Temporal Lobe Tau Research Articles

Spatiotemporal patterns of locus coeruleus integrity predict cortical tau and cognition.

Autopsy studies indicated that the locus coeruleus (LC) accumulates hyperphosphorylated tau before allocortical regions in Alzheimer's disease. By combining in vivo longitudinal magnetic resonance imaging measures of LC integrity, tau positron emission tomography imaging and cognition with autopsy data and transcriptomic information, we examined whether LC changes precede allocortical tau deposition and whether specific genetic features underlie LC's selective vulnerability to tau. We found that LC integrity changes preceded medial temporal lobe tau accumulation, and together these processes were associated with lower cognitive performance. Common gene expression profiles between LC-medial temporal lobe-limbic regions map to biological functions in protein transport regulation. These findings advance our understanding of the spatiotemporal patterns of initial tau spreading from the LC and LC's selective vulnerability to Alzheimer's disease pathology. LC integrity measures can be a promising indicator for identifying the time window when individuals are at risk of disease progression and underscore the importance of interventions mitigating initial tau spread.

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

Amyloid beta (Aβ) and tau pathology are cross-sectionally associated with atrophy and cognitive decline in aging and Alzheimer's disease (AD). We investigated relationships between concurrent longitudinal measures of Aβ (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). Entorhinal FTP change was correlated with EM decline regardless of Aβ, but meta-temporal FTP and global PiB change were only associated with EM and NM decline in Aβ+ 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. Our results show that longitudinal Aβ is linked to cognitive decline only in the presence of elevated Aβ, but longitudinal temporal lobe tau is associated with memory decline regardless of Aβ status. Entorhinal tau change was associated with memory decline in older adults (OA), regardless of amyloid beta (Aβ). Greater meta-region of interest (ROI) tau change correlated with memory decline in Aβ+ OA. Voxel-wise temporal tau change correlated with memory decline, regardless of Aβ. Meta-ROI tau and global amyloid change correlated with non-memory change in Aβ+ OA. Tau and amyloid accumulation were not associated with structural change in OA.

Amyloid and Tau PET Positivity in Progressive Apraxia of Speech and Agrammatic Aphasia

AbstractBackgroundThe spectrum of what is referred to as nonfluent/agrammatic primary progressive aphasia includes patients with isolated apraxia of speech (PPAOS), progressive agrammatic aphasia (PAA), or a combination thereof (AOS‐PAA). When AOS is present, there is typically an underlying 4R tauopathy (corticobasal degeneration; progressive supranuclear palsy); isolated PAA is more often associated with a 3R tauopathy (Pick’s disease). While pathological studies confirm the clinical syndrome is the sequela of these proteinopathies, beta‐amyloid (Aβ) deposition has also been observed. Given the growing number of treatment options, it is important to better understand the incidence of Alzheimer’s disease (AD) in PPAOS‐PAA spectrum disorders.Methods65 patients recruited by the Neurodegenerative Research Group at Mayo Clinic underwent Aβ‐PET imaging using Pittsburgh Compound B (PiB) and tau‐PET imaging with [18F]flortaucipir at the same visit (PPAOS = 23; PAA = 6; AOS‐PAA = 36). A global PiB SUVR (standardized uptake value ratio)≥1.48 and temporal lobe tau meta‐ROI SUVR≥1.25 were deemed Aβ and tau positive, respectively. The incidence of Aβ and tau positivity and clinical‐demographic profiles were compared among groups.ResultsThere was no difference in age, sex, APOE status, tau/Aβ positivity or PET SUVRs across clinical groups (Table 1). Patients differed on indices of aphasia and AOS severity, in concordance with group membership; there was no difference on a memory measure. Eight patients (12%) were both Aβ and tau positive (indicative of the presence of AD), with an additional 20 patients (31%) positive on only one biomarker (Table 1). Of the eight Aβ and tau positive patients, seven had AOS (six prosodic predominant AOS). Aβ more than tau SUVRs increased with age and were related to each other (Figure 1).ConclusionsAβ and tau positivity is not uncommon in AOS and/or PAA patients, particularly in older patients. Enrollment criteria for Aβ or tau targeted pharmacological trials should consider concordance of biological variables and clinical presentations, rather than simply biological biomarkers. Alternatively, if such patients are enrolled, the outcome measures should reflect the clinical impairments, as it is not yet known if or how concomitant AD influences the clinical presentation.

APOE3 Christchurch heterozygosity delays clinical onset in autosomal dominant Alzheimer’s disease

AbstractBackgroundWe previously reported a case of a homozygous woman with the APOE3 Christchurch (R136S, APOE3Ch) variant who demonstrated extreme resistance to autosomal dominant Alzheimer’s disease (ADAD) caused by the PSEN1 E280A variant. In this study, we examined the potential protective effects of APOE3Ch against ADAD by characterizing the clinical profile of individuals who were heterozygous for the APOE3Ch variant from the Colombian kindred with the PSEN1 E280A variant.MethodsA total of 421 carriers of the PSEN1 E280A variant were included. Of the 421 carriers, 12 were heterozygous for APOE3Ch (including the previously reported homozygous for APOE3Ch). Clinical and neuropsychological assessments were performed in Spanish at the University of Antioquia in Colombia. Four of the APOE3Ch carriers also donated their brains for postmortem studies. A PSEN1 E280A who is heterozygous for the APOE3Ch variant also underwent structural MRI and amyloid and tau PET imaging.ResultsOur findings showed that PSEN1 E280A carriers who are heterozygous carriers of the APOE3Ch variant had a significantly delayed onset for mild cognitive impairment (MCI, median age of 51 vs. 45 years; p = 0.0048) and dementia (52.5 vs. 48 years; p = 0.016), compared to PSEN1 E280A carriers without the APOE3Ch variant. Specifically, APOE3Ch carriers had seven‐time higher odds of developing MCI and three‐time higher odds of developing dementia at a later age than 75% of all the PSEN1 E280A carriers (odds ratio [OR] = 7.6; 95% confidence interval [CI] 1.9, 29.2, p<0.05); dementia OR = 3.07; 95% CI 1.01, 9.33). Initial characterization of brain imaging of a PSEN1 E280A carrier who is heterozygous for the APOE3Ch variant showed levels of medial temporal lobe tau pathology and hippocampal atrophy that were lower than expected for a typical carrier of their age, and similar to our observations in the previously reported APOE3Ch homozygote case.ConclusionsThese clinical, cognitive, and neuroimaging data provide evidence that APOE3Ch heterozygosity delays the onset of cognitive decline and may have a protective, dose‐dependent effect against tau pathology and neurodegeneration. These results provide support for the potential of the APOE3Ch variant as a target for the development of new treatments for AD.

Relationship of structural and functional visual biomarkers with measures of amyloid, tau, and neurodegeneration across the AD continuum

AbstractBackgroundThe eye often reflects changes seen in the brain in neurodegenerative diseases. This study sought to examine the relationship of contrast sensitivity measured using frequency doubling technology (FDT) and retinal thickness measured using optical coherence tomography (OCT) with temporal lobe neurodegeneration, cerebral tau deposition, and mean plasma ptau181 in older adults along the Alzheimer’s disease (AD) continuum.MethodParticipants included 28 individuals with subjective cognitive decline (SCD), 18 mild cognitive impairment (MCI), 4 with AD, and 30 age‐matched cognitive normal (CN) from the Indiana Memory and Aging Study at the Indiana ADRC. Participants were excluded from the study if they had significant eye disease determined to interfere with OCT, FDT, non‐AD dementia, or exclusion for MRI or PET. Mean deviation (MD) and pattern standard deviation (PSD) from FDT were used as measures of contrast sensitivity. OCT scans from each eye to measure retinal thickness in the retinal nerve fiber layer (RNFL) and macula. MRI scans were processed using Freesurfer v6 to measure medial (MTL) and lateral temporal lobe (LTL) volumes. LTL SUVR values were extracted from [18F]flortaucipir PET scans. Plasma ptau 181 was measured using a SIMOA assay. Finally, the association between contrast sensitivity, average RNFL thickness, macular volumes with temporal lobe volumes, LTL tau, and mean plasma ptau181 was assessed using a partial Pearson correlation, covaried for age, sex, and diagnosis. p<0.05 was considered significant.ResultRNFL thickness was decreased in patients with AD. Hippocampal volume correlated with RNFL thickness and macular volume in both eyes and with PSD in the left eye. The inferior temporal volume correlated with MD in both eyes, while mean plasma ptau181 with PSD in both eyes. Finally, lateral temporal lobe tau was correlated with the inner retinal layers of ganglion cell layer plus inner plexiform layer thickness.ConclusionContrast sensitivity correlates with temporal lobe volumes and mean plasma ptau181. RNFL thinning and macular volumes are associated with hippocampal atrophy, and inner retinal nuclear layers correlate with lateral temporal tau. Imaging of the eye may represent a useful biomarker to screen patients at risk for AD prior to more invasive and prolonged testing.

Association between basal forebrain and medial temporal lobe tau, and gray matter volume

AbstractBackgroundTau pathology is a hallmark of Alzheimer’s disease (AD). The basal forebrain (BF) is a significant cholinergic projection site with cholinergic groups 1‐3 (Ch1‐3) projecting to the hippocampus, hypothalamus, and olfactory bulb, and group 4 (Ch4) projecting to the cortical mantle and amygdala. Braak stage 1 includes BF tau and recent literature suggests BF degeneration precedes medial temporal lobe (MTL) degeneration, thus implicating early involvement of the BF in AD. This study examines BF 18F‐flortaucipir (FTP) retention and gray matter (GM) volume, and their associations with MTL FTP retention and GM volume.MethodData were acquired for 111 older adults (Table 1) in the Baltimore Longitudinal Study of Aging. Binary masks for BF subregions Ch1‐3 and Ch4 were generated using a probabilistic atlas (Figure 1). We computed mean standardized uptake value ratio (SUVR) using an inferior cerebellar GM reference region and mean GM volume using average voxel‐based morphometry values for each BF subregion. Colocalized relationships between BF tau and volume were assessed using Pearson correlations. Proximal relationships between BF tau/GM and MTL tau/GM were assessed at the voxel level controlling for age, sex, and intracranial volume and corrected for multiple comparisons using non‐parametric permutations.ResultsWithin the BF, FTP‐SUVR in Ch1‐3 was strongly related to FTP‐SUVR in Ch4, and FTP‐SUVR was associated with larger volume in Ch1‐3, but not Ch4 (Figure 2). Voxelwise analyses showed strong BF‐MTL associations with higher Ch1‐3 and Ch4 FTP‐SUVR associated with higher FTP‐SUVR throughout the MTL. The strongest associations were observed anteriorly (amygdala, peri/entorhinal cortices) and medially along the longitudinal axis of the hippocampus/parahippocampal gyrus. Moreover, for both BF Ch groups, larger volume was associated with larger MTL volume. This association was strongest in the amygdala and hippocampal head and body.ConclusionAs expected, BF FTP‐SUVR was positively associated with MTL FTP‐SUVR, and BF volume was positively associated with MTL GM volume, supporting the use of these BF measures. Further analysis is necessary to better understand the positive associations between BF FTP‐SUVR and GM volume and to assess the temporal ordering of FTP‐SUVR accumulation in the BF and MTL.

Detection of PART in vivo using tau‐PET: preliminary findings using [18F]RO948

AbstractBackgroundPrimary age‐related tauopathy (PART) is a neuropathological entity describing tau pathology in the entorhinal cortex and hippocampus in the absence of amyloid‐β (Aβ) plaques. Though cross‐sectional work using [18F]flortaucipir tau‐PET has shown an association between medial temporal lobe signal and worse cognitive performance, longitudinal studies are needed to examine whether medial temporal lobe tau is associated with cognitive decline and cortical tau accumulation in cognitively unimpaired (CU) individuals. We here aimed to investigate whether CU individuals who are Aβ‐negative and tau‐PET positive in the medial temporal lobe show cognitive decline and increases in CSF phosphorylated tau (P‐tau) or tau PET over time.MethodsUsing BioFINDER‐2, PART was defined as i) CU individuals (not fulfilling criteria for mild cognitive impairment of dementia), ii) age ≥ 60 years, iii) Aβ‐negative (Centiloids < 20 and negative CSF Aβ42/40), and iv) an [18F]RO948 tau‐PET standardized uptake value ratio (SUVR) >1.26 (cut‐off based on Gaussian mixture modelling in BioFINDER‐2, n = 1754) in a volume‐weighted ROI encompassing the entorhinal cortex and hippocampus. [18F]RO948 data was collected 70 to 90 min post‐injection with longitudinal follow‐up collected after ∼2.5 years (average 2.73 ± 1.14 years). Longitudinal P‐tau217 was measured using immunoprecipitation‐mass spectrometry (average 2.67 ± 1.12 years). Longitudinal cognitive measures (average 2.75 ± 0.94 years) included the MMSE and modified PACC. For both longitudinal [18F]RO948, CSF P‐tau217 and cognition, change was assessed using slopes derived from linear mixed models.Results38 individuals fulfilled inclusion criteria (Table 1). These individuals showed significant increases in [18F]RO948 SUVR in the entorhinal cortex/hippocampus (p<0.05, t‐test vs 0)—but not in the temporal cortex—and in CSF P‐tau217 (p<0.01, t‐test vs 0) over time (Figure 1A). This group also showed cognitive decline over time using the PACC (p<0.01, t‐test vs 0) but not the MMSE (Figure 1B). Additional analyses are ongoing using two additional tau‐PET tracers and additional CSF‐based P‐tau measures.ConclusionsThese preliminary findings using [18F]RO948 suggest that PART can be detected in vivo using tau‐PET and that Aβ‐negative CU individuals who are tau‐PET positive in the medial temporal lobe are at risk for focal tau accumulation and cognitive decline.

Medial Temporal Lobe Tau Aggregation Relates to Divergent Cognitive and Emotional Empathy Abilities in Alzheimer's Disease.

In Alzheimer's disease (AD), the gradual accumulation of amyloid-β (Aβ) and tau proteins may underlie alterations in empathy. To assess whether tau aggregation in the medial temporal lobes related to differences in cognitive empathy (the ability to take others' perspectives) and emotional empathy (the ability to experience others' feelings) in AD. Older adults (n = 105) completed molecular Aβ positron emission tomography (PET) scans. Sixty-eight of the participants (35 women) were Aβ positive and symptomatic with diagnoses of mild cognitive impairment, dementia of the Alzheimer's type, logopenic variant primary progressive aphasia, or posterior cortical atrophy. The remaining 37 (22 women) were asymptomatic Aβ negative healthy older controls. Using the Interpersonal Reactivity Index, we compared current levels of informant-rated cognitive empathy (Perspective-Taking subscale) and emotional empathy (Empathic Concern subscale) in the Aβ positive and negative participants. The Aβ positive participants also underwent molecular tau-PET scans, which were used to investigate whether regional tau burden in the bilateral medial temporal lobes related to empathy. Aβ positive participants had lower perspective-taking and higher empathic concern than Aβ negative healthy controls. Medial temporal tau aggregation in the Aβ positive participants had divergent associations with cognitive and emotional empathy. Whereas greater tau burden in the amygdala predicted lower perspective-taking, greater tau burden in the entorhinal cortex predicted greater empathic concern. Tau burden in the parahippocampal cortex did not predict either form of empathy. Across AD clinical syndromes, medial temporal lobe tau aggregation is associated with lower perspective-taking yet higher empathic concern.

Age-, sex-, and pathology-related variability in brain structure and cognition

This work aimed to investigate potential pathways linking age and imaging measures to early age- and pathology-related changes in cognition. We used [18F]-Flutemetamol (amyloid) and [18F]-Flortaucipir (tau) positron emission tomography (PET), structural MRI, and neuropsychological assessment from 232 elderly individuals aged 50–89 years (46.1% women, 23% APOE-ε4 carrier, 23.3% MCI). Tau-PET was available for a subsample of 93 individuals. Structural equation models were used to evaluate cross-sectional pathways between age, amyloid and tau burden, grey matter thickness and volumes, white matter hyperintensity volume, lateral ventricle volume, and cognition. Our results show that age is associated with worse outcomes in most of the measures examined and had similar negative effects on episodic memory and executive functions. While increased lateral ventricle volume was consistently associated with executive function dysfunction, participants with mild cognitive impairment drove associations between structural measures and episodic memory. Both age and amyloid-PET could be associated with medial temporal lobe tau, depending on whether we used a continuous or a dichotomous amyloid variable. Tau burden in entorhinal cortex was related to worse episodic memory in individuals with increased amyloid burden (Centiloid >12) independently of medial temporal lobe atrophy. Testing models for sex differences revealed that amyloid burden was more strongly associated with regional atrophy in women compared with men. These associations were likely mediated by higher tau burden in women. These results indicate that influences of pathological pathways on cognition and sex-specific vulnerabilities are dissociable already in early stages of neuropathology and cognitive impairment.

Neuropathological evidence that the association between APOE‐e4 genotype and higher medial temporal lobe tau burden is mediated by higher local amyloid‐β levels

AbstractBackgroundEvidence from previous PET imaging studies suggests that increased neocortical tau seen in APOE‐ε4 carriers can be explained by the higher levels of neocortical amyloid‐β (Aβ) pathology also seen in this group. However, these studies also suggest an amyloid‐independent association between APOE‐ε4 and medial temporal lobe (MTL) tau. Using neuropathological data, we investigated whether amyloid‐β in the MTL, which is difficult to accurately measure with PET, may fully mediate the association between APOE‐ε4 carriership and MTL tau burden.MethodAmyloid‐β and tau pathology in MTL and neocortical areas have been measured in a total of 2,704 individuals from two independent neuropathological datasets (Arizona Study of Aging and Neurodegenerative Disorders, Brain and Body Donation Program, n=1,117 and ROSMAP, n=1,587; Table 1). Regression models were used to investigate the associations between APOE‐ε4 carriership and neocortical and local (MTL) amyloid‐β on MTL tau, adjusting for age, sex and presence of co‐pathologies. Based on these results, we also tested whether local (MTL) amyloid‐β mediated the association between APOE‐ε4 carriership and MTL tau.ResultSupporting results from previous studies, APOE‐e4 carriers showed higher tau burden in the MTL (p<0.001) when amyloid‐β was not included in the model in both datasets. In independent models, both local and neocortical amyloid‐β were associated with MTL tau, with local amyloid‐β showing a stronger association with MTL tau in both datasets (Arizona: βMTL=0.93 vs. βneoc=0.76; ROSMAP: βMTL=0.42 vs. βneoc=0.40). When both measures were included in the model, local amyloid‐β also showed a stronger association with MTL tau in ROSMAP (βMTL=0.28 vs. βneoc=0.19). In the Arizona dataset, neocortical amyloid‐β effect became non‐significant (p=0.252) when local amyloid‐β was also included in the model. Finally, with mediation analyses we observed that MTL amyloid‐β fully mediated the APOE‐ε4 effect on MTL tau in both datasets (Figure 1). All statistics are reported in Table 2.ConclusionIn two large neuropathological datasets, we showed that the association between APOE‐ε4 genotype and higher medial temporal lobe tau burden is mediated by higher local amyloid‐β levels. This finding contradicts some previous imaging literature, where only global amyloid‐β burden was considered.

APOE2 is associated with amyloid independent effects on tau PET signal in preclinical AD

AbstractBackgroundAlthough APOE is strongly associated with risk of amyloid‐positivity during the preclinical stage of AD, less is known regarding independent effects on regional tau PET burden.MethodWe examined 385 Amyloid‐positive (A+) clinically unimpaired (CU) individuals that had APOE genotype available and additionally underwent amyloid (florbetapir) and tau (flortaucipir) PET imaging as part of the A4‐LEARN study (Table 1A, mean age=72.1±4.8). PET data were processed locally using FreeSurfer defined regions to quantify regional tau and combined to form a large cortical target composite for amyloid. Multiple regression was used to examine associations between APOE genotype (number of e2 and number of e4 modeled as two predictors) with global amyloid, regional tau (entorhinal, amygdala, and inferior temporal).ResultAmong the A+ group, each APOE2 allele was associated with a decrease of 0.045 SUVR while each APOE4 allele was associated with an increase of 0.068 SUVR units of global amyloid compared to the APOE3/3 group (Table 1B). APOE2 was significantly associated with reduced tau across medial temporal lobe ROIs whereas APOE4 was associated with elevated tau in the medial temporal lobe ROIs (Table 1B, Figure 1). Although continuous amyloid levels were associated both with APOE genotype, the total effect of both APOE2 and APOE4 dosage on tau PET was largely independent of continuous amyloid levels (Figure 2).ConclusionAPOE genotype is related to early medial temporal lobe tau burden, independent of continuous amyloid burden within the A+ range. These findings highlight that APOE genotype influences heterogeneity in tau burden among individuals with preclinical AD.

APOE Genotype Moderates the Relationship Between Plasma Phosphorylated‐tau181 and Pattern Separation Performance in Non‐demented Adults

AbstractBackgroundThe apolioprotein e (APOE) e4 allele enhances risk for Alzheimer’s disease (AD), particularly an amnestic AD phenotype with medial temporal lobe tau pathology. Pattern separation, the ability to discern novel yet similar information from previously learned information, is a cognitive marker of hippocampal function. APOE e4 carriers often exhibit pattern separation deficits prior to conversion to AD dementia, however the impact of APOE on tau‐related pattern separation performance is unknown. We examined the relationship between plasma P‐tau181 and pattern separation performance in non‐demented adults, and tested whether this association was dependent on APOE e4 genotype.MethodsPlasma P‐tau181 levels were measured (Quanterix Simoa) in 171 non‐demented adults (139 cognitively unimpaired, 32 mild cognitive impairment; 29% APOE e4+, 54% female, aged 52‐92) who completed a validated behavioral task of visual pattern separation recognition. The lure discrimination index (LDI), reflecting ability to discriminate similar ‘lure’ items from old items, was modeled as the primary outcome. Linear regression examined LDI scores as a function of plasma P‐tau181, APOE4 genotype, and their interaction, controlling for age, sex, and education.ResultAPOE e4+ had higher plasma P‐tau181 than e4‐ (Cohen’s d=0.64, p<0.001), but APOE4 groups did not differ on LDI scores (Cohen’s d=0.27, p=0.124). In the full sample, higher plasma P‐tau181 significantly related to lower (worse) LDI scores (β=‐0.17, p=0.028). APOE4 status significantly moderated the relationship between plasma P‐tau181 and LDI scores (β=‐0.29, p=0.030) such that higher P‐tau181 related to lower LDI scores in e4+ (β=‐0.38, p=0.004) but not in e4‐ individuals (β=‐0.02, p=0.824).ConclusionsAPOE e4+ individuals had elevated plasma P‐tau181, which in turn related to worse pattern separation performance only within e4+ individuals. These data suggest that APOE4‐related elevations in plasma P‐tau181 may be particularly sensitive to hippocampal functioning outcomes prior to frank dementia, which could reflect underlying hippocampal hyperexcitability due to e4‐mediated GABAergic interneuron loss. Future work incorporating imaging markers of brain structure and function may help elucidate whether P‐tau181‐related alterations in pattern separation among e4+ individuals are mediated by hippocampal‐specific mechanisms.

Causal links among amyloid, tau, and neurodegeneration.

Amyloid-β pathology is associated with greater tau pathology and facilitates tau propagation from the medial temporal lobe to the neocortex, where tau is closely associated with local neurodegeneration. The degree of the involvement of amyloid-β versus existing tau pathology in tau propagation and neurodegeneration has not been fully elucidated in human studies. Careful quantification of these effects can inform the development and timing of therapeutic interventions. We conducted causal mediation analyses to investigate the relative contributions of amyloid-β and existing tau to tau propagation and neurodegeneration in two longitudinal studies of individuals without dementia: the Baltimore Longitudinal Study of Aging (N = 103, age range 57-96) and the Alzheimer's Disease Neuroimaging Initiative (N = 122, age range 56-92). As proxies of neurodegeneration, we investigated cerebral blood flow, glucose metabolism, and regional volume. We first confirmed that amyloid-β moderates the association between tau in the entorhinal cortex and in the inferior temporal gyrus, a neocortical region exhibiting early tau pathology (amyloid group × entorhinal tau interaction term β = 0.488, standard error [SE] = 0.126, P < 0.001 in the Baltimore Longitudinal Study of Aging; β = 0.619, SE = 0.145, P < 0.001 in the Alzheimer's Disease Neuroimaging Initiative). In causal mediation analyses accounting for this facilitating effect of amyloid, amyloid positivity had a statistically significant direct effect on inferior temporal tau as well as an indirect effect via entorhinal tau (average direct effect =0.47, P < 0.001 and average causal mediation effect =0.44, P = 0.0028 in Baltimore Longitudinal Study of Aging; average direct effect =0.43, P = 0.004 and average causal mediation effect =0.267, P = 0.0088 in Alzheimer's Disease Neuroimaging Initiative). Entorhinal tau mediated up to 48% of the total effect of amyloid on inferior temporal tau. Higher inferior temporal tau was associated with lower colocalized cerebral blood flow, glucose metabolism, and regional volume, whereas amyloid had only an indirect effect on these measures via tau, implying tau as the primary driver of neurodegeneration (amyloid-cerebral blood flow average causal mediation effect =-0.28, P = 0.021 in Baltimore Longitudinal Study of Aging; amyloid-volume average causal mediation effect =-0.24, P < 0.001 in Alzheimer's Disease Neuroimaging Initiative). Our findings suggest targeting amyloid or medial temporal lobe tau might slow down neocortical spread of tau and subsequent neurodegeneration, but a combination therapy may yield better outcomes.

Tau pathology progression across PET‐based stages of regional amyloid deposition

AbstractBackgroundPrevious research has consistently reported widespread tau aggregation in the presence of global amyloid‐β (Aβ) pathology, but the association of Aβ pathology severity with tau accumulation remains unclear. Here, we studied cross‐sectional and longitudinal tau aggregation in relation to progressive stages of regional Aβ deposition as determined by a recently established Aβ PET‐based staging approach.MethodWe examined 244 cognitively unimpaired (CU) and 180 impaired (CI) subjects from the Alzheimer’s Disease Neuroimaging Initiative with concurrent T1 MRI, 18F‐Florbetapir‐PET (FBP), and 18F‐Flortaucipir‐PET (FTP) scans. A subset of 153 individuals had at least one follow‐up FTP scan. An Aβ PET‐based staging method for FBP was used to stratify participants into four progressive stages of Aβ deposition. Linear regressions adjusted for age and sex were used to assess regional FTP uptake across Aβ stages in CU and CI individuals (additionally controlled for clinical diagnosis ‐ MCI/AD). Longitudinal tau accumulation was assessed in the pooled CU and CI sample, using linear mixed effects models adjusted for age, sex, and clinical diagnosis. Finally, we assessed cross‐sectional tau‐related markers (p‐tau181 and p‐tau181/Aβ1‐42) in cerebrospinal fluid (CSF) across Aβ stages in another subset of participants (n=227).ResultCross‐sectionally, FTP uptake in Braak I/II regions increased gradually from Aβ stages 1 through 4, though only Aβ stage 4 in CU and stages 3 and 4 in CI yielded widespread neocortical tau deposition compared to stage 0 (Fig. 1). Similarly, faster longitudinal FTP increases in Braak I/II regions were observed from Aβ stage 2 onwards, but only Aβ stages 3 and 4 showed faster tau accumulation in regions exceeding Braak I/II (Fig. 2). Corroborating the PET findings, cross‐sectional levels of p‐tau181 and p‐tau181/Aβ1‐42 in CSF showed gradual increases across Aβ stages 2‐4 (Fig. 3).ConclusionEarly stages of Aβ pathology selectively affect medial temporal lobe tau deposition, but more severe and widespread tau pathology does not occur before more advanced stages of Aβ deposition. Since these only cover a subpopulation of Aβ‐positive individuals as conventionally defined, specifically recruiting individuals at advanced Aβ stages might represent an effective strategy for clinical trials in which longitudinal tau PET is used as an outcome measure.

The cortical origin and initial spread of medial temporal tauopathy in Alzheimer's disease assessed with positron emission tomography.

Advances in molecular positron emission tomography (PET) have enabled anatomic tracking of brain pathology in longitudinal studies of normal aging and dementia, including assessment of the central model of Alzheimer's disease (AD) pathogenesis, according to which TAU pathology begins focally but expands catastrophically under the influence of amyloid-β (Aβ) pathology to mediate neurodegeneration and cognitive decline. Initial TAU deposition occurs many years before Aβ in a specific area of the medial temporal lobe. Building on recent work that enabled focus of molecular PET measurements on specific TAU-vulnerable convolutional temporal lobe anatomy, we applied an automated anatomic sampling method to quantify TAU PET signal in 443 adult participants from several observational studies of aging and AD, spanning a wide range of ages, Aβ burdens, and degrees of clinical impairment. We detected initial cortical emergence of tauopathy near the rhinal sulcus in clinically normal people and, in a subset with longitudinal 2-year follow-up data (n = 104), tracked Aβ-associated spread of TAU from this site first to nearby neocortex of the temporal lobe and then to extratemporal regions. Greater rate of TAU spread was associated with baseline measures of both global Aβ burden and medial temporal lobe TAU. These findings are consistent with clinicopathological correlation studies of Alzheimer's tauopathy and enable precise tracking of AD-related TAU progression for natural history studies and prevention therapeutic trials.

Predicting future rates of tau accumulation on PET.

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 thecognitively 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.

Better stress coping associated with lower tau in amyloid-positive cognitively unimpaired older adults.

ObjectiveResearch in animals has shown that chronic stress exacerbates tau pathology. In humans, psychological stress has been associated with higher risk of Alzheimer disease clinical syndrome. The objective of this cross-sectional study was to assess the hypothesis that stress coping ability (assessed via the Brief Resilience Scale [BRS]) is associated with tau burden and to evaluate whether these associations differed by sex and amyloid status (A+/A−) in cognitively unimpaired (CU) older adults.MethodsWe included 225 CU participants (mean age 70.4 ± 10.2 years, 48% female) enrolled in the population-based Mayo Clinic Study of Aging who completed the BRS and underwent amyloid-PET (Pittsburgh compound B–PET) and tau-PET (AV1451-PET). We fitted multiple regression and analysis of covariance models to assess the associations between BRS and tau-PET and the interaction with amyloid status and sex. We focused on entorhinal cortex (ERC) tau burden and also performed voxel-wise analyses. Age, sex, education, depression, and anxiety were considered as covariates.ResultsHigher stress coping ability was associated with lower tau burden in the medial temporal lobe (including ERC) and occipito-temporal and cuneal/precuneal cortices. The association was present in both A+ and A− but weaker in A− CU older adults. There was an interaction between amyloid status and stress coping ability that was restricted to the medial temporal lobe tau such that A+ CU older adults with lower stress coping abilities showed higher tau. There were no significant interactions between stress coping and sex.ConclusionsA faster termination of the stress response (higher coping ability) may limit the negative effects of stress on tau deposition. Conversely, lower stress coping ability may be an early sign of accumulating tau pathology. Longitudinal studies are warranted to clarify whether stress mechanisms act to exacerbate tau pathology or tau influences stress-related brain mechanisms and lowers the ability to cope with stress.

Is tau in the absence of amyloid on the Alzheimer's continuum?: A study of discordant PET positivity.

The amyloid cascade model of Alzheimer’s disease posits the primacy of amyloid beta deposition preceding tau-mediated neurofibrillary tangle formation. The amyloid-tau-neurodegeneration biomarker-only diagnostic framework similarly requires the presence of amyloid beta for a diagnosis on the Alzheimer’s continuum. However, medial temporal lobe tau pathology in the absence of amyloid beta is frequently observed at autopsy in cognitively normal individuals, a phenomenon that may reflect a consequence of aging and has been labelled ‘primary age-related tauopathy’. Alternatively, others argue that this tauopathy reflects an early stage of the developmental continuum leading to Alzheimer’s disease. We used positron emission tomography imaging to investigate amyloid beta and tau positivity and associations with cognition to better inform the conceptualization of biomarker changes in Alzheimer’s pathogenesis. Five hundred twenty-three individuals from the Alzheimer’s Disease Neuroimaging Initiative who had undergone flortaucipir positron emission tomography imaging were selected to derive positron emission tomography positivity thresholds using conditional inference decision tree regression. A subsample of 301 individuals without dementia (i.e. those with normal cognition or mild cognitive impairment) had also undergone florbetapir positron emission tomography imaging within 12 months and were categorized into one of the four groups based on cortical amyloid and Braak stage I/II tau positivity: A−/T−, A+/T−, A−/T+, or A+/T+. Tau positivity in the absence of amyloid beta positivity (i.e. A−/T+) comprised the largest group, representing 45% of the sample. In contrast, only 6% of the sample was identified as A+/T−, and the remainder of the sample fell into A−/T− (22%) or A+/T+ (27%) categories. A−/T− and A+/T− groups had the best cognitive performances across memory, language and executive function; the A−/T+ group showed small-to-moderate relative decreases in cognition; and the A+/T+ group had the worst cognitive performances. Furthermore, there were negative associations between Braak stage I/II tau values and all cognitive domains only in the A−/T+ and A+/T+ groups, with strongest associations for the A+/T+ group. Among our sample of older adults across the Alzheimer’s pathological spectrum, 7-fold fewer individuals have positron emission tomography evidence of amyloid beta pathology in the absence of tau pathology than the converse, challenging prevailing models of amyloid beta’s primacy in Alzheimer’s pathogenesis. Given that cognitive performance in the A−/T+ group was poorer than in individuals without either pathology, our results suggest that medial temporal lobe tau without cortical amyloid beta may reflect an early stage on the Alzheimer’s pathological continuum.

Tau-positron emission tomography correlates with neuropathology findings

IntroductionComparison of tau (flortaucipir) positron emission tomography (FTP-PET) to autopsy is important to demonstrate the relationship of FTP-PET to neuropathologic findings. MethodsAutopsies were performed on 26 participants who had antemortem FTP-PET. FTP-PET standardized uptake value ratios (SUVRs) were compared to autopsy diagnoses and Braak tangle stage. Quantitative tau burden was compared to regional FTP-PET signal. ResultsParticipants with Braak stages of IV or greater had elevated FTP-PET signal. FTP-PET was elevated in participants with Alzheimer's disease. An FTP-PET SUVR cut point of 1.29 was determined to be optimal. Quantitative measurements of hippocampal and temporal lobe tau burden were highly correlated to FTP-PET signal (rho's from 0.61 to 0.70, P ≤ .02). ConclusionsElevated FTP-PET reflects Braak IV or greater neuropathology. Participants with primary age-related tauopathy and hippocampal sclerosis did not show elevated FTP-PET signal. Secondary neuropathologic diagnoses of Alzheimer's disease neuropathologic change can lead to borderline elevated FTP-PET signal.

Sleep as a Potential Biomarker of Tau and β-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 β-amyloid (Aβ). Here we combined PET measures of Aβ 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. Aβ 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 Aβ 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 β-amyloid (Aβ), 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 Aβ burden are associated with distinct impairments in sleep physiology or changes in sleep across the lifespan. Using polysomnography, retrospective questionnaires, and tau- and Aβ-specific PET, the present study reveals human sleep signatures that dissociably predict levels of brain tau and Aβ in older adults. These results suggest that a night of polysomnography may aid in evaluating tau and Aβ burden, and that treating sleep deficiencies within decade-specific time windows may serve in delaying AD progression.