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Background: The noradrenergic locus coeruleus (LC) nucleus is critical in regulating many brain functions and processes, including arousal and emotion. Autopsy studies suggested that the LC is one of the earliest regions harboring hyperphosphorylated tau. Previous imaging work demonstrated that lower novelty‐related LC activity correlates with tau deposition in the entorhinal cortex. Here, we investigated the variability in activity across the rostro‐caudal LC under different arousal levels and its relationship with plasma markers of phosphorylated tau, including p‐tau231, p‐tau217, and p‐tau181. Method: 61 individuals (age range = [51,85], Male = 30) underwent a task‐based 7T BOLD‐fMRI scan and fasting blood draw. The task consisted of 100 high‐ or low‐arousing context images. The fMRI data were preprocessed using a brainstem‐specific denoising methodology to increase the LC signal‐to‐noise ratio. P‐tau181 and p‐tau231 were measured using in‐house Simoa methods, and p‐tau217 using MSD immunoassay. Voxel‐wise linear model analyses were performed to detect brainstem regions exhibiting significant high>low arousal (h>l) activation. Average h>l contrast values across activated voxels within an ex‐vivo validated LC region of interest (ROI) were extracted, and age‐ and sex‐adjusted associations between LC activity and p‐tau were evaluated using robust linear regression. Similar associations were also investigated for a control ROI defined ventral to the LC. Result: We observed greater h>l activation of voxels in the bilateral LC (p<0.05 uncorrected–Fig.1A). We observed no regional differences in h>l activity along the LC rostral‐caudal axis (Fig.1B). Post‐hoc Mann‐Kendall trend analyses revealed a negative‐to‐positive trend in h>l LC activity across caudal‐to‐rostral LC. Lower h>l LC activity was associated with greater p‐tau217 (p = 0.042–Fig.2A). No significant associations were observed between h>l LC activity and either p‐tau231 or p‐tau181 (p>0.05–Fig.2B‐C), or between h>l activity in the control ROI and any plasma marker (p>0.05–Fig.2D‐F). Conclusion: Our results show that lower h>l LC activation is associated with greater concentrations in p‐tau217. As p‐tau217 has been shown to correlate with LC neuronal loss, cortical tau‐ and amyloid‐β‐PET measures, our results suggest that LC dysfunction in higher states of arousal may signal LC degeneration. Future work includes investigating the mediating role of amyloid‐β on the observed relationship between h>l LC activation and p‐tau217. [ABSTRACT FROM AUTHOR]

Background: In preclinical human Alzheimer's disease (AD), novelty‐related functional connectivity of the locus coeruleus (LC) with the medial temporal lobe (MTL) (ConnLC‐MTL) predicted beta‐amyloid (Aβ)‐related longitudinal cognitive decline. In animals, LC lesions in AD models led to dwindling LC projections to the hippocampus, hippocampal atrophy, and cognitive impairment. Following these observations, we investigated the contribution of cross‐sectional and longitudinal atrophy in early Braak stages as a potential mechanism underlying this relationship. Method: We included 128 participants of the Harvard Aging Brain Study (HABS) with baseline Pittsburgh Compound‐B Positron Emission Tomography – Distribution Volume Ratio (PiB PET, DVR; 36 Aβ+), as well as baseline functional and longitudinal structural MRI (ntot = 372; ∼ every 3 years; follow‐up 5±3.4 years) and yearly cognitive assessments (PACC5 = Preclinical Alzheimer's Cognitive Composite; ntot = 874; follow‐up 6.5±3.3 years) (Table 1). ConnLC‐MTL values were derived voxel‐wise and averaged across significant clusters. FreeSurfer‐estimated cortical thickness and hippocampus/amygdala volume (adjusted for intracranial volume) were z‐scored and averaged in two variables (THV2/THV3), encompassing regions associated with Braak stage II and III respectively (Table 1). Baseline associations were evaluated with linear models, longitudinal relationships between ConnLC‐MTL and THV2/THV3 with mixed‐effects models (random intercept and slope). Mediation of ConnLC‐MTL and PACC5 slopes (year 5‐13) by THV2/THV3 slopes (year 0‐5) was calculated (n = 79; bootstrapped n = 1000; Table 1). All models contained age, sex and education as covariates. Result: At baseline, ConnLC‐MTL positively associated with THV2 (p = 0.005) and with PACC5 (p = 0.045), but not with THV3 (p = 0.26; Figure 1A‐C). Longitudinally, ConnLC‐MTL did not predict changes in THV2 nor THV3. However, we observed faster cortical atrophy with lower ConnLC‐MTL at higher levels of neocortical PiB (THV2: p = 0.02; THV3: p<0.001; Figure 1D‐E). Finally, THV2, but not THV3, mediated the relationship between ConnLC‐MTL and PACC5 decline (p = 0.024) and this effect was stronger in PiB+ individuals compared to PiB‐ (p = 0.026; Figure 2). Conclusion: Worse LC‐MTL connectivity was associated with downstream atrophy in the target Braak‐stage II areas, which impacted cognitive performance in preclinical AD. Given that in similar previous animal findings activation of the norepinephrine LC system reversed memory deficits, maintaining optimal ConnLC‐MTL may be a promising intervention target to delay disease progression. [ABSTRACT FROM AUTHOR]

Background: The locus coeruleus (LC), the primary noradrenergic nucleus in the brainstem, is among the earliest brain structures to accumulate tau pathology, one of the neuropathologic hallmarks of Alzheimer's disease (AD). Tau pathology in the earlier stages and significant cell loss in the disease's later stages can affect the metabolic turnover of the LC. In addition, alterations in the LC's metabolic turnover have been associated with tau formation and propagation. We investigated differences in LC glucose metabolism across AD clinical diagnostic and biomarker groups and its association with longitudinal tau, beta‐amyloid, and cognitive measurements. Method: We investigated LC FDG‐PET signal of 295 participants from the ADNI‐1 and ADNI‐2/GO cohorts, who were equally distributed across the CSF beta‐amyloid (A) and phosphorylated‐tau (T) biomarker groups (Table 1). An in‐house developed joint‐entropy‐penalized image deblurring algorithm was used to quantify Positron Emission Tomography (PET) signal within small brain regions (Figure 2A). ANCOVA was used to investigate diagnostic and biomarker‐based group differences in LC metabolism. Post‐hoc Tukey contrasts corrected for multiple comparisons in subsequent pairwise analyses. Linear mixed‐effects models investigated the predictive value of LC metabolism on the rate of change in CSF‐based p‐tau, beta‐amyloid and cognitive scores. Result: Low LC FDG‐PET signal was observed in the amyloid and tau‐positive group compared to the other groups (p<0.0001). Pair‐wise differences between the diagnostic groups did not survive correction for multiple comparisons. Combining biomarker and diagnostic status, we observed lower LC metabolism in A+T+ MCI and AD groups compared to CN and MCI A+T‐ and A‐T‐ groups (p<0.001; Figure 1B). Lower LC metabolism predicted accumulation of p‐tau (t(127) = ‐2.65, p = 0.009) and PACC decline (t(128) = 2.2, p = 0.029; Figure 2). LC metabolism did not significantly predict changes in beta‐amyloid levels or MMSE scores. Conclusion: This is the first study relating in‐vivo spatially specific measures of LC metabolism to AD‐related biomarker status. Low LC metabolism was most pronounced in those with evidence of underlying AD pathologic change and cognitive impairment. Furthermore, lower LC metabolism predicted greater CSF‐based p‐tau accumulation and declining cognition over time, providing an early marker of AD progression. [ABSTRACT FROM AUTHOR]

Background: The locus coeruleus (LC) is one of the first regions to accumulate tau in Alzheimer's disease (AD). As the disease progresses, tau in the LC has been related to increasing allocortical tau. Recent autopsy work reported that LC neurodegeneration correlated with parietal amyloid, suggesting that the LC may impact both Ab and tau, but with regionally varying contributions. We investigated whether cross‐sectional and longitudinal relationships between in vivo LC integrity and regional tau or Ab are uniquely determined by one pathology or exhibit shared vulnerabilities. Method: 213 individuals from the Harvard Aging Brain Study (mean age:71.6 years, 58% female; 11% cognitively impaired; Figure 1) who underwent 3T LC‐MRI, Ab‐ and tau‐PET imaging were included. Of these, 62 individuals received a second MRI and PET session. For the LC, we extracted the 5 highest normalized intensity voxels. PET‐data was referenced to cerebellar gray and partial volume corrected. Linear regressions associated LC integrity to tau or Ab and variance contributions were quantified. Mixed effects models examined LC changes to changes in tau or Ab. Mediation analyses examined whether local Ab mediated relationships between LC integrity and local tau. Analyses were adjusted for age, sex and multiple comparisons using FDR‐correction. Result: LC integrity was negatively associated with medial‐lateral temporal tau, and widespread Ab. Multivariable analyses demonstrated that LC integrity associated uniquely with tau in medial temporal lobe (MTL) regions and with Ab in frontoparietal regions. LC integrity was associated with both tau and Ab in inferior temporal (IT) and posterior cingulate cortices, and mediation analyses showed that LC integrity – tau associations in these regions were Ab‐mediated (Figure 2). Longitudinal analyses revealed stronger local associations between LC integrity and tau changes, compared to Ab. LC integrity changes were uniquely associated with tau changes in MTL, but longitudinal LC integrity‐IT tau correlations were mediated by local Ab (Figure 3). Conclusion: The LC may have anatomically distinct cortical tau and Ab‐pathways in AD, with MTL correlations being almost uniquely tau‐related, frontoparietal associations uniquely Ab‐related and lateral temporal regions showing Ab‐mediated tau accumulation. Potential underlying mechanisms can include synaptic plasticity alterations, glial activation or neuronal hyperactivation. [ABSTRACT FROM AUTHOR]

Background: 7T MRI allows implementation of high‐resolution quantitative susceptibility mapping (QSM) which can be used to assess the cerebral microvascular/hypoperfusion pathogenic hypothesis in Alzheimer's disease (AD) and in the post‐SARS‐CoV2 setting to explore if there may be similarities in brain changes in these two conditions. The magnetic susceptibility (reflective of tissue iron) of hippocampal subfields was assessed in patients with 1) CSF‐Amyloidß‐status AD; 2) mild COVID‐19 over 6 months previously (Cv); 3) severe COVID‐19 with ICU admission >6 months previously (ICU‐Cv); and 4) age‐matched healthy controls (HC). Methods: 33 participants (10 HC, 14 Cv, 9 ICU‐Cv) for the COVID study and 24 participants (14 AD, 11HC) from AD patients with confirmed CSF‐Amyloidß levels, aged 42‐79, were scanned on a 7T scanner with the following protocol T2* GRE for the AD groups (0.7×0.7×0.7mm3,TE/TR = 20/31ms) and T2* multi‐echo GRE for the Cv groups (0.38×0.38×0.75mm3,TE1/TE2/TR = 8.2/18.4/24ms). Data were processed using QSMbox1 to produce susceptibility maps. PSIR (0.55×0.55×0.55mm3,TE/TR = 3.1/6.9ms) and T2‐weighted FSE (0.38×0.39×1.5mm3, TE/TR = 117/5900ms) images were used to segment the hippocampal subfields (Figure 1)2. One‐way analyses were used in SPSS for comparison between the HC group and each of the Cv, ICU‐Cv, and AD groups. Results: There was no change in susceptibility for the whole hippocampus between AD and HC, but there was a significant difference for the DG subfield (p = 0.045), Figure 2. For COVID patients, there was a significant difference between the susceptibility of the whole hippocampus in the ICU‐Cv group (p = 0.035), but not in the Cv group (p = 0.788), Figure 3, compared to HC. In subfield analyses there was a trend towards decreased susceptibility in the subiculum, an area known to be affected by Alzheimer pathology, in the ICU‐Cv group (p = 0.032) compared to HC. Conclusion: The lower susceptibility within the hippocampal structures observed in AD and ICU‐Cv patients may reflect less iron either from cerebral hypoperfusion or vascular injuries in AD or additionally result from sequelae of hypoxaemia in ICU‐Cv. The study provides preliminary evidence of detectable in vivo microstructural changes in hippocampal subfields in both AD and post‐COVID settings. Funding: Medical Research Council, UK (MR/T005580/1); National Institute of Health, USA (1R56AG074467‐01) References: 1. https://doi.org/10.1016/j.neuroimage.2018.07.065 2. https://doi.org/10.1002/hbm.22627 [ABSTRACT FROM AUTHOR]

Background: Despite considerable advances in beta amyloid (Aβ)‐PET imaging over the last decade, the standard approach of estimating the average neocortical Aβ burden remains largely unchanged. However, as research and clinical trials increasingly shift earlier in the disease process, measures of how far Aβ has spread throughout the cortex (spatial extent) may prove more sensitive than average neocortical magnitude for detecting and quantifying early Aβ deposits and their association with future tau proliferation and cognitive decline. Method: Clinically‐normal individuals (n = 214) were included from the Harvard Aging Brain Study with longitudinal PIB‐PET (2‐4 scans, median = 4.7±2.7 years) and annual cognitive data (median = 5.2±2 years), as well as a subset (n = 181) with flortaucipir (FTP)‐PET. Spatial extent (EXT) was computed as the number of cortical ROIs (n = 62, Desikan atlas) above their ROI‐specific threshold for Aβ positivity. EXT was compared to a traditional mean neocortical DVR using logistic growth modeling. Receiver Operator Characteristic (ROC) curve analyses evaluated EXT's ability to identify baseline PIB‐ individuals (<1.19DVR/24CL) who progressed to PIB+ at 3‐year follow‐up. Linear Mixed Effects (LME) modeling assessed baseline EXT (or DVR) as a predictor of increasing inferior temporal tau (IT FTP SUVR) and cognitive decline on the Preclinical Alzheimer's Cognitive Composite (PACC). Result: EXT begins rising below the neocortical DVR threshold (Figure1A), reaching a maximal growth rate of 14 ROIs per 0.1 DVR increase (∼10CL) and plateauing as full cortical EXT is achieved starting at ∼1.5DVR/68CL. A 3‐ROI EXT threshold predicts progression from PIB‐ to PIB+ in 3 years (AUC =.97, SE =.82,SP =.97), outperforming neocortical DVR (AUC =.92, SE =.65,SP =.94, Figure1B). EXT provides a stronger biomarker of Aβ change than DVR (lower coefficient of variation, Figure2) across the Aβ continuum due to its low variance, even after EXT has plateaued. Baseline EXT is also a stronger predictor of increases in IT FTP SUVR (Figure 3A, η2EXT =.25, η2DVR =.20) and PACC decline (Figure3B, η2EXT =.28, η2DVR =.22). Conclusion: By describing the spread of Aβ throughout the cortex rather than average neocortical Aβ burden, spatial extent provides a more sensitive measure of Aβ at early, preclinical stages of AD that may improve design of AD prevention trials and open new avenues for research into AD pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Topographical staging of tauopathy in preclinical Alzheimer's disease (AD) posits early deposition in the entorhinal region (medial temporal lobe; MTL) followed by spread to adjacent neocortical (NEO) regions. Predictive models support a cascade of tau deposition as baseline MTL tau robustly predicts NEO tau accumulation. In clinically normal (CN) Ab+, elevated tau in MTL and NEO is associated with accelerated progression to dementia relative to those with only elevated MTL tau. The frequency and profile of neocortical tau resistance (defined as MTL+/NEO‐) remain unclear. Method: We defined tau resistance using two longitudinal datasets. To compare directly across MTL (entorhinal/amygdala/parahippocampal) and NEO (inferior‐temporal/fusiform/middle‐temporal/inferior‐parietal) composites, we averaged regional SUVrs within each composite then normed them to independent samples of younger CNAb‐ adults. We selected CN participants from ADNI and HABS with ≥2 time‐points of Flortaucipir‐PET (nHABS = 200; nADNI = 149; cerebellar‐greyreference). We extracted slopes from a linear mixed model covarying for age, APOEe4 and Abstatus. We compared baseline MTLnormed values with slopes in a NEOnormed. We defined tau resistance as those with elevated baseline MTLnormed tau‐PET but no change in NEOnormed tau‐PET over time. We used non‐parametric group comparisons to determine differences in a range of variables (Table1). Result: We found a poor to moderate correlation between baseline MTLnormed values and adjusted NEOnormed slopes (rHABS = 0.12; rADNI = 0.36; Fig.1), with a non‐linear association at higher levels of MTLnormed. In HABS, tau resistance was identified in 13% (n = 10) of those with elevated MTLnormed. There was a trend for Black/African American individuals to be less tau resistant (Table.1). In ADNI, 26% were identified (n = 11), there was a trend toward less APOEe4 carriers in the resistant group. Although the ranges of change were different across the two cohorts, adjusted MTLnormed and NEOnormed slopes were similarly strongly correlated (rHABS = 0.69; rADNI = 0.74; Fig.2). Conclusion: Our preliminary findings suggest that resistance to neocortical tau in CN exists in up to a quarter of those with elevated MTL. Given the complexities with determining cross‐sectional and longitudinal tau‐PET thresholds, our approach to identifying MTL+ or NEO+ may be too conservative. Future work will validate tau resistance via cognitive decline and clinical progression. [ABSTRACT FROM AUTHOR]

Background: The Stress and Adversity Inventory (STRAIN) systematically assesses lifetime stressor exposure, but its validity has yet to be established in The Netherlands. This work aims to validate the Dutch translation of STRAIN and its association with key biological correlates: cortisol measures and the locus coeruleus (LC), a brainstem nucleus involved in stress responses and accumulating phosphorylated tau early in adulthood. Methods: Eighty‐seven cognitively unimpaired Dutch participants (31‐81 years; ∼45% female; Table 1) completed stress‐ and affective‐related questionnaires, cognitive testing, salivary and plasma cortisol measurements, and 7T‐MRI. The STRAIN was administered after translation into Dutch. LC MRI signal intensity was extracted from an MT‐TFL sequence by normalizing LC signal against the pontine tegmentum (reference region) and creating a sample‐specific LC template. Pearson correlation models assessed associations between STRAIN summary scores (total stressor count and severity), and stress‐related (MIA‐Anxiety, PSS, DASS‐Stress, NEO PI‐R‐Neuroticism), affective (DASS‐Anxiety‐Depression, HDRS), cognitive (WLTDR, LDST, STR3), stress‐related biological (salivary‐, plasma cortisol), and LC measures (Table 1). HDRS models employed Spearman correlations. Age and sex were included as covariates, additionally including education for cognitive measures. Analyses were FDR‐corrected and conducted based on complete cases. Results: Overall, the sample had relatively low lifetime stressor counts (M = 14.08; Figure 1A). When assessing concurrent validity, the STRAIN was positively associated with other stress measures (r =.21,.36; pFDR<.05; Figure 1B,C). Models including cortisol revealed that less stressor exposure and severity were associated with higher cortisol levels (r = ‐.22,‐.23; pFDR<.05). Affective and cognitive measures were investigated for discriminant validity. STRAIN was not associated with DASS, but was positively associated with HDRS (r =.17,.28; pFDR<.05). Generally, greater stressor exposure was related to poorer cognitive performance (r =.13,‐.19; pFDR<.05), except for a positive association between WLTDR and stressor severity (r =.18; pFDR<.05). No significant associations were found with LC MRI signal intensity (Figure 1B). Conclusion: This study demonstrates preliminary good concurrent and discriminative validity for the Dutch STRAIN translation, even among individuals with low‐to‐moderate self‐reported stress levels. We found no direct associations between LC integrity and lifetime stressors. Future research will investigate associations with other STRAIN domains and potential moderating effects of Alzheimer's Disease‐related biomarkers on the relationship between cumulative stressor exposure and LC integrity. [ABSTRACT FROM AUTHOR]

Background: Recent autopsy and in vivo MRI studies supported structural integrity of the brainstem locus coeruleus (LC) as a potential indicator of initial AD‐related pathological processes. Importantly, in the earliest stages of the disease, these changes to the neuronal density of the LC are associated with changes to the somatic morphology and dendritic atrophy. Here, we aimed to examine whether LC microstructural integrity, assessed in vivo with advanced diffusion‐weighted magnetic resonance imaging (dMRI), is related to plasma AD biomarkers in a sample of cognitively unimpaired individuals. Method: Fifty‐seven cognitively unimpaired participants (mean age = 59.3±14.7y; 28 females) (Table 1) underwent a dMRI scanning session using a multi‐shell, high angular resolution acquisition protocol in a 7T scanner. LC microstructure was evaluated by applying the Neurite Orientation Dispersion and Density Imaging (NODDI) biophysical model on the dMRI data, yielding two metrics of microstructural integrity: Neurite Density Index (NDI) and Orientation Dispersion Index (ODI). Additionally, blood samples were analyzed to assess AD plasma biomarkers, including Aβ42/40 ratio, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and tau phosphorylated at threonine 181 (pTau181) or threonine 231 (pTau231). Result: Higher age was associated with lower LC ODI (t = ‐2.77, p = 0.008) but not LC NDI values (t = 0.44, p = 0.658). Multiple linear regressions adjusted for age, sex, and estimated Total Intracranial Volume (eTIV) showed that lower NDI in the LC was associated with higher plasma GFAP levels (t = ‐2.08, p =.04, Figure 1). In addition, we found a negative association between ODI within the LC and Aβ42/40 (t = ‐2.79, p =.007, Figure 2). No significant relationships were found between LC NDI/ODI values and plasma NfL or pTau biomarkers. Conclusion: Consistent with animal studies, these findings suggest that microstructural changes in the LC are associated with astroglial activation in the earliest stages of the disease. Associations with Aβ42/40 were unexpected but might reflect loss of white matter compartments or changes in lipid density. In future analyses, we will further examine the biological interpretation of the NODDI metrics in subcortical regions, in particular in the context of AD‐related processes. [ABSTRACT FROM AUTHOR]

Background: Altered 24‐h rest‐activity rhythms have been previously associated with higher burden of Alzheimer's disease (AD) pathological hallmarks, as measured with positron emission tomography or cerebrospinal fluid collection. Recent developments in fluid biomarkers now allow to non‐invasively measure levels of AD‐related pathology in the plasma. Here, we examined whether actigraphy‐derived 24‐h rest‐activity patterns could be linked to plasma markers of neurodegeneration and AD pathology in a sample of cognitively unimpaired participants. Method: Ninety‐three asymptomatic individuals (mean age = 59.73 ± 13.74 y., range = 30 – 85 y., 48 females, Table 1) underwent 10 days of actigraphic recordings, and blood drawing. Standard non‐parametric indices of 24‐h rest‐activity rhythm fragmentation (intradaily variability, IV) and stability (interdaily stability, IS) were extracted using the GGIR package (v2.8‐2) in R. Plasma concentrations of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), 40 and 42 amino acid‐long amyloid‐β (Aβ40 and Aβ42, respectively), total tau, and phosphorylated tau at threonine 181 (pTau181) or threonine 231 (pTau231) were measured using Single molecule array technology. Result: Multiple linear regression models adjusted for age, sex, education, and body mass index, showed that worse rest‐activity rhythm fragmentation, as indicated by higher IV values, was strongly associated with elevated levels of plasma NfL (t = 4.53, p <.0001, Figure 1), but also with higher levels of plasma GFAP (t = 2.44, p =.02, Figure 2) and lower plasma Aβ42/40 ratio (t = ‐2.23, p =.03, Figure 2). Similarly, increased day‐to‐day rest‐activity rhythm stability, as indicated by higher IS values, was associated with lower levels of plasma NfL (t = ‐2.37, p =.02, Figure 1). By contrast, no significant relationships were found between IV or IS values and total tau or phosphorylated tau plasma biomarkers (all p >.27). Conclusion: These findings provide further evidence that disrupted rest‐activity patterns, in particular fragmentation of rest‐activity rhythms, may constitute a sensitive marker of incipient AD pathology and neurodegeneration in cognitively unimpaired individuals. Our study therefore highlights the clinical utility of monitoring rest‐activity patterns for improved detection of individuals at‐risk for neurodegenerative diseases, including AD. [ABSTRACT FROM AUTHOR]

Background: The COVID‐19 pandemic has disproportionately affected ethno‐racial minority populations and people with greater social deprivation. It is unknown whether such disparities influence research participation for investigations of long‐term neuro‐cognitive effects of SARS‐CoV‐2 infection. Method: Across 3 US and 1 UK sites, we are enrolling a multi‐racial cohort of SARS‐CoV‐2 infected individuals and age, sex, race‐matched non‐infected controls. Utilizing harmonized protocols for cognitive assessments and 7‐Tesla MRI, we aim to provide ultra‐high‐field data on natural history of COVID‐19 driven microstructural and microvascular cerebral changes and associated cognitive trajectories. We will also compare the imaging markers to those observed in an existing cohort of early onset Alzheimer's Disease and Related Dementias (ADRD). We analyzed screening and enrollment data to determine potential age, sex, race, ethnicity, and social deprivation disparities in research participation. We derived address‐based Area Deprivation Index (ADI) (scale 1 ‐10), with higher ADI indicating greater deprivation. Logistic regression models were fit to evaluate associates of non‐response and refusal. Odds Ratios (OR) and 95% confidence intervals (CI) are reported. Result: Over a 11‐month period, at a single US site, a total of 1,046 SARS‐CoV‐2 infected people and their controls were contacted, and 379 (36.2%) responded. In univariable analyses, non‐response was associated with younger age, male sex, non‐White race, and higher ADI (Table 1). In the fully adjusted model, non‐White race was independently associated with higher likelihood of non‐response [OR (CI) for Black vs. White: 1.49 (1.04, 2.12) and for Asian vs. White: 1.88 (1.28, 2.76)]., Independent of race, higher ADI was also associated with likelihood of non‐response (Table 2 and Figure 1). Among the responders, 228 (60.2%) refused. Although, no socio‐demographic factors were significantly associated with likelihood of refusal, the point estimates in the fully adjusted model suggest potential racial disparities in providing consent (Tables 1 and 2). Aggregated data from all sites will be presented. Conclusion: It is imperative to recognize and mitigate persistent disparities in the COVID‐19 pandemic, particularly pertaining to participation in long‐COVID research. Mechanisms of such persistent disparities need to be studied in context of cultures, beliefs, access, and clinical factors. [ABSTRACT FROM AUTHOR]

Background: Optimizing longitudinal cognitive and biomarker trajectories can distill multiple observations from one individual into a single metric. Relative to other individuals, this metric can represent an individual's distance from an anchor‐point based on their rate and non‐linearity of change. We have recently developed a cognitive time (c‐time) based on the cognitive trajectories of clinically normal older adults. We examined the association between c‐time and a previously published 'time‐to‐Aβ+ threshold' and how these metrics align with demographics and other biomarkers. Method: We identified 135 clinically normal older adults from the Harvard Aging Brain Study (Agemean:73years(±5.9); Female:61%) with ≥3 neuropsychological assessments and PiB‐PET, ≥1 Flortaucipir‐PET, ≥2 volumetric MRI, and diagnostic follow up. We defined c‐time using iterative non‐linear least‐squares optimization to define a curvilinear function that described the group‐level Preclinical Alzheimer Cognitive Composite (PACC) trajectory (Fig1D). Each participant's PACC trajectory was subsequently located on the curve using the same optimization framework (Fig1E). We identified the anchor‐point of cognitive decline (c‐time) using piecewise linear mixed‐effects models. Time‐to‐Aβ+ was calculated using the published sampled iterative local approximation (SILA; Fig1A) algorithm with the anchor‐point indicating Aβ+ threshold (Fig1B). We examined associations between c‐time and time‐to‐Aβ+ using linear regression. Individuals were subsequently placed into groups depending on their position relative to the anchor‐point on each axis, as well as the line‐of‐best‐fit (Fig2). We compared the groups on demographics, and both cross‐sectional and longitudinal indices of medial temporal (MTL) Flortaucipir‐PET (entorhinal, parahippocampal, amygdala) and ICV‐adjusted hippocampal volume. Result: C‐time and time‐to‐Aβ+ were significantly associated (r = 0.42,p<0.001). Only one participant (who progressed to MCI/dementia) was post‐c‐time and remained pre‐time‐to‐Aβ+, supporting the notion that time‐to‐Aβ+ occurs prior to cognitive inflection. Individuals post‐c‐time and post‐time‐to‐Aβ+ (Group 1) were more likely to be APOEε4 carriers, progressors to MCI/dementia, have significantly higher baseline MTL tau and lower hippocampal volume, and faster hippocampal atrophy (Fig3). Group 2 (post‐time‐to‐Aβ+/pre‐c‐time) were more likely APOEε4 carriers. Notably, no age or other effects were apparent between groups. Conclusion: Optimizing longitudinal cognitive and biomarker data to estimate a preclinical disease continuum can provide unique, and potentially age‐independent, information about the distance an individual might be from disease‐relevant events. [ABSTRACT FROM AUTHOR]

Background: In men and women, sex steroid hormones are associated with increased risk of Alzheimer's disease (AD) dementia. In older men, lower levels of testosterone are associated with higher rates of AD dementia. The relationship between estradiol levels on AD dementia risk in post‐menopausal women, however, is less clear, with studies reporting protective, deleterious and no effects. Finally, higher levels of sex hormone binding globulin (SHBG), a glycoprotein that regulates, and actively influences sex hormones, has been consistently linked with increased risk for AD dementia. Studies have yet to examine mid‐life hormonal levels in association with later‐life in vivo AD biomarkers in cognitively healthy adults. Method: 175 women and 159 men from the Framingham Study 3rd Generation cohort underwent blood (hormones) collection in 2002‐2005, and 18F‐Flortaucipir (FTP)‐PET and 11C‐PiB‐PET scans in 2016‐2020 (Table1). We examined FTP‐PET signal (referenced to cerebellar grey) in six a priori regions that previously demonstrated sex differences (entorhinal, inferior temporal, rostral middle frontal, inf/sup parietal and lateral occipital). Linear regressions examined sex‐stratified analyses of free/total testosterone, estradiol, and SHBG in each region, adjusting for age, age2, PET camera and plasma‐PET date‐difference (mean = 15(±2)yrs). Separate models examined interactions with a neocortical PiB‐PET composite and APOEε4. Result: In men, elevated SHBG was associated with lower FTP‐PET in entorhinal (p = 0.007), inferior temporal (p = 0.04) and rostral middle frontal regions (p = 0.02; Table2). Higher total testosterone was marginally associated with lower FTP‐PET signal in the latter region (p = 0.06), but other relationships were apparent. In women, higher total testosterone associated with lower FTP‐PET signal in inferior temporal (p = 0.05) and parietal regions (p = 0.04). Women APOEε4 carriers with higher estradiol showed higher levels of entorhinal FTP‐PET signal (p = 0.03;Table3). Conclusion: Higher levels of SHBG are associated with lower risk of AD‐related comorbidities, such as osteoporosis, diabetes, and visceral weight gain. A strong link between higher SHBG levels and higher HDL‐cholesterol may suggest a potential protective cardiovascular pathway for men against higher tau burden later in life. A lack of protective effect of pre‐menopausal estradiol in female APOEε4 carriers supports the notion that the role of estrogen in AD risk is centered around timing of decline. [ABSTRACT FROM AUTHOR]

Background: Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline in dementia. Recent neuroimaging and pharmacological studies have also ascribed a protective role of the LC against cognitive decline, possibly mediated by prefrontal functional connectivity (FC). Interestingly, higher left frontoparietal network (LFPN) FC provides resilience against cognitive decline in preclinical sporadic or autosomal Alzheimer's disease (AD). Given that the FPN and the LC play an important role in attentional control, and attention deficits are affected early in the disease process, we aimed to examine whether LFPN‐FC can counteract the impact of poor LC structural health on attention in the context of AD pathology. Method: 143 participants from the Harvard Aging Brain study who underwent 3T resting‐state functional MRI, LC structural imaging, PiB(Aβ)‐PET, and up to 4 years of cognitive follow‐ups were included (90 F, mean age = 75±9.88, Table 1). The Digit Symbol Substitution Test (DSST) assessed attentional control. Robust linear regression associated LC integrity or LFPN connectivity to DSST performance at baseline. Robust mixed effect analyses examined the associations between DSST decline and (i) the two‐way interaction between LC integrity (or LFPN‐FC) and PiB (DVR‐PVC), or (ii) the three‐way interaction between LC integrity, LFPN‐FC, and PiB (DVR‐PVC). All analyses were adjusted for age, sex, and years of education. Result: At baseline, lower LFPN‐FC (p = 0.001) was related to worse performance on the DSST, while no such association was found for LC integrity (p = 0.26). Longitudinally, both, lower LC integrity (p<0.001) and LFPN‐FC (p = 0.026) were associated with faster DSST decline, especially at higher PiB levels (Figure 1). The modulating effect of LFPN‐FC is most prominent under lower LC structural integrity values, where higher levels of LFPN‐FC were associated with less steep decline on the DSST, in particular in individuals with higher PiB (p = 0.036, Figure 2). Conclusion: Our findings demonstrate that when LC structural health is poor, higher LFPN‐FC can maintain cognitive performance even at higher levels of Aβ deposition in preclinical AD. These results provide critical insights and targets to support specific brain mechanisms that delay symptom progression in the early stages of the disease. [ABSTRACT FROM AUTHOR]

Background: Misfolded tau protein, an Alzheimer's Disease (AD) hallmark, accumulates decades before the emergence of cognitive decline. Autopsy and neuroimaging studies support the locus coeruleus (LC) as an early site of tau and its contribution to disease progression. However, whether tau in LC precedes cortical tau deposition remains unclear. Understanding the topography of tau progression and the biological factors making specific neuronal systems prone to AD‐related pathology is essential to target interventions appropriately. We examined the spatiotemporal relationships between LC integrity and cortical tau accumulation and its relevance to cognition., Methods: We combined longitudinal LC‐integrity (T1‐TSE‐imaging) and tau pathology (18F‐FTP‐PET) data from 77 adults (Fig1A). We used whole‐brain voxel‐wise GLM analysis to investigate the relationship between baseline LC‐integrity (inverted signal) and longitudinal tau accumulation and compared the correlation distributions in both directions. Robust regression analysis was used to examine whether the observed tau spreading pathway predicts PACC5 performance at follow‐up. We used neuropathological measures from 160 cognitively unimpaired or MCI/AD adults (Fig1B) to support the in‐vivo neuroimaging data. Spearman‐rank partial correlations were used to relate LC tangle density to tangles in temporal cortex areas. Using AHBA, the biological backgrounds underlying the connectomic‐genetic relationships related to LC were explored using a whole‐brain region‐wise transcriptomic similarity analysis., Results: Correlations between baseline LC‐integrity and follow‐up tau were stronger than the inverse correlations, indicative of lower LC‐integrity preceding tau accumulation in MTL (Fig1C‐D). LC tangle density was strongly related to tangles in MTL structures (Fig1E). Longitudinal tau accumulation in the LC‐MTL axis is associated with lower cognitive performance (Fig2). Common neurogenetic profiles exist between LC and MTL/limbic regions, supporting a shared connectomic‐transcriptomic substrate. The genetic profile displays specific biological functions in protein transport regulation and lipid biosynthetic processes (Fig3)., Conclusion: Our results suggest that changes in LC‐integrity may occur before tau spreads into the MTL, which jointly contributes to lower cognitive performance. The neurogenetic profiles can provide a biological framework for identifying individuals more likely to be at risk for AD disease progression. Future developments could examine the intersection between amyloid and LC‐related tau progression in the context of AD. [ABSTRACT FROM AUTHOR]

Introduction: Autopsy studies recognize the locus coeruleus (LC) as one of the first sites accumulating tau in Alzheimer's disease (AD). Recent AD work related in vivo LC magnetic resonance imaging (MRI) integrity to tau and cognitive decline; however, relationships of LC integrity to age, tau, and cognition in autosomal dominant AD (ADAD) remain unexplored. Methods: We associated LC integrity (3T‐MRI) with estimated years of onset, cortical amyloid beta, regional tau (positron emission tomography [PET]) and memory (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word‐List‐Learning) among 27 carriers and 27 non‐carriers of the presenilin‐1 (PSEN1) E280A mutation. Longitudinal changes between LC integrity and tau were evaluated in 10 carriers. Results: LC integrity started to decline at age 32 in carriers, 12 years before clinical onset, and 20 years earlier than in sporadic AD. LC integrity was negatively associated with cortical tau, independent of amyloid beta, and predicted precuneus tau increases. LC integrity was positively associated with memory. Discussion: These findings support LC integrity as marker of disease progression in preclinical ADAD. [ABSTRACT FROM AUTHOR]

Background: Previous work has shown that neuropsychiatric symptoms (NPS) such as depression in older adults are associated with cognitive decline and brain pathology related to Alzheimer's disease (AD), but the constellation of NPS driving these associations is unclear. Traditionally, depressive symptoms have been assessed with the Geriatric Depression Scale (GDS), but newer NPS assessments, such as the Mild Behavioral Impairment‐Checklist (MBI‐C), have shown promise for identification of specific early features of symptomology. Here we examined the two affective domains of the MBI‐C in cognitively unimpaired older adults with moderate‐to‐severe depressive symptoms and non‐depressed older adults, and the association between these domains and neuroimaging biomarkers of AD. Method: 21 clinically normal (CN) older adults who met DSM5 criteria for major depression (MDD) (73.0±4.3 y.o., 62% female) and 25 non‐depressed older adults from related observational studies at our site (70.8±3.7 y.o., 64% female) underwent a clinical battery that included the GDS and MBI‐C self‐report domains focused on decreased interest‐motivation‐drive and increased dysphoria‐anhedonia‐anxiety (Range for each domain: 0–18). Participants completed neuroimaging consisting of MRI, amyloid‐(C11‐PiB)‐PET, and tau‐(F18‐FTP)‐PET. We focused analyses on neocortical amyloid and regional tau and atrophy in the amygdala and hippocampus. A Pearson correlation was used to assess the association between GDS total score and MBI‐C component scores. Linear regressions adjusted for age were used to investigate relationships between MBI‐C domains and ATN biomarkers. Result: GDS total score was correlated with both MBI‐C domains across all participants (Fig.1, p<0.01). In participants with MDD, the MBI‐C decreased interest‐motivation‐drive domain was associated with elevated FTP in the amygdala and hippocampus, while the increased dysphoria‐anhedonia‐anxiety domain was not significantly related to PET signal (Table 2, Fig.2). MBI‐C domains were not related to PET signal or atrophy in non‐depressed control participants. Conclusion: Preliminary findings with the MBI‐C suggest that the decreased interest‐motivation‐drive domain may be associated with tau pathology in older adults with moderate‐to‐severe depression. Additional work needs to be done in a larger depressed cohort to further understand the associations between specific depressive phenotypes and AD pathology. [ABSTRACT FROM AUTHOR]

Background: The locus coeruleus (LC) is considered one of the earliest regions accumulating hyperphosphorylated tau before this pathology emerges in the entorhinal cortex (EC). Recent animal work suggested that LC phasic activity, which can be induced with exposure to novelty, can protect the cognitive downstream effects of tauopathy. Here we investigate whether activity of the LC during novelty is associated with memory decline and whether this association is mediated by EC‐tau deposition. Method: 92 participants (51 F, mean age at imaging (baseline) = 69.55±10.17 years) from the Harvard Aging Brain Study underwent both longitudinal memory testing (mean follow‐up = 4.8±1.9 years) and PiB(Aβ)‐, FTP(tau)‐PET, and 3T task‐fMRI scans performed within 1 year of each other (mean time difference = 0.29±0.24 years). The fMRI‐task consisted of novel and repeated face‐name pairs that the participants were instructed to remember. Voxel‐wise mixed‐effects analyses were performed to detect regions exhibiting significant novelty‐related activation. Vertex‐wise linear regression analyses were used to detect significant associations between LC activity and cortical tau deposition. Both analyses were adjusted for age, sex and multiple comparisons (pcl<0.05). The association between LC activity and memory decline (composite, Fig. 3 caption) was evaluated using linear regression adjusted for age, sex and education. Mediation analyses were performed using a quasi‐Bayesian bootstrap (n = 1000) approach to investigate whether EC‐tau mediates the association and whether this mediation effect is moderated by Aβ status. Result: We observed greater novelty‐related activation within the bilateral LC, amygdala, hippocampus, and fusiform and insular cortices (Fig. 1). LC activation was associated with tau in the EC, inferior‐temporal and fusiform cortices (confirmed by EC‐ROI analyses‐Fig. 2). Lower LC activation was associated with steeper memory decline (p<0.05‐Fig. 3a), and this association was found to be mediated by EC‐tau (p<0.05‐Fig. 3b). This mediation effect was significantly stronger for the Aβ+ compared to the Aβ– group (p<0.05‐Fig. 3c). Conclusion: This work demonstrates that lower LC activity is associated with tau deposition in the medial‐ and inferior‐temporal lobe, consistent with the spatial patterns of tau observed in preclinical Alzheimer's disease. Moreover, our observation that EC‐tau mediates the relationship between LC activity and memory decline suggests that lower LC function may indicate risk associated with Alzheimer's‐related processes. [ABSTRACT FROM AUTHOR]

Background: Hippocampal volume (HV) atrophy is a well‐known biomarker of cognitive impairment. However, it is not specific for Alzheimer's disease (AD). To disentangle the contributions of AD and other neuropathologies to cognitive decline, we investigated the longitudinal associations between HV and cognition, adjusting for Aβ and tau in participants from the Harvard Aging Brain Study who were clinically normal (CN) at inclusion. Methods: Serial MRI (HV [1.3‐7.0y], PiB‐PET (Aβ, [1.9‐8.5y]), Flortaucipir‐PET (tau, [0.8‐6.0y]), and the Preclinical Alzheimer Cognitive Composite (PACC, [3.0‐8.8y]) were observed over an average five‐year follow‐up in 128 CN participants, including ten who progressed to symptomatic AD during the study. Longitudinal HVs were processed using Freesurfer v.6 and adjusted for intracranial volume. PiB was measured in a neocortical aggregate, Flortaucipir in inferior temporal (IT) and entorhinal cortex (EC). PET data were expressed as PVC‐SUVr scaled to subcortical white matter. We predicted cognition and imaging data over time with random intercept and slope in linear mixed‐models and extracted PACC, PiB, FTP, and HV slopes for each subject. Baseline imaging and slope data were entered in age‐adjusted linear regressions to evaluate their associations with PACC slope. Results: Without covariate, faster HV atrophy was correlated with faster PACC decline (Fig.1, R2=0.28, p<0.0001). Adjusting for age, the correlation was reduced, but significant (R2=0.20, p<0.0001, Table 2). Entering all predictors into sequential regression models, we observed that HV atrophy was associated with PACC decline independently of PiB and Tau (Table 3, model‐D). HV atrophy was explained by EC Tau, but not by PiB or IT Tau (model‐C, Fig.2). When comparing all biomarkers, HV slope uniquely accounted for 10% of the variance in PACC decline. IT Tau explained most of the association between EC Tau, PiB, and PACC. Altogether, 45% of the variance in PACC decline was explained by longitudinal changes in imaging biomarkers. Conclusions: In older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of amyloid and tau, suggesting that non‐AD neuropathologies (TDP43, vascular) contribute to hippocampal‐mediated cognitive decline. Serial HV measures, in addition to AD‐specific biomarkers, may help evaluate the contribution of non‐AD pathologies that cannot be measured in‐vivo but are important for cognition. [ABSTRACT FROM AUTHOR]

Background: As clinical trials shift towards prevention, there has been increasing interest in improving early detection of beta‐amyloid (Aβ), below standard global PET positivity thresholds. While many studies have demonstrated that some regions appear more vulnerable to the earliest deposits, those regions have varied widely across studies. We sought to develop more flexible metrics for identifying subthreshold individuals at risk for progression to global Aβ positivity by evaluating a wide range of early regional targets and expanding our measurement beyond tracer retention (DVR/SUVR) to include spatial extent. Method: 269 clinically‐normal older adults were included from the Harvard Aging Brain Study, focusing on 150 initially globally PIB‐ adults with longitudinal PET. Region‐specific positivity thresholds were computed using iterative longitudinal two‐level linear mixed effect models that identified the cutoff beyond which local accumulation significantly increases over time. Next, we identified all regions significantly predictive of future global accumulation in initially PIB‐ adults and generated 3 aggregate masks at liberal (p<.05), moderate (p<.001) and conservative a‐levels (Bonferroni p<.0007). DVR and spatial extent (number of elevated ROIs) were computed in each mask. Receiver operator characteristic (ROC) curve analysis determined sensitivity/specificity of each metric to predict future global positivity. External validation was performed using globally florbetapir‐negative (FBP‐) healthy controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI, n=211). Result: Regional variations in measurement reliability were detected (Fig1) and accounted for by employing accumulation‐based regional positivity thresholds. A broad set of ROIs were identified as potential early targets based on prediction of global accumulation, encompassing bilateral cingulate, medial frontal/parietal cortices and left‐lateralized lateral frontal/parietal/temporal cortices (Fig2). ROC analyses demonstrated that spatial extent outperformed DVR in predicting progression to global PIB+ within 3 years (Fig3), with 82% sensitivity and 97% and 98.5% specificity, respectively, for the two larger aggregate masks. External validation in ADNI (Fig4) again demonstrated the superior performance of spatial extent (SE=100%, SP=91.6%) in predicting progression to global positivity within 3 years. Conclusion: Our findings demonstrate that due to a high level of heterogeneity in early Aβ deposition, measures of spatial extent across a broad set of neocortical regions are more sensitive to detect early Aβ than traditional DVR/SUVR. [ABSTRACT FROM AUTHOR]

Background: The ATN framework is defined by cross‐sectional biomarkers of β‐amyloid (Aβ), tau and neurodegeneration. Given that prevention trials, e.g., AHEAD 3‐45, are focused on individuals who have lower Aβ than established thresholds, we investigated whether defining the ATN framework using longitudinal biomarker trajectories might better identify an at‐risk sample within this boundary. Here, we applied a data‐driven method to re‐define the ATN with longitudinal biomarker data from the Harvard Aging Brain Study (HABS) and we then replicated this longitudinal framework in ADNI. Method: 157 HABS participants were clinically‐normal at baseline and underwent at least two Pittsburgh Compound‐B [PiB]‐PET, Flortaucipir‐PET, and T1‐weighted MRI scans. To define longitudinal ATN, we applied latent class mixture models (LCMM) to each biomarker (global Aβ DVR, entorhinal tau SUVr, ICV‐adjusted hippocampal volume) separately, adjusting for age, and including random intercept and slopes. Akaike information criteria (AIC) determined the best‐fitting models out of two‐group or three‐group solutions with linear or spline‐link functions. We compared longitudinal ATN profiles on demographics and an optimized estimate of cognitive change (derived from longitudinal Preclinical Alzheimer Cognitive Composite (PACC) data). Result: Aβ trajectories (Fig.1a) were best categorized by one stable (A→) and two accumulating subgroups, a predominantly amyloid‐negative at baseline subgroup (A‐↑) and an entirely amyloid positive at baseline subgroup (A+↑). Tau (Fig.1b) and neurodegeneration (Fig.1c) were optimally defined by stable (T→/N→) vs accumulating/atrophying (T↑/N↑) groups, respectively. These groups were replicated in ADNI (Fig.2). The entire A‐↑ subgroup were stable on T and N (A‐↑/T→/N→) and were predominantly A‐/T‐/N‐ at baseline (86%; Table 1). By contrast, 38% of A+↑ individuals changed on T, or T&N. A‐↑/T→/N→ demographically most closely resembled the longitudinally‐stable ATN group (A→/T→/N→), but were older, more likely to carry e4+ and exhibited higher baseline Aβ (Table 2). Although demonstrating Aβ accumulation, A‐↑/T→/N→ did not exhibit greater cognitive decline versus the stable group (A→/T→/N→; Fig. 3). Conclusion: Our findings suggest that a longitudinal biomarker run‐in of Aβ‐PET may be useful for the identification of early‐risk groups for prevention trials. Future work will establish whether other features (e.g. genetics, neuroinflammatory markers, functional imaging) can help to distinguish this cohort. [ABSTRACT FROM AUTHOR]

Background: As Alzheimer's clinical trials shift earlier and earlier in the disease process, current global PET measures of beta‐amyloid (Aβ) positivity may be insufficient for detecting the earliest Aβ deposits. Regional PET measures may better detect the earliest deposits. Previous efforts to identify early‐accumulating regions have inferred which regions may be most vulnerable based on older adults. Our aim was to identify early vulnerable areas by looking earlier in the lifespan. Method: 235 clinically‐normal adults ages 33‐74 from the Framingham Heart Study (FHS) underwent one time‐point of dynamic Pittsburgh Compound B (PIB) PET (Tab.1). PIB was regionally quantified in Desikan regions using distribution volume ratio (DVR, cerebellar reference). Linear and quadratic (Age + Age2) models were run to determine association of age with region of interest (ROI) PIB DVR, and ROIs with significantly increasing DVRs were selected for the generation of candidate early vulnerable area (EVA) aggregates. Multiple aggregate EVA DVRs (EVA2‐EVA11) were generated by sequential addition of regions in rank order of descending Age2 estimate. EVA positivity was derived from both full‐sample GMM and <45 sample mean+2SD thresholds. Finally, EVA aggregates were tested using an independent cohort of older adults from the Harvard Aging Brain Study (HABS) that were imaged under an identical protocol (n=250, ages 50‐92), computing sensitivity and specificity of each aggregate at baseline to predict progression to global PIB positivity 3 years later. Result: Of 35 Desikan regions each evaluated on the left and right, 11 emerged as quadratic age relationships (p<0.05; Fig.1) and were used to generate EVA aggregates (Fig.2). Independent validation in baseline global PIB‐ individuals from HABS indicated EVA9 and EVA10 best predicted future accumulation (Fig.3). GMM‐based thresholds provided excellent specificity (SP=1.0) but weak sensitivity (SE=0.41) to predict progression to global PIB positivity 3 years later, while the more liberal mean+2SD thresholds improved sensitivity but decreased specificity (SE=0.88, SP=0.88). Conclusion: Utilizing lifespan data from FHS, we identified a set of early vulnerable regions that are predictive of future accumulation in an independent sample of older adults. These findings are potentially useful in identifying the earliest deposits of Aβ for use in clinical trial design. [ABSTRACT FROM AUTHOR]

Background: Cortical neurodegeneration is, along with Alzheimer's Disease (AD) pathology, an important feature of AD, which correlates highly with tauopathy and cognitive decline. Post‐mortem data show that the locus coeruleus (LC) loses approximately 8.4% volume per cortical Braak stage. This work investigates whether LC integrity, as indexed by LC MRI signal intensity, is associated with cortical thickness, and whether this is exacerbated by the presence of AD pathology. Method: Cross‐sectional data from 165 Harvard Aging Brain Study participants (age range=50‐94 years; female=∼60%; cognitively unimpaired: n=149, cognitively impaired: n=16; Table 1) who underwent 3T‐MRI, PiB‐PET (cut‐off=1.324 DVR) and T807‐PET scanning was selected. LC MRI signal intensity was assessed by normalizing the LC to the pontine tegmentum (reference region) for each individual and averaging clusters of 5 voxels with the highest intensities. Unilateral cortical thickness (CT) values were extracted utilizing the Desikan‐Killiany atlas (FreeSurfer 6) and averaged across hemispheres to obtain regional bilateral values. PET measures were corrected for partial‐volume effects. Associations between CT and i) LC intensity, or ii) LC intensity interacted with pathology (i.e., inferior temporal (IT) tau, entorhinal (EC) tau and global amyloid), were examined with bootstrapped linear regressions, while controlling for age, sex, and education, and applying FDR‐correction. Result: We found a positive association between LC intensity and CT for medial and lateral temporal regions (p‐FDR<0.05; Figure 1). Models interacting LC intensity with IT or EC tau revealed that lower LC intensity was associated with lower CT especially in temporal regions. This effect was greater in individuals with elevated tau (p‐FDR<0.05; Figure 2‐3). Results still held after controlling for amyloid (p‐FDR<0.05). Similarly, interacting LC intensity with amyloid showed a relation between lower LC intensity and lower CT in temporal and some occipital regions, which was stronger in individuals with elevated amyloid (p‐FDR<0.05; Figure 4). Conclusion: This work demonstrates that lower LC integrity is associated with bilateral cortical thinning in regions aligning with the expected topographical distribution of tau in preclinical AD. Additionally, these spatial patterns are more widespread in individuals with elevated AD pathology. These results suggest that LC integrity is closely related to the downstream neurodegenerative sequela of AD pathology. [ABSTRACT FROM AUTHOR]

Background: Autopsy studies reported that the locus coeruleus (LC) is one of the first sites of tau accumulation. In addition, LC‐mediated norepinephrine (NE) signaling is thought to play a role in blood‐brain‐barrier maintenance and neurovascular coupling through its projections to the microvasculature, suggesting that the NE‐LC system interacts with cerebrovascular disease and Alzheimer's disease (AD) pathology. Since vascular risk factors are prevalent in older individuals and contribute to vascular pathology, a common co‐pathology of AD, understanding interrelationships among vascular health, tau and LC integrity as early as possible, can guide prevention. Method: We included 124 individuals (Table1) from the Harvard Aging Brain Study with MRI and 18F‐Flortaucipir and 11C‐Pittsburgh‐Compound‐B PET‐imaging within one year of each other. LC‐MRI signal intensity was extracted from 5 maximum‐intensity voxels and normalized to pontine tegmentum. White matter signal abnormalities (WMSA intracranial volume adjusted) were obtained from FreeSurfer6. PET measures were partial‐volume corrected. The Framingham‐Risk‐Score (FRS‐CVD, likelihood of a cardiovascular event in 10 years) was calculated. Structural Equation Models were used to test hypothetic models (1: WMSA mediate the relationship between FRS‐CVD and LC, leading to entorhinal (EC) tau; 2: FRS‐CVD is associated with WMSA and LC, and the LC influences WMSA, both leading to EC tau) against the null model (independent paths of LC and WMSA between FRS‐CVD and EC tau;Figure1). Models were bootstrapped (n = 2000). Model fit measures determined which model described the data best (CFI >0.90, RMSEA <0.08, SRMR <0.08). Age and sex were included as covariates. Result: Models null and 2 had poor fit. Model‐1 had an excellent fit, suggesting that a higher likelihood of a cardiovascular event in ten years is positively associated with WMSA, WMSA is associated with LC intensity, which in turn is associated with EC tau (Table2). Posthoc, global Aβ (DVR) was added as covariate in model‐1, this did not change the model‐fit or outcomes. Conclusion: Previous work demonstrated that LC‐intensity correlates strongly with entorhinal tau. Our findings now suggest that presence of increased cardiovascular risk is associated with lower LC‐intensity through its effects on white‐matter damage, emphasizing the importance of mitigating risk factors earlier in life. [ABSTRACT FROM AUTHOR]

Background: The brainstem locus coeruleus (LC) was recently put forward as a key nucleus to connect early sleep‐wake disruption and Alzheimer's disease (AD) pathophysiological processes. Here, we sought to investigate the relationships between post‐mortem LC hypopigmentation, reflecting LC neurodegeneration, and retrospective subjective/objective sleep‐wake regulation metrics in two longitudinal datasets. Method: LC pigmentation ratings were extracted from autopsy data across 517 Rush Memory and Aging Project (MAP) and 637 National Alzheimer's Coordinating Center (NACC) cases. Actigraphy‐derived intradaily variability, an objective measure of rest‐activity rhythm fragmentation, was obtained in the MAP dataset, and subjective evaluations of sleep quality were retrieved from the NACC cohort. For both studies, sleep‐wake measures were extracted at the furthest and closest available time points, on average 6.8 y. and 2.5 y. before death, respectively. Logistic regressions adjusted for age at death, sex, race, and post‐mortem interval were used to assess whether sleep‐wake variables could predict post‐mortem LC pigmentation ratings. In the next step, additional models including AD‐related variables of APOE genotype and cortical neuropathology (amyloid‐beta and tau burden) were further performed to test for independence in the relationships between sleep‐wake measures and LC pigmentation. Results: In the MAP cohort, higher rest‐activity rhythm fragmentation at both time points was significantly associated with greater odds of LC hypopigmentation at autopsy (Table 1). In models considering additional AD‐related variables, these relationships remained significant independently of the effects of APOE and cortical AD neuropathology (Table 1). In the NACC dataset, worse subjective sleep quality at the closest time point, but not at the furthest, was significantly linked to greater odds of LC hypopigmentation at autopsy (Table 2). Likewise, additional models indicated that this relationship is independent of APOE and cortical AD neuropathology (Table 2). Conclusion: These findings highlight the utility of evaluating sleep and wakefulness, especially with objective measurements, to predict LC neurodegenerative processes in older populations, as far as 6.8 years before death and beyond the effects of APOE genotype and cortical AD neuropathology. Our results thus have implications for improved detection of at‐risk individuals. [ABSTRACT FROM AUTHOR]

Background: Autopsy studies indicated that the locus coeruleus (LC) is one of the first regions to accumulate pretangle material, and imaging work demonstrated that the LC MRI‐signal correlates with entorhinal tau in cognitively normal individuals. Recently developed phosphor‐tau (ptau) blood‐based biomarkers correlated well with cortical tau‐PET and have been suggested as early markers of aberrant tau phosphorylation. Here we evaluated the relationship between LC‐MRI signal intensity and plasma markers of tau (ptau231, ptau217, ptau181), neurodegenerative processes (total tau (t‐tau), neurofilament light (NfL)) and amyloidosis (Aβ42/40). Method: 99 cognitively normal individuals across the lifespan (30‐85 years, n=52 female) underwent dedicated 7T LC‐imaging and fasting blood draw. A sample‐specific template for the LC was generated and transformed into a surface. All plasma markers were quantified in duplicate using Single molecule array methods (Simoa, Quanterix) or Meso‐Scale Discovery. Voxel‐wise robust regressions associated LC intensity values with plasma markers, adjusted for age and sex (or Aβ42/40). Interactions between Aβ42/40 and ptau, t‐tau or NfL were also tested. Multiple comparisons were corrected using Threshold‐Free‐Cluster‐Enhancement (p<0.001). Bootstrapped sliding window analyses determined the age‐window of significant plasma marker–LC intensity associations. Result: Older age was associated with higher ptau181, NfL and lower Aβ42/40 (Figure 1). Higher ptau231 was associated with lower LC intensity in bilateral dorso‐rostral clusters. Ptau181, ptau217 and t‐tau correlated negatively with LC intensity in right dorso‐rostral clusters. Small clusters of negative associations between LC intensity and NfL were distributed across the length of the LC. LC intensity was not associated with Aβ42/40 (Figure 2). Adjusting for Aβ42/40 did not change these results. We did not find interactions between Aβ42/40 and ptau, t‐tau or NfL. The association between LC intensity and ptau231 became significant from age 55.5 years, and for ptau181 and ptau217 from age 60 years (Figure 3). Conclusion: Plasma ptau231 showed robust and earlier relationships with LC intensity compared to ptau217 or ptau181 in asymptomatic individuals across the lifespan. Given that tau phosphorylation at threonine 231 is one of the earliest events in the phosphorylation cascade hindering tubulin assembly, these findings suggest that LC intensity may reflect processes related to early tau aggregation. [ABSTRACT FROM AUTHOR]

Background: Autopsy studies reported the locus coeruleus (LC) as one of the initial regions in the brain harboring hyperphosphorylated tau pathology. MR signal intensity in the LC has been proposed as a measure of LC integrity, but the contribution of tau pathology, commonly found in LC, to this signal intensity is not currently measurable in vivo. We related in‐vivo LC MR signal intensity to Alzheimer’s disease (AD) phenotype and PET measures and used ROSMAP autopsy data to guide interpretation of the MR LC measure as tau‐related or cellular integrity‐related. Method: One‐hundred seventy‐two participants from the Harvard Aging Brain Study (HABS) underwent 3T LC‐MRI imaging, FTP and PiB‐PET imaging (median age: 75 years, 58% female, n=22 with CDR=0.5/1). In 160 individuals from ROSMAP, LC tangle density and neuronal density were quantified at autopsy (median age at death: 89 years, 67% female, 66 control, 53 mild cognitively impaired, 41 AD patients; Figure 1). Groups were compared using ANCOVA. LC measures were related to Mini‐Mental State Examination (MMSE) scores using Spearman correlations (age‐adjusted). In HABS, LC integrity was vertex‐wise regressed on tau‐PET. In ROSMAP, Spearman correlations related LC tangle or neuronal density to cortical tangle density or Braak staging. Result: LC measures correlated with measures of disease progression: in HABS, LC integrity was lower in impaired individuals compared to controls, and correlated positively with MMSE score. In ROSMAP, LC tangle density was higher in MCI/AD patients compared to controls; and correlated negatively with MMSE scores. No associations were found for LC neuronal density (Figure 2). Furthermore, lower LC integrity correlated with higher tau in medial‐lateral temporal regions in HABS, mirroring the consecutive Braak‐staging. Similarly, In ROSMAP, higher LC tangle density, but not LC neuronal density, correlated positively with cortical tangle burden and Braak staging (Figure 3). Conclusion: The comparable associations of MRI‐LC integrity or LC tangle density with disease progression and tau suggest that MRI‐measures of LC integrity may be a proxy for tau pathology, rather than neuronal density. Future verification using head‐to‐head comparison is warranted, but our results indicate that LC integrity holds promise as marker for detection of initial AD‐related processes. [ABSTRACT FROM AUTHOR]

Background: The brainstem consists of various nuclei that accumulate tau early in the Alzheimer’s disease (AD) trajectory. Previous studies discovered the genetic loci linked to brainstem volume, revealing genetic overlap with several neurological disorders, including AD. We aimed to investigate whether the volume of distinct parts of the brainstem are related to AD pathology, amyloid or tau, and whether this effect is modified by APOE genotype. Finally, we evaluated whether genetic variants related to total brainstem volumes are related to AD‐pathology by aggregating previously reported genetic loci into a brainstem polygenic risk score. Method: We included 267 individuals from the Framingham Heart Study who underwent 3T MRI, Flortaucipir (n=238) and PiB‐PET imaging on Siemens HR+ or GE‐Discovery GE PET cameras(mean age: 54 (SD:8) years, 51% male; 24% APOE‐E4; Figure 1). Subregional brainstem volumes were quantified using FreeSurfer 6.0 and adjusted for total cranial volume. Regional FTP‐PET, neocortical PiB‐PET signal were referenced to cerebellar grey and partial volume corrected (PVC). We performed several hierarchical regressions: 1) to associate each brainstem volume to neocortical PiB and tau in temporal lobe regions 2) to examine interactions between PiB and brainstem volumes on tau and 3) interactions between APOE and brainstem volume on tau. We then examined whether the brainstem polygenic risk score was associated with AD‐pathology. Covariates included age, sex and PET‐camera. Result: In both the PVC and non‐PVC analyses, lower medulla and pons volumes were consistently associated with greater neocortical PiB binding (Figure 2). Midbrain volume was at trend‐level negatively associated with inferior temporal and amygdala tau. No other associations were observed with tau. We observed no interactions between brainstem volumes and PiB or APOE on regional tau. The brainstem polygenic risk score was not associated with AD‐pathology (Figure 3). Conclusion: Lower brainstem volume, in particular medulla and pons, is associated with amyloid deposition in a cohort of middle‐aged individuals. There is no evidence for associations with known brainstem loci, suggesting that these associations may occur via different or indirect pathways, or that lower brainstem volumes may be a reflection of overall disease progression and neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Developments in neuroimaging have demonstrated that the structural integrity of the locus coeruleus (LC) changes around age 50‐55, which correlates with cognitive performance, and – consistent with postmortem studies – correlates with accumulation of cortical tau pathology. It remains unknown whether the LC is similarly affected in individuals with autosomal dominant Alzheimer's disease due to a PSEN‐E280A mutation, as brain pathology is evident as early as age 28, an average of 16 years before estimated clinical onset. Here, we aimed to investigate associations between LC integrity, age, cortical tau and amyloid deposition and cognition in carriers and non‐carriers. Method: 27 mutation carriers (19 cognitively unimpaired and 8 impaired) and 27 non‐carriers from the Colombian‐kindred underwent PiB‐PET, Flortaucipir‐PET, 3T‐MRI and memory testing. Of these, 10 carriers underwent a follow‐up imaging and testing session. Using previously reported methods, we extracted LC intensity (or integrity) from the MRI‐images (referenced to pontine tegmentum). Group differences were tested with the Wilcoxon rank test, and correlations were tested using Spearman rank correlations. Longitudinal associations between LC integrity and tau accumulation were evaluated with mixed effects models and repeated measures correlation for change‐on‐change models. Result: The direction of the age‐associations and LC integrity differed between carriers and non‐carriers, with a negative association in carriers (peak at 31.5 years). LC integrity was lower in impaired carriers as compared to unimpaired carriers and non‐carriers (Figure 1). LC integrity was associated with widespread tau accumulation in carriers, while in non‐carriers only with the entorhinal cortex. The longitudinal analyses showed that baseline LC integrity as well as declines in LC integrity predicted precuneus tau accrual in the unimpaired carriers and across all carriers (Figure 2). LC integrity correlated positively with word list learning and delayed recall in all carriers. The positive LC integrity – delayed recall association was mediated by medial parietal tau deposition in carriers (Figure 3). Conclusion: LC integrity is associated with the initial pathologic and clinical phenotypes of autosomal dominant Alzheimer's disease. These relationships are observed earlier in life than in sporadic AD, suggesting that LC integrity is not merely age‐related but can be an early indicator of disease progression. [ABSTRACT FROM AUTHOR]

Background: The long‐term impact of COVID‐19 on global health is still unknown. Sensorimotor biomarkers may be promising indicators of lasting effects of COVID‐19. Although normal aging may cause changes in sensorimotor function, more severe changes may indicate the subsequent impacts of COVID‐19 on brain health. The objective of this study was to investigate the association between COVID‐19 and sensorimotor markers (grip strength, gait, and smell) in the 7T neuroCOVID consortium, which is comprised of 5 sites: The University of Texas Health Science Center at San Antonio, Houston Methodist Research Institute, The University of Pittsburgh, Massachusetts General Hospital, and Nottingham University (UK). Methods: We studied 101 adult participants (mean age 60.9 ± 8.5 years, range 45‐80 years, 51% women) without prior cognitive impairment or cerebrovascular disease from the 7T consortium across 3 US and 1 UK sites. The sample included 77 COVID‐19 survivors and 24 healthy controls. Sensorimotor markers were measured for olfaction (n = 59; 12‐item Brief Smell Identification Test (B‐SIT)), grip strength (n = 97; measured using a hand dynamometer), and Gait (n = 101; 4‐meter normal walk time and n = 99; 4‐meter fast‐paced walk time). To assess the association between COVID‐19 and sensorimotor outcomes, we performed a series of linear regression models adjusting for age, sex, site, and handedness (grip strength only). Statistical significance was set at a 5% level. Results: As compared to healthy controls, COVID‐19 survivors, on average had a significantly reduced hand grip in the right hand (β ± standard error: ‐0.18 ± 0.07, p = 0.006). We also observed associations with reduced gait speed. COVID‐19 survivors, on average, had a slower walk time in both normal (0.17 ± 0.06, p = 0.004) and fast‐paced (0.04 ± 0.02, p = 0.022) as compared to healthy controls. We did not observe any statistical associations between COVID‐19 survivors and left‐hand grip strength or B‐SIT. Conclusions: These results highlight that Covid‐19 infection may have a detrimental impact on sensorimotor function. Additional analysis with a larger sample size are ongoing, which will allow us to further assess the effect of infection severity. Future studies will look to evaluate the association between sensorimotor markers, cognition, and ultra‐high field 7T MRI‐based imaging markers. Funding: R56AG074467 P30AG066546 [ABSTRACT FROM AUTHOR]

Background: The brainstem locus coeruleus (LC) constitutes the primary source of norepinephrine (NE) in the central nervous system and has been reported as one of the earliest accumulation sites of hyperphosphorylated tau protein in Alzheimer's disease (AD). Autopsy and animal studies suggested that this aggregation of hyperphosphorylated tau in the LC is associated with hyperactivity in LC neurons and elevated concentrations of NE metabolites. Here, we investigated whether elevated concentrations of 3‐methoxy‐4‐hydrophenylglycol (MHPG), a NE metabolite measured in the plasma, is associated with plasma phosphorylated tau, a biomarker of AD pathology. Method: Ninety‐eight cognitively unimpaired participants (age = 59.82 ± 13.13 [30‐84] y, 52 females, Table 1) underwent a blood draw. Plasma MHPG concentrations were measured and adjusted for NE. Levels of total tau, phosphorylated tau at threonine 181 (pTau181) and threonine 231 (pTau231) were quantified by single molecule array (Simoa), while phosphorylated tau at threonine 217 (pTau217) was quantified by the Meso Scale Discovery (MSD) platform. Multiple linear regression models tested for the relationship between MHPG concentrations and plasma levels of tau‐related measures, while controlling for age and sex. Result: PTau231 and MHPG concentrations were positively correlated (t = 2.26, p =.03, Figure 1). No significant relationships were found between MHPG and other phosphorylated tau biomarkers (all p >.23), but we observed a trend for a positive association with plasma total tau levels (t = 1.88, p =.06). Conclusion: Consistent with previous CSF studies as well as animal studies, we found that elevated NE metabolism co‐occurs with the earliest events in the phosphorylation cascade of tau proteins, suggesting an important role of a dysregulated NE system early in the AD pathophysiologic cascade. Future work will need to determine the evolution of theses associations as the disease progresses, potential effect modifications by beta‐amyloid and the downstream effects of these processes on cognition and behavior. [ABSTRACT FROM AUTHOR]

Background: Globally, over six hundred million cases of SARS‐CoV‐2 have been confirmed. As the number of individuals in recovery rises, examining long‐term neurological effects, including cognitive impairment and cerebral microstructural and microvascular changes, has become paramount., We present preliminary cognitive findings from an ongoing multi‐site study investigating the long‐term neurological impacts of COVID‐19 using 7 Tesla MRI‐based neuroimaging. Methods: Across 3 US and 1 UK sites, we identified adult (> = 18) COVID‐19 survivors (CS) and healthy controls (HC) without significant pre‐existing medical, neurological, or psychiatric illness. Using the National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS‐3) battery and Norms Calculator, 12 cognitive scores were adjusted for age, sex, and education and classified as either unimpaired or mild (<9th percentile), moderate (<2nd percentile), or severely impaired (<1st percentile). The observed frequency of impairment across the two groups is reported along with proportional differences (PD) and confidence intervals (CI). Illness severity and time since infection were evaluated as potential associates of cognitive impairment. Results: Over a period of 11 months, we enrolled 108 participants. At the time of reporting, 80 (46.3% female; mean age: 60.3 ± 8.6; 61 CS, 19 HC) had completed cognitive assessments. Of the participants for whom we ascertained time since symptom onset and illness severity (n = 51 and 43, respectively), 31.4% had their index COVID‐19 infection within the past year, and 60.5% had a severe to critical infection (Table 1). Table 2 reports observed frequency of impairment for each metric. Aggregating all 12 cognitive metrics, we found 45 (73.8%) of CS had at least one impairment [vs HC: 10 (52.6%)]. A significantly greater proportion of CS had at least one moderate to severe or severe impairment (Figure 1). CS also had significantly higher frequencies of presenting with two or more mild to severe impairments [PD 0.33 (0.13, 0.54)]. Illness severity and time since infection were not significantly associated with cognitive impairment. Conclusion: Our preliminary results are consistent with potentially sustained COVID‐associated cognitive impairment in a subset of participants. Enrollment in the multi‐site cohort is ongoing, and updated results will be presented along with ultra‐high field MRI‐based neuroimaging correlates. [ABSTRACT FROM AUTHOR]

Background: The SARS‐CoV‐2 coronavirus has been associated with structural brain changes, consistent with its neurological manifestations. Recent studies showed a specific predilection for brainstem glial activation and hypometabolism, possibly indicating involvement of the locus coeruleus. The locus coeruleus (LC) modulates many cognitive functions and behaviors and its norepinephrine projections regulate both immune responses and vascular reactivity. We aimed to examine differences in LC integrity between COVID‐19 survivors and controls. Method: Participants are enrolled across 3 US and 1 UK sites using harmonized cognitive and 7T MR‐imaging protocols. Here, we analyzed data from 18 participants enrolled at Houston Methodist (12 COVID‐19 survivors, 6 controls; Figure 1). COVID‐19 survivors were required to have had a positive antigen test and an illness syndrome consistent with COVID‐19. Healthy controls were required to have no significant pre‐existing medical, neurologic, or psychiatric illness and no illness requiring hospitalization in the last 2 years. LC imaging was performed using a dedicated 7T MT‐TFL sequence (0.4×0.4×0.5mm). A site‐specific normalized template was constructed using ANTs/FSL. The entire average LC integrity as well as voxel‐wise integrity values were compared between COVID‐19 survivors and controls using a robust linear regression (age‐controlled and threshold free cluster enhancement corrected). LC integrity was correlated with age, sex, ethnicity and cognition using Spearman's rank correlation. Result: Average LC integrity was not correlated with age, sex, or Hispanic ethnicity (p>0.3). COVID‐19 survivors did not differ from Controls when examining the entire LC (p = 0.54). Voxel‐wise analyses revealed a small cluster (19 voxels) in the middle portion of the left LC where COVID‐19 survivors exhibited lower LC integrity than controls (p = 0.005; Figure 2). Integrity of this cluster was not related to age or Hispanic ethnicity (p = 0.9). LC integrity did not correlate with cognitive performance within the COVID‐19 survivors (Trail Making Test B: p = 0.43; Craft Story delayed recall p = 0.47; MoCA p = 0.84). Conclusion: Consistent with previous animal and human studies, our initial findings provide evidence for neuroinvasive potential of SARS‐CoV‐2 localized in the middle LC. In the future, we aim to expand our sample and link these observations to the neurocognitive sequelae of COVID‐19. [ABSTRACT FROM AUTHOR]

Background: Network hyperexcitability has emerged as an important contributor to cognitive dysfunction and clinical progression in Alzheimer's disease (AD), with work in animal AD models supporting a mechanistic, feed‐forward link between neuronal hyperexcitability and amyloid and tau pathology. Seizures are a quintessential manifestation of network hyperexcitability in AD. AD is associated with a 2‐3‐fold increased risk of developing epilepsy, and epilepsy in AD is most often a focal, unilateral temporal lobe epilepsy. We hypothesized that if network hyperexcitability is mechanistically linked to AD pathology, then focal unitemporal hyperexcitability in individuals with AD and epilepsy would be associated with increased deposition of tau and/or amyloid within the epileptogenic hemisphere. Method: We studied eight individuals with early clinical stages of AD who developed focal epilepsy early in the course of AD. All individuals underwent overnight scalp EEG, 3T structural brain MRI, and PET imaging with 11C‐PiB and 18F‐MK‐6240. We performed region‐of‐interest based imaging analyses and calculated asymmetry indices (AI) as: 200 * (Ipsilateral ‐ Contralateral) / (Ipsilateral + Contralateral), where ipsilateral and contralateral are relative to the epileptogenic hemisphere. Result: Tau deposition was asymmetrically increased within the epileptogenic hemisphere. Individuals with a higher global tau burden showed asymmetrically increased tau in the lateral temporal lobe, medial and lateral parietal lobes, and frontal lobes of the epileptogenic hemisphere, while those with a lower global tau burden demonstrated a highly focal, discrete tau accumulation within the lateral temporal lobe. Amyloid deposition was also increased within the epileptogenic hemisphere, particularly in the lateral temporal, medial and lateral parietal, and frontal regions, though the magnitude of amyloid AI was lower than that of tau AI. We also found increased cortical atrophy in the lateral temporal and lateral parietal regions of the epileptogenic hemisphere. Conclusion: Our study reveals a spatial association between focal epilepsy and asymmetries in tau and amyloid deposition and cortical atrophy in early clinical stages of AD. While historically, individuals with AD and epilepsy have been excluded from most studies in AD, our findings demonstrate that studying these individuals can provide unique insights on mechanisms that underlie the clinical and pathologic heterogeneity of AD. [ABSTRACT FROM AUTHOR]

Background: Clinically normal older females exhibit higher cross‐sectional 18F‐Flortaucipir (FTP)‐PET signal, but not Aβ‐PET, than males, particularly in temporal regions. What remains unclear is the extent to which these findings represent a real biological phenomenon as opposed to a methodological bias. Here, we explored sex differences in longitudinal tau accumulation, and how contemporaneous rates of FTP‐PET, Aβ‐PET and cognitive change may be modified by sex. Method: We examined 128 clinically‐normal participants from the Harvard Aging Brain Study (HABS; 60% Female, Age=75(6.6)years) with at least two time‐points of contemporaneous FTP‐PET, PiB‐PET and cognition. Also, 153 ADNI participants with at least two time‐points of FTP‐PET (nCN=94/nMCI=59; 50% Female, Age=73(6.4)years), and with prospective longitudinal AV45‐PET and cognition (n=131). Mean follow up was 3.3yrs (range=1.2‐6.2yrs) and 1.4yrs (range=0.6‐3.3yrs), respectively. For FTP‐PET we exclusively examined the inferior temporal lobe (non‐partial volume corrected, cerebellar greyreference), for Aβ‐PET we used the PiB summary measure in HABS (cerebellar greyreference) and the AV‐45 summary measure in ADNI (whole cerebellumreference). For cognition, we used the Preclinical Alzheimer Cognitive Composite (PACC). We examined relationships between contemporaneous longitudinal FTP‐PET, Aβ‐PET, and cognitive performance using linear mixed models, adjusting for age, years of education and random intercept. Result: In HABS, females exhibited faster rates of FTP‐PET accumulation than males, but only with increasing rates of Aβ‐PET accumulation (t=1.93, p=0.003; see Figure 1A). In ADNI, females exhibited faster rates of FTP‐PET accumulation, not moderated by Aβ‐PETchange (t=2.92, p=0.004; see Figure 1B). Sex did not moderate the relationship between FTP‐PET and PACC change in HABS or ADNI (see Figure 2.). We did, however, find that females with higher baseline FTP‐PET resulted in faster PACC decline than men in only clinically‐normal individuals in both cohorts (t=‐1.86ADNI,‐2.72HABS, p∼0.02; see Figure 3.). Conclusion: These findings support a female susceptibility to tau as a biological phenomenon of accelerated tau accumulation in AD‐vulnerable regions. A lack of an association between changing tau and changing cognition remains to be understood. It is possible that our models are picking up more on the 'severity of burden' (e.g. baseline tau) to influence faster rates of decline in females, rather than dynamic change per se. [ABSTRACT FROM AUTHOR]

Background: Hippocampal atrophy is observed in Alzheimer's disease (AD), but also in older adults with no evidence of amyloid‐β (Aβ) plaques. To understand the pathophysiology of hippocampal volume (HV) loss, we investigated the associations between longitudinal HV, age, genotype, Aβ, and tau in clinically normal (CN) participants from the Harvard Aging Brain Study. Method: Serial MRI (HV [1.3‐7.0y], PiB‐PET (Aβ, [1.9‐8.5y]), and Flortaucipir‐PET (tau, [0.8‐6.0y]) measures were obtained from 128CN participants (72 [56%] females, 38 [30%] e4 carriers, median age at baseline: 71.3, follow‐up duration: 5.1y). Participants had a median of 3MRIs [2‐5], 3PiB‐PET [2‐5], and 2Flortaucipir‐PET [2‐4]. Longitudinal HVs were processed using Freesurfer v.6 and adjusted for intracranial volume. PiB was measured in a neocortical aggregate, Flortaucipir in inferior temporal (IT) and entorhinal cortex (EC). PET data were expressed as PVC‐SUVr scaled to subcortical white matter. We predicted imaging data over time with random intercept and slope in linear mixed‐models and extracted PiB, FTP, and HV slopes for each subject. Baseline PET and slope data were entered in age‐adjusted linear regressions to evaluate their associations with HV slope. Result: Faster HV loss was observed at older ages (Figure 1), and marginally in e4 carriers (Table, #1‐2). It was also associated with higher baseline PiB levels (#3). The PiB association was stronger than the one of e4 status (#3). HV slope did not correlate with PiB slope (#4). HV loss was associated with baseline EC‐FTP (#5) and baseline IT‐FTP (#6). The association between HV loss and EC‐FTP was also observed in the low‐PiB only (#7), but not the one with IT‐FTP (#8). IT‐FTP, but not EC‐FTP, interacted with baseline PiB to predict HV slope (Figure 2‐3). FTP slopes measures were associated with HV slope, above and beyond the baseline association (#9‐10). Altogether PET data explained 40% of the variance in HV slope; but faster HV loss was still associated with age after taking PET measures into account. Conclusion: In preclinical AD, hippocampal atrophy is associated with an Aβ‐independent entorhinal tau accumulation and an Aβ‐dependent neocortical tau accumulation. It is also likely associated with pathological processes that our biomarkers did not measure. [ABSTRACT FROM AUTHOR]

Background: Tauopathy can be detected in the locus coeruleus (LC) decades before clinical symptoms or Aβ‐pathology. Following involvement of the LC, tau progresses to the medial temporal lobe (MTL), possibly via hyperactivity or connectivity. Given LC's modulating role on brain function and its early involvement in proteinopathies that affect LC's interaction with other brain regions, it is conceivable that individual variability in LC functional connectivity (FC) with the MTL will be related to Alzheimer's disease (AD)‐related cognitive functioning. The LC plays an important role in novelty processing, learning and memory. Therefore, we aimed to examine whether LC‐MTL FC during novelty predicts Aβ‐related cognitive decline. Method: All participants (N = 153; number of observations = 772; Figures 1,2) were clinically normal and part of the Harvard Aging Brain Study. Baseline PiB‐PET (cut‐off = 1.324 DVR), 3T‐fMRI data on a face‐name encoding task and longitudinal neuropsychological PACC5 data were obtained. The fMRI‐task instructed participants to remember face‐name pairs and stimuli consisted of novel and repeated faces. A dilated ex‐vivo validated LC‐template was registered to each individual using ANTs. SPM and ICA‐AROMA were used for motion and physiological artefact removal. An FDR‐corrected gPPI‐analysis (with age, sex, education covariates) established five regressors: novelty; repetition; LC BOLD‐activity; novelty x LC BOLD‐activity; repetition x LC BOLD‐activity. A linear contrast was created by subtracting the repetition interaction regressor from the novelty interaction regressor. LME models assessed whether the association between PACC5 and FC was dependent on PiB (linearly and quadratic), while correcting for age, sex, education and their interactions with time. Bonferroni correction was applied. Result: The gPPI‐analysis demonstrated negative LC‐MTL FC during novelty versus repetition for every region of interest (p‐FDR<0.05; Figure 3), thereby indicating hypoconnectivity. The LME‐analysis revealed that hypoconnectivity of the LC‐Parahippocampal Gyrus predicted worse PACC5 performance, which accelerated at elevated PiB levels (p = 0.013; f = 0.11; Bonferroni‐adjusted; Figure 4). Similar results were apparent for LC‐hippocampus and LC‐amygdala FC. Conclusion: This study demonstrates that the LC is less functionally connected with the MTL during novelty, and that this hypoconnectivity predicts Aβ‐related cognitive decline. This suggests that LC‐MTL hypoconnectivity might act as a marker of AD‐related processes. Future work will assess the relationship between LC FC and tau pathology. [ABSTRACT FROM AUTHOR]

Background: Autopsy studies report that the locus coeruleus (LC) is the first site to accumulate tau, after which it spreads topographically to the entorhinal cortex (EC) and limbic regions. Once tau has reached the cortex, its spread is assumed to occur via connectivity and to be facilitated by Aβ. We aimed to examine whether lower LC integrity is related to tau accumulation in the EC, followed by spreading of tau to cingulate regions. In addition, we examined whether Aβ facilitates tau accumulation beyond these initial regions. Method: One‐hundred‐and‐five individuals (Figure 1) from the Harvard Aging Brain Study underwent 3T‐MRI (including LC imaging),Aβ and tau‐PET imaging and neuropsychological assessments. Assessments up to 8 years prior to LC‐imaging were included (median:5.02 years). LC intensity (normalized to pontine tegmentum) was regressed onto each vertex of the cortical mantle of the PET data. Robust regressions and mediation analyses related LC intensity to tau, Aβ and cognition (composites and subtests). LME models examined interactions between LC intensity and Aβ on cognitive changes. Covariates were age, sex and education. Results were compared to LME models of tau spread via connectivity in a previously examined extended sample (n=252). Result: LC intensity was associated with medial and lateral temporal tau (peak:EC (t=4.69)). These associations became more widespread with increasing Aβ (Figure 2). This is consistent with results in the extended sample showing that spread from the EC to the posterior cingulate cortex via structural connections was greater in individuals with elevated Aβ (Figure 3). LC intensity was specifically positively associated with cross‐sectional memory (p=0.024) (Figure 4A‐B) and this was mediated by entorhinal tau (mediation: p=0.007, Figure 4C‐D). Finally, lower LC intensity predicted Aβ‐associated retrospective memory decline (Figure 5, p=0.0009). In the extended sample, lower connectivity and higher downstream‐connected tau accrual was associated with greater prospective memory decline in elevated Aβ persons (Figure 3). Conclusion: LC intensity measures are associated with initial cortical Alzheimer's disease (AD) pathology. Elevated Aβ facilitates tau spread to regions outside the medial temporal lobe and accelerates AD‐related cognitive decline. These results mimic autopsy findings of the anatomy of tau spreading and can advance early detection. [ABSTRACT FROM AUTHOR]

Background: In Alzheimer’s disease, cognitive decline is associated with a rapid increase in tau pathology, making tau‐PET a potentially useful outcome in prevention trials. To identify individuals most at‐risk of tau accumulation, we investigated the longitudinal associations between amyloid and tau in clinically normal (CN) and impaired (MCI/AD) participants from the Harvard Aging Brain Study. Method: Serial Flortaucipir tau‐PET measures (2‐4 observations over a median 2.2years [0.8 to 6.0]) were obtained from 128CN and 11MCI/AD participants (Table 1). PiB (amyloid‐PET) data were expressed as Centiloid (CL) values. Flortaucipir data were expressed as PVC‐SUVr in inferior temporal neocortex scaled to subcortical white matter. We obtained tau slopes per subject from linear mixed‐effect models with random intercept and slopes. We tested in the entire sample, and in CN only, the association between Tau slope and baseline PiB and Tau‐PET. Linear, quadratic, and cubic relationships were tested. Age and sex were used as covariates. We computed power curves simulating therapeutic trials. Result: In the entire sample (n=139), both baseline Tau (R2=0.34, Fig. 1 red‐line) and PiB (R2=0.30, Fig. 2 red‐line) were linearly associated with subsequent tau slope. In CN (n=128), these associations were lower than in MCI/AD, but significant (Tau: R2=0.16, PiB: R2=0.15, p≤0.00001). Importantly, a cubic fit best matched the PiB data (Fig. 2 blue‐line): A positive association between baseline PiB and Tau changes was only observed between PiB CL=‐2 and CL=66, with a maximal association at CL=32. In CN, the greatest tau changes were observed at CL=66. There was evidence of slowing in tau accumulation rate in the small number of CN with higher PiB CL. As a result, trials simulations demonstrated that increasing the Centiloid threshold to enroll CN participants did not increase power (Fig. 3 blue‐lines); in contrast, power was increased when excluding CN with CL>66 (Fig. 3 red‐line) or when enrolling CN with high baseline tau (Fig. 4 red‐lines). Enrolling MCI patients in therapeutic trials had a similar effect than enrolling high‐amyloid CN participants with baseline Tau SUVr>1.30 (Fig. 4 blue‐line). Conclusion: A combination of amyloid and tau thresholds proved more effective to increase the power of Tau‐PET outcomes in prevention trials than using only amyloid. [ABSTRACT FROM AUTHOR]

Background: The Framingham Heart Study (FHS), a three‐generation community‐based cohort studying cardiovascular disease across the adult lifespan, has expanded to include positron emission tomography (PET) of beta‐amyloid (Aβ) and tau. Our aim is to characterize these pathologies in this unique sample and utilize the wide age range to assess the spatiotemporal ordering of emerging Aβ and tau. Method: 211 clinically‐normal adults aged 33‐74 from FHS underwent Pittsburgh Compound B (PIB) and Flortaucipir (FTP) PET. PIB and FTP were regionally quantified in Desikan regions using distribution volume ratio (DVR) for PIB and standardized uptake volume ratio (SUVR) for FTP. Three approaches were used to identify early accumulating regions: 1. A series of Age*APOE linear models to identify regions accumulating earlier in the lifespan in ε4 carriers. 2. Identification of early regions as those more frequently elevated as previously used in older adults, with Gaussian mixture models (GMM) conducted to evaluate bimodality and set biomarker positivity thresholds for each region. 3. Applied the same frequency approach using well‐validated PIB GMM thresholds based on older adults from the Harvard Aging Brain Study (HABS). Result: For PIB, significant Age*APOE interactions (Fig. 1) were seen across multiple regions previously implicated as early‐accumulating based on elevation frequencies from older adult samples, as well as the pars opercularis (p=0.005) and lateral parietal cortices (p<0.04). PIB was significantly bimodal across all ROIs (LRT>36.1, p<0.001; Fig. 1). Application of GMM‐based regional positivity frequencies derived within FHS versus from HABS thresholds led to substantial discrepancies in the spatiotemporal ordering of PIB (rs=0.30, p=0.17). Age*APOE effects were not detected for any tau regions, but inferior temporal (IT), middle temporal (MT), and amygdala (AM) increased with age (Fig. 2). Higher global Aβ was also associated with higher FTP SUVR in IT, MT, and a trend for AM, as well as inferior parietal and precuneus (Fig. 2). Conclusion: Aβ and tau mainly follow spatiotemporal patterns consistent with prior evidence in older adult samples. GMM‐based methods used in older adult samples to dichotomize biomarker positivity may be suboptimal in younger samples. Continuous approaches may better capture early Aβ and tau in younger populations. [ABSTRACT FROM AUTHOR]

Background: AD clinical trials are increasingly looking towards intervention at the earliest stage of preclinical AD, when beta‐amyloid (Aβ) is emerging and tau pathology remains restricted to the MTL. While some evidence suggests subtle cognitive changes start at this early stage, it is unclear what cognitive measures may be most sensitive to emerging pathology and whether they reflect Aβ, tau or both. Method: 143 clinically‐normal adults with longitudinal PIB‐PET, FTP‐PET and cognitive data (median follow‐up: 7.68(1.17) years) were included from the Harvard Aging Brain Study (HABS). Analyses focused first on those initially PIB‐ (

Background: Women’s Health Initiative Memory Study (WHIMS) findings suggest that hormone therapy increases risk of dementia. Conversely, evidence from the Kronos Early Estrogen Prevention Study (KEEPS) implicates estrogen hormone therapy (HT) as protective against ß‐amyloid (Aß) burden. We sought to explore if self‐reported HT use is associated with rates of Aß accumulation in an observational sample of clinically‐unimpaired older adults. Method: 134 participants (Age=73yrs±5.8) underwent at least three timepoints of Pittsburgh compound‐B (PiB)‐PET scans over an average of 9.7 years. Longitudinal PiB‐PET was examined as aggregate neocortical DVR (composite reference region: whole cerebellum + eroded white matter). Concurrent with baseline PiB‐PET, female participants self‐reported if they ever took HT. Participants were thus identified as: females who never used HT (HT‐:n=36), females who have ever taken HT to any extent (HT+:n=42), and males (M:n=56). We examined the relationship between these three groups and longitudinal PiB‐PET using linear mixed models, adjusting for baseline age, and with random slopes and intercepts. Post‐hoc analyses adjusted for APOEε4 status and examined interactions between HT and baseline PiB‐PET on change in PiB‐PET from baseline. Result: While we found no significant sex (male/female) difference in PiB‐PET accumulation (t=1.5,p>0.05,Fig 1A), we observed significant HT group differences with HT‐ exhibiting approximately half the PiB‐PET rate of change than M (t=2.3,p=0.02) and HT+ (t=1.8,p=0.07; Fig 1B). There was no significant slope difference between M and HT+ (t=0.32,p=0.75). These differences survived after covarying for APOEε4. A three‐way interaction with baseline PiB‐PET revealed a greater slope difference between HT‐ and M (t=2.1,p=0.04) in those with higher baseline PiB‐PET relative to lower baseline PiB‐PET (Fig 2). Conclusion: HT‐ showed significantly slower rates of Aß accumulation than males and a trend‐level slower rate compared to HT+; these differences appear heightened with greater baseline Aß burden. With similar ages across HT groups (p=0.20), these differences did not appear to be a function of chronological age. It remains unclear whether the introduction of estrogen, a mediating commonality, or collider bias is driving these results. Our findings, in conjunction with other studies, suggest the relationship between HT and Aß is complicated and necessitates examination of HT type and duration. [ABSTRACT FROM AUTHOR]

Background: Cognitively‐normal (CN) older women exhibit elevated tau‐PET signal in medial temporal and neocortical regions compared with men. The effect of menopause on tau deposition remains unclear. We explored menopausal status as a moderator of sex differences in tau deposition in middle‐aged adults. Method: 273 CN (Age=55yrs(±8), Female(n)=134, Post‐menopausal(n)=70) from the Framingham Study 3rd generation cohort underwent 18F‐Flortaucipir (FTP)‐PET and/or 11C‐Pittsburgh Compound‐B (PiB)‐PET scans. We examined FTP‐PET signal in four a priori regions that demonstrate large sex differences in CN older adults (entorhinal, rostral middle frontal, inferior parietal and lateral occipital). FTP‐PET and global PiB‐PET signal were referenced to cerebellar grey. Linear regression examined sex differences in each ROI, adjusting for age and PET camera. Separate models examined menopausal status (post‐menopause/pre‐menopause females), menopausal age (≤|>50 years), and interactions with APOEε4. Sensitivity analyses included age‐matched males ('pseudo‐premenopausal'/'pseudo‐menopausal') against the menopause groups to account for confounds with chronological age. Result: Middle‐aged females exhibited higher FTP‐PET signal in the inferior parietal, rostral middle frontal and lateral occipital regions than males by ∼0.04SUVr (p<0.009; Fig. 1). No sex or menopause differences were evident in PiB‐PET. Post‐menopausal females exhibited higher FTP‐PET signal in the lateral occipital lobe than pre‐menopausal (p=0.05; Fig. 2). Menopause age≤50 years corresponded with higher lateral occipital and rostral middle frontal FTP‐PET signal than >50years (p<0.05; Fig. 2). Post‐menopausal females maintained higher signal in lateral occipital, inferior parietal and rostral middle frontal regions compared with even age‐matched 'pseudo‐menopausal' males (Table 1). Finally, a significant menopause*APOEε4 interaction suggested that the menopause effect was only evident in APOEε4 non‐carriers, localized to the parietal lobe (p∼0.03; Fig. 3). Conclusion: Sex differences in tauopathy are apparent in CN individuals approximately 20 years earlier than previously demonstrated. Our findings suggest that sex differences are exacerbated by menopause, particularly when the age‐at‐menopause is below 50 years. Chronological age did not appear to confound the results, as age‐matched males exhibited significantly lower tau signal. Finally, the effect of APOEε4 carriership may ameliorate menopause effects; only pre‐menopausal APOEε4 non‐carriers appeared to exhibit protective effects of circulating estradiol relative to post‐menopausal non‐carriers. Future work will need to identify direct hormonal contributions, the impact of surgery and hormone‐therapy. [ABSTRACT FROM AUTHOR]

Background: Clinically normal females exhibit greater [18]F‐flortaucipir (FTP) PET signal than males in both temporal and neocortices. It remains unclear whether sex differences in neocortical regions are primarily explained by technical variability issues. We aimed to investigate the contribution of signal spillover/off‐target skull binding to sex differences in FTP‐PET. Next, we explored partial volume effects (PVE) by simulating sex differences in smoothed FTP‐PET signal. Discerning sex differences in tau signal versus noise is pivotal to understanding sex differences in the pathology of Alzheimer's disease and associated tauopathies. Method: 343 clinically normal (female=58%; mean[SD]=73.8[8.5] years) (female=38%; mean[SD]=76.9[7.3] years) participants from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative underwent cross‐sectional FTP‐PET (standardized uptake value ratios [SUVrs]). For skull analyses, we created skull ROIs based on signal 12mm from the outer perimeter of voxels in FreeSurfer‐defined tau ROIs. Linear regression models estimated the main effects of sex across cortical tau ROIs while correcting for local skull binding. We simulated PVE by convolving group‐level SUVr means in each ROI with 6mm Gaussian kernels, and then compared the sexes with linear regression models post‐smoothing. Result: Widespread sex differences in skull binding were observed (Table 1). Covarying for skull binding ameliorated weaker sex differences in cortical FTP signal but did not impact the largest effects. Sex differences in PVE were observed in both female and male directions; no clear sex‐related biases in PVE were found to impact cortical tau sex differences except for the rostral middle frontal region (Figure 1). Conclusion: Our findings suggest that sex differences in FTP‐PET are not solely attributed to skull 'clouding' or PVE, but rather support hypotheses of female‐related tau vulnerability. Nevertheless, as only two potential confounds were investigated, and gross morphology/volumetric issues remain a key concern, further investigation is needed to fully elucidate this phenomenon. Investigations of sex differences in longitudinal tau accumulation (a few preliminary reports already suggest faster rates in females) will add further support to the argument that noise properties inherent in FTP‐PET do not significantly contribute to sex differences in cortical tau signal. [ABSTRACT FROM AUTHOR]