3 we aimed to investigate this relationship with a plasma biomarker which shows earlier abnormality during disease progression. Therefore, given our results in this analysis, plasma measures of p-tau181 show potential as a simple tool for the diagnosis and monitoring of AD, as well as for the screening of individuals for disease-modifying clinical trials.
The validity of our results is potentially influenced by methodological limitations. First, we only included ADNI participants with a 24-month follow-up [ 18 F]FDG PET relative to plasma p-tau181 assessment as imaging data was not consistent at later time points (i.e. at 36 and 48 months). As a consequence, we may have observed stronger and more compelling associations between plasma p-tau181 and [ 18 F]FDG PET, as accepted biomarker models of Alzheimer's disease demonstrate that tau accumulation occurs upstream of metabolic dysfunction and neurodegeneration. 3 Moreover, the ADNI cohort, from which all subjects in this study were selected, does not encompass individuals with neurodegenerative or tau-related diseases other than Alzheimer's disease. Therefore, it is not known how plasma p-tau181 may perform in predicting current and future metabolic dysfunction in other neurodegenerative diseases. Further studies should conduct similar analyses in other more varied observational cohorts, as well as track brain metabolism through [ 18 F]FDG PET over a longer time frame.
Our study provides evidence for associations between plasma measures of p-tau181 and brain metabolic dysfunction as measured by [ 18 F]FDG PET. Subgroup analyses revealed more widespread associations in CI individuals as compared to CU individuals. Moreover, extensive associations were observed in Abþ individuals, whereas no associations between plasma p-tau181 and [ 18 F]FDG PET were observed in AbÀ individuals. Finally, baseline levels of plasma p-tau181 were associated with rates of metabolic decline in CI individuals. Together, our results suggest that plasma p-tau181 provides interrelated information to [ 18 F]FDG PET in the differential diagnosis of individuals with cognitive impairment and may be useful to predict metabolic dysfunction associated with Alzheimer's disease.

Supplementary material
Supplementary material is available at Brain Communications online.