Chronic psychological stress has been implicated as a risk factor for Alzheimer’s disease (AD), potentially through cortisol-mediated acceleration of disease progression. However, the molecular pathways underlying this relationship remain poorly understood. Epigenetic regulation of the glucocorticoid and mineralocorticoid receptor genes (NR3C1 and NR3C2), which encode receptors for cortisol, may play an important role, but has not been examined in relation to AD progression. Therefore, this study investigated associations between DNA methylation of NR3C1/NR3C2 and AD-related phenotypes, including cognition, brain amyloid-β (Aβ) burden, and regional brain volumes. These associations were examined in two independent cohorts of cognitively unimpaired individuals with accumulating brain Aβ (n = 89–298 across outcomes) using linear regression and meta-analyses. The study also explored whether DNA methylation within NR3C1 and NR3C2 interacted with depression symptoms to influence relationships with AD-related phenotypes. While only nominal associations were observed in direct analyses, stronger associations emerged in interaction with depressive symptoms. Interaction analyses showed that relationships between DNA methylation and AD-related phenotypes (cognition, hippocampal volume and ventricular expansion) differed depending on the presence of depression symptoms. Consistent patterns across cohorts were observed, with associations primarily evident among individuals with clinically relevant depressive symptoms. One site (NR3C1 cg24052866) was associated with cognitive decline, one (NR3C1 cg08845721) with cross-sectional hippocampal volume, and eight (NR3C1 cg21979215, cg16594263; NR3C2 cg27460943, cg17253842, cg04867484, cg10993059, cg25672354, cg27234800) with ventricular expansion. These exploratory findings suggest epigenetic variation within cortisol receptor genes may influence AD-related neurodegeneration in a depression-dependent manner.

Brain network dynamics have been extensively explored in patients with subjective cognitive decline (SCD). However, these studies are susceptible to individual differences, scanning parameters, and other confounding factors. Therefore, how to reveal subtle SCD-related subtle changes remains unclear. Cross-sectional and longitudinal resting-state functional magnetic resonance imaging data from both Chinese and Western populations were analyzed. We proposed a framework of dynamic proportional loss of functional connectivity (DPLFC). After its stability was validated, the optimal parameters were applied for the clinical diagnosis of SCD. DPLFC yielded a relatively high intraclass correlation coefficient. In particular, the DPLFC of the left superior frontal gyrus (SFG) progressively decreased along the Alzheimer’s disease (AD) continuum. Compared with the traditional index, the DPLFC had better classification performance between cognitively normal controls and patients with SCD. Furthermore, DPLFC was related to Aβ deposition and scale scores. Patients with lower DPLFC values had a greater risk of cognitive decline. Decreased DPLFC in the left SFG may be a potential AD-related neuroimaging biomarker at an early stage.

Alzheimer’s disease is defined by the presence of β-amyloid plaques and neurofibrillary tau tangles potentially preceding clinical symptoms by many years. Previously only detectable post-mortem, these pathological hallmarks are now identifiable using biomarkers, permitting an in vivo definitive diagnosis of Alzheimer’s disease. 18F-flortaucipir (previously known as 18F-T807; 18F-AV-1451) was the first tau positron emission tomography tracer to be introduced and is the only Food and Drug Administration-approved tau positron emission tomography tracer (Tauvid™). It has been widely adopted and validated in a number of independent research and clinical settings. In this review, we present an overview of the published literature on flortaucipir for positron emission tomography imaging of neurofibrillary tau tangles. We considered all accessible peer-reviewed literature pertaining to flortaucipir through 30 April 2022. We found 474 relevant peer-reviewed publications, which were organized into the following categories based on their primary focus: typical Alzheimer’s disease, mild cognitive impairment and pre-symptomatic populations; atypical Alzheimer’s disease; non-Alzheimer’s disease neurodegenerative conditions; head-to-head comparisons with other Tau positron emission tomography tracers; and technical considerations. The available flortaucipir literature provides substantial evidence for the use of this positron emission tomography tracer in assessing neurofibrillary tau tangles in Alzheimer’s disease and limited support for its use in other neurodegenerative disorders. Visual interpretation and quantitation approaches, although heterogeneous, mostly converge and demonstrate the high diagnostic and prognostic value of flortaucipir in Alzheimer’s disease.

Background There is an increasing interest in utilizing tau PET to identify patients early in Alzheimer’s disease (AD). In this work, a temporal lobe composite ( Eτ ) volume of interest (VOI) was evaluated in a longitudinal flortaucipir cohort and compared to a previously described global neocortical VOI. In a separate autopsy-confirmed study, the sensitivity of the Eτ VOI for identifying intermediate (B2) neurofibrillary tangle (NFT) pathology was evaluated. Methods A total of 427 subjects received flortaucipir, florbetapir, MRI, and cognitive evaluation at baseline and 18 months. In a separate autopsy study, 67 subjects received ante-mortem flortaucipir scans, and neuropathological findings were recorded according to NIA-AA recommendations by two experts. Two VOIs: Eτ comprising FreeSurfer volumes (bilateral entorhinal cortex, fusiform, parahippocampal, and inferior temporal gyri) transformed to MNI space and a previously published global AD signature-weighted neocortical VOI (AD signature ) (Devous et al., J Nucl Med 59:937–43, 2018), were used to calculate SUVr relative to a white matter reference region (PERSI) (Southekal et al., J Nucl Med Off Publ Soc Nucl Med 59:944–51, 2018). SUVr cutoffs for positivity were determined based on a cohort of young, cognitively normal subjects. Subjects were grouped based on positivity on both VOIs ( Eτ+ /AD signature +; Eτ+ /AD signature –; Eτ −/AD signature −). Groupwise comparisons were performed for baseline SUVr, 18-month changes in SUVr, neurodegeneration, and cognition. For the autopsy study, the sensitivity of Eτ in identifying intermediate Braak pathology (B2) subjects was compared to that of AD signature-weighted neocortical VOI. The average surface maps of subjects in the Eτ+ /AD signature − group and B2 NFT scores were created for visual evaluation of uptake. Results Sixty-four out of 390 analyzable subjects were identified as Eτ+ /AD signature –: 84% were Aβ+, 100% were diagnosed as MCI or AD, and 59% were APOE ε4 carriers. Consistent with the hypothesis that Eτ+ /AD signature – status reflects an early stage of AD, Eτ+ /AD signature – subjects deteriorated significantly faster than Eτ– /AD signature – subjects, but significantly slower than Eτ+ /AD signature + subjects, on most measures (i.e., change in AD signature SUVr, Eτ ROI cortical thickness, and MMSE). The AD signature VOI was selective for subjects who came to autopsy with a B3 NFT score. In the autopsy study, 12/15 B2 subjects (including 10/11 Braak IV) were Eτ+ /AD signature –. Surface maps showed that flortaucipir uptake was largely captured by the Eτ VOI regions in B2 subjects. Conclusion The Eτ VOI identified subjects with elevated temporal but not global tau ( Eτ+ /AD signature –) that were primarily Aβ+, APOE ε4 carriers, and diagnosed as MCI or AD. Eτ+ /AD signature – subjects had greater accumulation of tau, greater atrophy, and higher decline on MMSE in 18 months compared to Eτ −/AD signature − subjects. Finally, the Eτ VOI identified the majority of the intermediate NFT score subjects in an autopsy-confirmed study. As far as we know, this is the first study that presents a visualization of ante-mortem FTP retention patterns that at a group level agree with the neurofibrillary tangle staging scheme proposed by Braak. These findings suggest that the Eτ VOI may be sensitive for detecting impaired subjects early in the course of Alzheimer’s disease.

Importance:An increased tau positron emission tomography (PET) signal in the medial temporal lobe (MTL) has been observed in older individuals in the absence of amyloid-β (Aβ) pathology. Little is known about the longitudinal course of this condition, and its association with Alzheimer disease (AD) remains unclear. Objective:To study the pathologic and clinical course of older individuals with PET-evidenced MTL tau deposition (TMTL+) in the absence of Aβ pathology (A-), and the association of this condition with the AD continuum. Design, Setting, and Participants:A multicentric, observational, longitudinal cohort study was conducted using pooled data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and the AVID-A05 study, collected between July 2, 2015, and August 23, 2021. Participants in the ADNI, HABS, and AVID-A05 studies (N = 1093) with varying degrees of cognitive performance were deemed eligible if they had available tau PET, Aβ PET, and magnetic resonance imaging scans at baseline. Of these, 128 participants did not meet inclusion criteria based on Aβ PET and tau PET biomarker profiles (A+ TMTL-). Exposures:Tau and Aβ PET, magnetic resonance imaging, cerebrospinal fluid biomarkers, and cognitive assessments. Main Outcomes and Measures:Cross-sectional and longitudinal measures for tau and Aβ PET, cortical atrophy, cognitive scores, and core AD cerebrospinal fluid biomarkers (Aβ42/40 and tau phosphorylated at threonine 181 p-tau181 available in a subset). Results:Among the 965 individuals included in the study, 503 were women (52.1%) and the mean (SD) age was 73.9 (8.1) years. A total of 51% of A- individuals and 78% of A+ participants had increased tau PET signal in the entorhinal cortex (TMTL+) compared with healthy younger (aged <39 years) controls. Compared with A- TMTL-, A- TMTL+ participants showed statistically significant, albeit moderate, longitudinal (mean [SD], 1.83 [0.84] years) tau PET increases that were largely limited to the temporal lobe, whereas those with A+ TMTL+ showed faster and more cortically widespread tau PET increases. In contrast to participants with A+ TMTL+, those with A- TMTL+ did not show any noticeable Aβ accumulation over follow-up (mean [SD], 2.36 [0.76] years). Complementary cerebrospinal fluid analysis confirmed longitudinal p-tau181 increases in A- TMTL+ in the absence of increased Aβ accumulation. Participants with A- TMTL+ had accelerated MTL atrophy, whereas those with A+ TMTL+ showed accelerated atrophy in widespread temporoparietal brain regions. Increased MTL tau PET uptake in A- individuals was associated with cognitive decline, but at a significantly slower rate compared with A+ TMTL+. Conclusions and Relevance:In this study, individuals with A- TMTL+ exhibited progressive tau accumulation and neurodegeneration, but these processes were comparably slow, remained largely restricted to the MTL, were associated with only subtle changes in global cognitive performance, and were not accompanied by detectable accumulation of Aβ biomarkers. These data suggest that individuals with A- TMTL+ are not on a pathologic trajectory toward AD.

Alzheimer’s disease is defined by the presence of β-amyloid plaques and neurofibrillary tau tangles potentially preceding clinical symptoms by many years. Previously only detectable postmortem, these pathological hallmarks are now identifiable using biomarkers, permitting an in vivo definitive diagnosis of Alzheimer’s disease. 18F-flortaucipir (previously known as 18F-T807; 18F-AV-1451) was the first tau positron emission tomography tracer to be introduced and is the only Food and Drug Administration approved tau positron emission tomography tracer (Tauvid™). It has been widely adopted and validated in a number of independent research and clinical settings. In this review, we present an overview of the published literature on flortaucipir for positron emission tomographyimaging of neurofibrillary tau tangles. We considered all accessible peer-reviewed literature pertaining to flortaucipir through April 30, 2022. We found 474 relevant peer-reviewed publications, which were organized into the following categories based on their primary focus: Typical Alzheimer’s disease, mild cognitive impairment, and pre-symptomatic populations; atypical Alzheimer’s disease; non- Alzheimer’s disease neurodegenerative conditions; head-to-head comparisons with other Tau positron emission tomography tracers; and technical considerations. The available flortaucipir literature provides substantial evidence for the use of this positron emission tomographytracer in assessing neurofibrillary tau tangles in Alzheimer’s disease and limited support for its use in other neurodegenerative disorders. Visual interpretation and quantitation approaches, although heterogeneous, mostly converge and demonstrate the high diagnostic and prognostic value of flortaucipir in Alzheimer’s disease.

Positron emission tomography (PET) imaging with [18F]flortaucipir allows for in-vivo visualization of aggregated tau in Alzheimer’s disease (AD). The FDA-approved label for [18F]flortaucipir PET provides a standardized, clinically applicable definition of tau-PET positivity by visual interpretation. Here, we studied the concordance between this visual interpretation and quantitative approaches employed in research. We included 2692 participants (cognitively unimpaired [CU] and impaired [CI, MCI or AD dementia]) from four cohorts (Mayo Clinic Study of Aging and ADRC, ADNI, A4, and A05) with available [18F]flortaucipir PET (mean age: 70.2 y, 50.0% females). Three trained readers assessed each [18F]flortaucipir PET scan according to the FDA-approved method. Visual reads were compared to an established approach for defining tau-PET positivity based on SUVR values in a temporal meta-ROI (Jack, et al. Alzheimers Dement. 2017). Previously defined “lenient” (SUVR = 1.22) and “conservative” (SUVR = 1.30) cut-points were explored. In addition, visual reads were compared to tau-PET positivity as defined by a scheme based on the expected spatial progression of tau pathology from the medial temporal lobe (MTL) to the temporal neocortex (NEO) (Ossenkoppele, et al. Nat Med. 2022; cut-points: SUVRMTL = 1.30, SUVRNEO = 1.37). Concordance between visual and quantitative approaches was limited (Figure 1): the “lenient” and MTL-NEO methods yielded high rates of quantitative-positive, visual-negative scans (73-52% and 26-18% for CU and CI, respectively), while the “conservative” cut-point failed to detect 45% and 13% of the CU and CI visual-positive scans, respectively. The prevalence of tau-PET positivity in Aß-negative individuals was highest with the “lenient” cut-point (∼24%) and lowest with visual interpretation (∼3%) (Figure 2). Visual-positive, quantitative-negative individuals were more frequently Aß-positive than visual-negative, quantitative-positive individuals (“lenient”: 86% vs 50%, p<0.001; “conservative”: 87% vs 58%, p<0.001; MTL-NEO: 85% vs 70%, p = 0.005). Among visually-positive participants, 164 (28%) showed a tau deposition pattern that deviated from the expected MTL to NEO progression (Figure 3). Visual and quantitative methods for [18F]flortaucipir PET are non-exchangeable. Tau-PET positivity based on visual interpretation aligns better with Aß-pathology. A significant number of visually-positive participants showed a pattern of tau accumulation that deviated from the expected stereotypical spatial progression and was not detected by standard quantitative methods.

AbstractBackgroundThe advent of positron emission tomography (PET) imaging with tracers such as [18F]flortaucipir (FTP) has allowed in‐vivo visualization of aggregated tau in Alzheimer’s disease (AD). Recently, a clinically applicable visual interpretation method for FTP PET yielding negative, moderate, and advanced AD visual patterns was developed, leading to its subsequent approval by the US Food and Drug Administration (FDA). Yet, the prevalence and longitudinal clinical outcomes of the different AD‐associated visual patterns, in particular the moderate AD pattern, have not been investigated systematically across the clinical spectrum of AD.MethodWe included cognitively normal individuals and patients with mild cognitive impairment and AD dementia from five observational cohort studies — Alzheimer’s Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain study (HABS), A4 study, AVID’s A05 study and Geneva Memory Clinic cohort — all of which had available FTP PET scans. Furthermore, Aβ status, established with Aβ PET, was available in 1924 participants (98%), and longitudinal clinical and cognitive data was obtained for 968 participants over an average follow‐up time of 2.2 years. Three readers, blinded to clinical and imaging information, will independently evaluate each FTP PET scan, and an individual’s FTP uptake pattern will be interpreted as negative, moderate, or advanced AD tau pattern, based on the majority read of the three readers. Multinomial generalized additive models (GAM) will be fitted to provide prevalence estimates of each FTP AD pattern. Mixed models for repeated measures (MMRM) will be used to estimate cognitive decline trajectories.ResultA total of 1963 participants had available FTP PET scans. We will investigate the prevalence of the different FTP AD patterns as a function of age per diagnostic group, stratifying participants by β‐amyloid status and APOE genotype. Further, in the subset of participants with available longitudinal clinical data, we will explore how the different FTP patterns associate with clinical decline across the aforementioned diagnostic groups.ConclusionOur large‐scale study will contribute significantly to elucidating the clinical relevance of FTP visual reads across the AD spectrum, potentially widening its applicability and promoting its use in patient assessment and in clinical prevention trials.

Alzheimer’s disease (AD)-like tau pathology in the medial temporal lobe (MTL) is also commonly observed in older individuals without amyloid-β (Aβ) pathology, a condition termed primary age-related tauopathy (PART). Little is known about the longitudinal course of this condition and its association with the AD continuum remains controversial. We used serial PET, MRI, and CSF data to study the longitudinal pathologic course of older individuals who show PET-measured MTL tau pathology in the absence of Aβ pathology. We included older individuals with varying degrees of cognitive performance from the Alzheimer’s Disease Neuroimaging Initiative, the Harvard Aging Brain Study, and AVID’s A05 Study who had undergone baseline (n=1097) and follow-up [ 18 F]flortaucipir (FTP) (n=489, follow-up: 1.83±0.84 years) and Aβ-PET scanning (n=398, follow-up: 2.36±0.76 years). Participants were separated into three groups according to Aβ and tau positivity (A-T-, A-T+, A+T+), using a cut-off of 12 centiloids for A+ and the 95 th percentile of entorhinal (ERC) FTP SUVR values in healthy young controls ( n =16, ≤39y) for T+. In complementary analyses we also assessed longitudinal changes in CSF biomarkers (n=99, follow-up: 2.34±1.05 years) and cortical atrophy on MRI (n=650, follow-up: 2.00±0.86 years). 43% of A- individuals and 81% of A+ individuals were ERC-tau positive. Cross-sectionally, A-T+ showed elevated FTP SUVR restricted to the medial/inferior temporal lobe, while A+T+ displayed a more AD-characteristic pattern of widespread cortical FTP uptake (Fig. 1A). A-T+ showed moderate FTP SUVR increases over time largely limited to the temporal lobe, whereas FTP SUVR increases were widespread in A+T+ (Fig. 1B). Notably, A-T+ individuals did not increase Aβ accumulation over time (Fig. 1C). CSF analysis confirmed longitudinal tau increases in A-T+ in the absence of increased Aβ accumulation (Fig. 1D). Compared to A-T-, A-T+ individuals demonstrated accelerated MTL atrophy, whereas A+T+ showed more widespread AD-typical cortical atrophy (Fig. 2). Elevated MTL tau-PET signal is frequently observed in older individuals without notable Aβ pathology, reminiscent of pathology-defined PART. These A-T+ individuals exhibit a comparably slow course of progressive tau accumulation and neurodegeneration confined to the temporal lobe and do not appear to be on a pathologic trajectory towards AD.

The introduction of tau positron emission tomography (PET) ligands has allowed for the in vivo assessment of tau pathology in Alzheimer’s disease (AD). The recent development and FDA approval of [ 18 F]flortaucipir (FTP) reader guidelines has enabled standardized visual assessment of FTP PET scans as showing negative, moderate or advanced AD tau patterns, thereby facilitating implementation of FTP scans in clinical practice. Although various studies have reported associations between regional FTP signal and neurodegeneration, the relationship between the standardized visual FTP AD patterns and markers of neurodegeneration has not yet been studied. This study aims to understand how FTP AD visual patterns relate to markers of neurodegeneration from structural MRI and FDG-PET scans. Specifically, it focusses on characterizing regional neurodegeneration associated with the moderate AD pattern, both in cognitively normal (CN) and cognitively impaired participants (CI). Participants from five cohorts were included: the Alzheimer’s Disease Neuroimaging Initiative, Harvard Aging Brain Study, A4 study, the Geneva Memory Clinic cohort and AVID’s A05 study. These cohorts include CN participants, mild cognitively impaired and AD dementia patients who have available FTP, MRI and/or FDG scans, a subset also received follow-up MRI scans. Furthermore, Centiloid values are available for all participants to quantitatively determine amyloid-β (Aβ) positivity. All FTP scans are currently independently evaluated by three trained readers, blinded to clinical and imaging information. Majority read is used to assign scans to the negative, moderate or advanced AD tau pattern groups. A total of 1948 participants underwent baseline FTP PET and MRI scans, a subset of 462 participants also underwent FDG-PET scans. Between-group differences in MRI- and FDG-derived patterns of neurodegeneration are evaluated cross-sectionally. In addition, the value of FTP AD patterns for predicting longitudinal neurodegeneration using MRI-derived atrophy measures is assessed using Linear Mixed Models. All analyses are conducted separately for CN and CI participants, as well as stratified by Aβ (positive vs. negative) status. NB. Results of these analyses will be presented during the conference. This study will contribute to our understanding of the clinical relevance and prognostic value of the moderate and advanced FTP AD patterns in CN and CI individuals.

Tau PET tracers have proven useful for diagnostic purposes, but their prognostic utility for predicting future cognitive changes over time is unclear. We aimed to examine the prognostic accuracy of [18F]flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer’s disease (AD) spectrum.

Alzheimer’s disease (AD) is defined in vivo by evidence of amyloid and tau, usually accompanied by neurodegeneration, in accordance with the ATN criteria. Deposition of amyloid is thought to begin early in the disease process and, by the time symptoms become evident, can usually be detected as elevated PET signal in a stereotypical pattern across regions. In contrast tau deposition begins later in disease and the pattern and timing of evolution of tau deposition may vary across individuals. Thus, it is more difficult to assign a classification of tau positive that fits all purposes. Studies in autopsy confirmed patients indicate that tau PET visual interpretation methods may be effective in identifying subjects at the B3 (Braak V/VI) stage of deposition. B3 tau deposition is typically also associated with amyloid positivity, thus predicting a likely pathological diagnosis of high AD neuropathologic change at autopsy. However, a negative visual interpretation cannot rule out the presence of amyloid and tau levels sufficient to support a classification of intermediate AD neuropathological change. Quantitative methods focused on temporal lobe (particularly inferior and mesial temporal lobe) may be more sensitive to earlier stages of AD tau deposition, but confirmation of amyloid status may be required to rule out primary age-related tauopathy. Together visual and quantitative interpretation methods may identify patterns of tau distribution and density with implications for the expression of symptoms, and future progression of impairment, and may be of value in stratifying/selecting patients most likely to respond in clinical trials of AD therapeutics.

BACKGROUND:Tau neurofibrillary tangle burden increases with Alzheimer's disease (AD) stage and correlates with degree of cognitive impairment. Tau PET imaging could facilitate understanding the relationship between tau pathology and cognitive impairment.OBJECTIVE:Evaluate the relationship between 18F flortaucipir uptake patterns and cognition across multiple cognitive domains.METHODS:We acquired flortaucipir PET scans in 84 amyloid-positive control, mild cognitive impairment (MCI), and AD subjects. Flortaucipir standardized uptake value ratio (SUVr) values were obtained from a neocortical volume of interest (VOI), a precuneus VOI, and VOIs defined by the correlation between flortaucipir SUVr images and domain-specific cognitive tests. Cognitive assessments included Mini-Mental State Exam (MMSE), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), and a neuropsychological test battery (i.e., Wechsler Memory Scale-Revised Logical Memory (WMS-R), Trail Making Test, Boston Naming Test, Digit Symbol Substitution Test, Animal List Generation, WMS-R Digit Span, American National Adult Reading Test, Clock Drawing Test, Judgment of Line Orientation, and WMS-R Logical Memory II (Delayed Recall)) and the Functional Activities Questionnaire (FAQ). Correlation analyses compared regional and voxel-wise VOIs to cognitive scores.RESULTS:Subjects included 5 controls, 47 MCI, and 32 AD subjects. Significant correlations were seen between both flortaucipir and florbetapir SUVrs and MMSE, ADAS-Cog, and FAQ. Cognitive impairment was associated with increased flortaucipir uptake in regionally specific patterns consistent with the neuroanatomy underlying specific cognitive tests.CONCLUSION:Flortaucipir SUVr values demonstrated significant inverse correlations with cognitive scores in domain-specific patterns. Findings support the hypothesis that PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD.

Key Points Questions What is the association between flortaucipir positron emission tomography (PET) imaging visual classification using a clinically applicable and US Food and Drug Administration–approved method and 18-month cognitive and functional decline in patients with clinically diagnosed mild cognitive impairment and dementia owing to Alzheimer disease (AD)? Findings In this analysis of 2 open-label clinical trials, visual read of an advanced flortaucipir PET AD pattern was associated with an increased risk of 18-month cognitive and functional decline compared with other scan patterns. Meaning Clinically applicable visual reads of flortaucipir PET scans may provide valuable information regarding the risk of near-term clinical deterioration among patients with clinically diagnosed mild cognitive impairment or dementia owing to AD.

Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging.

Abstract Introduction Lanabecestat, a beta‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1) inhibitor, was investigated as a potential Alzheimer's disease (AD)‐modifying treatment. As previously reported, amyloid beta (Aβ) neuritic plaque burden reduction did not result in clinical benefit. Lanabecestat's effects on neuroimaging biomarkers and correlations between neuroimaging biomarkers and efficacy measures are reported. Methods AMARANTH and DAYBREAK‐ALZ were 104‐ and 78‐week, multicenter, randomized, double‐blind, placebo‐controlled studies of lanabecestat in early symptomatic AD (AMARANTH) and mild AD dementia (DAYBREAK‐ALZ). Patients randomly (1:1:1) received placebo, lanabecestat 20 mg, or lanabecestat 50 mg daily (AMARANTH, n = 2218; DAYBREAK‐ALZ, n = 1722). Florbetapir positron emission tomography (PET), fluorodeoxyglucose (FDG) PET, flortaucipir PET, and volumetric magnetic resonance imaging (MRI) were used to measure Aβ neuritic plaque burden, cerebral metabolism, aggregated tau neurofibrillary tangles, and brain volume, respectively. Additionally, florbetapir perfusion scans were performed in DAYBREAK‐ALZ. Efficacy measures included 13‐item Alzheimer's Disease Assessment Scale–Cognitive Subscale, Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory, Clinical Dementia Rating–Sum of Boxes, Functional Activities Questionnaire, and Mini‐Mental State Examination. These studies stopped early due to futility. Results Despite previously observed annualized reduction in Aβ neuritic plaque burden, there were no treatment differences in annualized change of aggregated tau neurofibrillary tangle burden (AMARANTH, n = 284; DAYBREAK‐ALZ, n = 70), cerebral metabolism (AMARANTH, n = 260; DAYBREAK‐ALZ, n = 38) and perfusion (DAYBREAK‐ALZ, n = 213). Greater brain volume reduction (AMARANTH, n = 1697 [whole brain]; DAYBREAK‐ALZ, n = 650 [whole brain]) occurred on lanabecestat compared to placebo. Higher baseline aggregated tau neurofibrillary tangle burden, lower cerebral metabolism, and lower brain volumes correlated with poorer baseline efficacy scores and greater clinical worsening. Lower baseline cerebral perfusion correlated with poorer baseline efficacy scores. Reduction in cerebral metabolism or whole brain volume correlated with clinical worsening, regardless of treatment assignment. Discussion Tau pathology and cerebral metabolism assessments showed no evidence of lanabecestat slowing pathophysiologic progression of AD. Lanabecestat exposure was associated with brain volume reductions. Correlations between imaging measures and cognitive assessments may aid future study design.

Key Points Question What is the prognostic value of tau positron emission tomography (PET) for predicting cognitive decline across the clinical spectrum of Alzheimer disease? Findings In this longitudinal, multicenter prognostic study including 1431 participants, baseline tau PET predicted change in Mini-Mental State Examination scores during a mean (SD) follow-up of 1.9 (0.8) years. Moreover, tau PET outperformed established volumetric magnetic resonance imaging and amyloid PET markers in head-to-head comparisons, especially in participants with mild cognitive impairment and cognitively normal individuals who were positive for amyloid-β. Meaning These findings suggest that tau PET is a promising prognostic tool for predicting cognitive decline in preclinical and prodromal stages of Alzheimer disease.

AbstractAlzheimer’s disease (AD) is characterized by the progressive spread of tau pathology throughout the cerebral cortex. The pattern of spread is thought to be fairly consistent across individuals, though more recent work has demonstrated substantial variability in the AD population that is often associated with distinct clinical phenotypes. Still, a systematic, unbiased, wholebrain characterization of spatiotemporal variation in tau deposition in AD is lacking. We analyzed 1612 tau-PET scans and applied to this sample a disease progression modeling framework designed to identify spatiotemporal trajectories of pathological progression. We identified four distinct trajectories of tau progression, ranging in prevalence from 18–33%, with no one progession predominating. We replicated previously described limbic-predominant and medial temporal lobe-sparing variants, while also discovering posterior and lateral temporal subtypes resembling atypical clinical variants of AD. These “subtypes” were stable during longitudinal follow-up, and could be replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes, however, no “typical” variant predominated. Across all subtypes, younger age was related to worse cognition and more rapid tau accumulation. Additionally, network diffusion models implicated that pathology originates and spreads through distinct corticolimbic in the different subtypes. Together, our results suggest variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of “typical AD”, and a revisiting of tau pathological staging.

AbstractBackgroundAvid Radiopharmaceuticals conducted a prospective case‐control clinicopathological study of flortaucipir F18 PET Imaging (AV‐1451‐A16) from October 2015 through June 2018. This presentation is an initial report of the detailed neuropathological findings of the 67 primary study subjects.MethodSixty‐seven valid study autopsies were performed. The cerebral patterns of flortaucipir PET images were visually assessed and compared to the patterns of immunohistochemical tau pathology. The study met pre‐specified success criteria, with imaging predicting an NIA‐AA B3 level of tau pathology (Braak V/VI) and a high level of Alzheimer’s disease neuropathologic change.ResultThere were 35 females and 32 males, mean age 82.6 (SD 9.4). Fifty‐three cases met intermediate or high ADNC levels, consistent with AD as a cause of cognitive impairment. Of these, many had additional major neuropathological findings (not mutually exclusive), meeting neuropathological diagnostic criteria for dementia with Lewy bodies (DLB; n=7), Parkinson’s disease (PD; n=1), progressive supranuclear palsy (PSP; n=5), hippocampal sclerosis (HS; n=5), vascular dementia (n=3) and corticobasal degeneration (CBD; n=1), while others had lesser findings of TDP‐43 proteinopathy restricted to the mesial temporal lobe (n=19), Lewy body pathology not meeting criteria for DLB or PD (n=18), age‐related tau astrogliopathy (ARTAG; n=15) or remote cerebral infarcts (n=10). Cases with less than intermediate ADNC (n=14) met neuropathological diagnostic criteria (not mutually exclusive) for PD (n=2), HS (n=2), DLB (n=1), PSP (n=1), CBD (n=1) and others had additional neuropathological findings of TDP‐43 proteinopathy restricted to the mesial temporal lobe (n=2), Lewy body pathology not meeting criteria for DLB or PD (n=4), ARTAG (n=3) or remote cerebral infarcts (n=2).ConclusionThis high proportion of mixed neuropathology is typical of what has been published for other elderly autopsied subjects. Correlations of flortaucipir F18 PET imaging with these varied neuropathological types will be undertaken.