Florbetaben amyloid PET acquisition time: Influence on Centiloids and interpretation.

INTRODUCTION: Amyloid positron emission tomography (PET) acquisition timing impacts quantification. METHODS: In florbetaben (FBB) PET scans of 245 adults with and without cognitive impairment, we investigated the impact of post-injection acquisition time on Centiloids (CLs) across five reference regions. CL equations for FBB were derived using standard methods, using FBB data collected between 90 and 110 min with paired Pittsburgh compound B data. Linear mixed models and t-tests evaluated the impact of acquisition time on CL increases. RESULTS: CL values increased significantly over the scan using the whole cerebellum, cerebellar gray matter, and brainstem as reference regions, particularly in amyloid-positive individuals. In contrast, CLs based on white matter-containing reference regions decreased across the scan. DISCUSSION: The quantification of CLs in FBB PET imaging is influenced by both the overall scan acquisition time and the choice of reference region. Standardized acquisition protocols or the application of acquisition time-specific CL equations should be implemented in clinical protocols. HIGHLIGHTS: Acquisition timing affects florbetaben positron emission tomography (PET) scan quantification, especially in amyloid-positive participants. The impact of acquisition timing on quantification varies across common reference regions. Consistent acquisitions and/or appropriate post-injection adjustments are needed to ensure comparability of PET data.

Associations Between Glucose Metabolism Measures and Amyloid-ß and Tau Load on PET 14 Years Later: Findings From the Framingham Heart Study.

OBJECTIVE: Type 2 diabetes and glucose metabolism have previously been linked to Alzheimer disease (AD). Yet, findings on the relation of glucose metabolism with amyloid-ß and tau pathology later in life remain unclear. RESEARCH DESIGN AND METHODS: We included 288 participants (mean age 43.1 years, SD 10.7, range 20-70 years) without dementia, from the Framingham Heart Study, who had available measures of glucose metabolism (i.e., one-time fasting plasma glucose and insulin) and positron emission tomography (PET) measures of amyloid-ß and/or tau 14 years later. We performed linear regression analyses to test associations of plasma glucose (continuously and categorically; elevated defined as >100 mg/dL), plasma insulin, homeostatic model assessment for insulin resistance (HOMA-IR) with amyloid-ß or tau load on PET. When significant, we explored whether age, sex, and APOE ε4 allele carriership (AD genetic risk) modified these associations. RESULTS: Our findings indicated that elevated plasma glucose was associated with greater tau load 14 years later (B [95% CI] = 0.03 [0.01-0.05], P = 0.024 after false discovery rate [FDR] correction) but not amyloid-ß. APOE ε4 carriership modified this association (B [95% CI] = -0.08 [-0.12 to -0.03], P = 0.001), indicating that the association was only present in APOE ε4 noncarriers (n = 225). Plasma insulin and HOMA-IR were not associated with amyloid-ß or tau load 14 years later after FDR correction. CONCLUSIONS: Our findings suggest that glucose metabolism is associated with increased future tau but not amyloid-ß load. This provides relevant knowledge for prevention strategies and prognostics to improve health care.

Identifying longitudinal cognitive resilience from cross-sectional amyloid, tau, and neurodegeneration.

BACKGROUND: Leveraging Alzheimer's disease (AD) imaging biomarkers and longitudinal cognitive data may allow us to establish evidence of cognitive resilience (CR) to AD pathology in-vivo. Here, we applied latent class mixture modeling, adjusting for sex, baseline age, and neuroimaging biomarkers of amyloid, tau and neurodegeneration, to a sample of cognitively unimpaired older adults to identify longitudinal trajectories of CR. METHODS: We identified 200 Harvard Aging Brain Study (HABS) participants (mean age = 71.89 years, SD = 9.41 years, 59% women) who were cognitively unimpaired at baseline with 2 or more timepoints of cognitive assessment following a single amyloid-PET, tau-PET and structural MRI. We examined latent class mixture models with longitudinal cognition as the dependent variable and time from baseline, baseline age, sex, neocortical Aß, entorhinal tau, and adjusted hippocampal volume as independent variables. We then examined group differences in CR-related factors across the identified subgroups from a favored model. Finally, we applied our favored model to a dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 160, mean age = 73.9 years, SD = 7.6 years, 60% women). RESULTS: The favored model identified 3 latent subgroups, which we labelled as Normal (71% of HABS sample), Resilient (22.5%) and Declining (6.5%) subgroups. The Resilient subgroup exhibited higher baseline cognitive performance and a stable cognitive slope. They were differentiated from other groups by higher levels of verbal intelligence and past cognitive activity. In ADNI, this model identified a larger Normal subgroup (88.1%), a smaller Resilient subgroup (6.3%) and a Declining group (5.6%) with a lower cognitive baseline. CONCLUSION: These findings demonstrate the value of data-driven approaches to identify longitudinal CR groups in preclinical AD. With such an approach, we identified a CR subgroup who reflected expected characteristics based on previous literature, higher levels of verbal intelligence and past cognitive activity.

Medial Amygdalar Tau Is Associated With Mood Symptoms in Preclinical Alzheimer's Disease.

BACKGROUND: While the amygdala receives early tau deposition in Alzheimer's disease (AD) and is involved in social and emotional processing, the relationship between amygdalar tau and early neuropsychiatric symptoms in AD is unknown. We sought to determine whether focal tau binding in the amygdala and abnormal amygdalar connectivity were detectable in a preclinical AD cohort and identify relationships between these and self-reported mood symptoms. METHODS: We examined 598 individuals (347 amyloid positive [58% female], 251 amyloid negative [62% female] subset in tau positron emission tomography and functional magnetic resonance imaging cohorts) from the A4 (Anti-Amyloid Treatment in Asymptomatic AD) Study. In the tau positron emission tomography cohort, we used amygdalar segmentations to examine representative nuclei from 3 functional divisions of the amygdala. We analyzed between-group differences in division-specific tau binding in the amygdala in preclinical AD. We conducted seed-based functional connectivity analyses from each division in the functional magnetic resonance imaging cohort. Finally, we conducted exploratory post hoc correlation analyses between neuroimaging biomarkers of interest and anxiety and depression scores. RESULTS: Amyloid-positive individuals demonstrated increased tau binding in the medial and lateral amygdala, and tau binding in these regions was associated with mood symptoms. Across amygdalar divisions, amyloid-positive individuals had relatively higher regional connectivity from the amygdala to other temporal regions, the insula, and the orbitofrontal cortex, but medial amygdala to retrosplenial cortex connectivity was lower. Medial amygdala to retrosplenial connectivity was negatively associated with anxiety symptoms, as was retrosplenial tau. CONCLUSIONS: Our findings suggest that preclinical tau deposition in the amygdala and associated changes in functional connectivity may be related to early mood symptoms in AD.

Parental History of Memory Impairment and ß-Amyloid in Cognitively Unimpaired Older Adults.

Importance: Studies have suggested that maternal history of late-onset Alzheimer disease, but not paternal, predisposes individuals to higher brain ß-amyloid (Aß) burden, reduced brain metabolism, and lower gray matter volumes. Objective: To characterize maternal vs paternal history of memory impairment in terms of brain Aß-positron emission tomography (Aß-PET) and baseline cognition among a large sample of cognitively unimpaired older adults. Design, Setting, and Participants: This cross-sectional study leveraged data from 4413 individuals who were screened for the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study, a randomized clinical trial conducted across 67 sites in the US, Australia, Canada, and Japan aimed at Alzheimer disease prevention. Data were collected between April 2014 and December 2017 and analyzed from December 2022 to June 2023. Participants were cognitively unimpaired adults (Clinical Dementia Rating = 0 and/or Mini-Mental State Examination score ≥25) between the ages of 65 and 85 years who underwent PET imaging to assess cortical Aß levels for trial eligibility. A total of 4492 participants were screened, and 79 missing data were excluded. Main Outcomes and Measures: Demographic characteristics (eg, age, sex, education), apolipoprotein E genotyping, participant-reported parental history of memory impairment and parental age at symptom onset were collected as variables. Parental history was assessed in terms of continuous neocortical 18F-florbetapir Aß-PET and the Preclinical Alzheimer Cognitive Composite. Results: Of 4413 individuals (mean [SD] age, 71.27 [4.66] years, 2617 women [59.3%]), mean Aß-PET was elevated in individuals with history of memory impairment in both parents (n = 455; mean [SD] standardized uptake value ratio [SUVR] = 1.12 [0.19]; Wilcoxon P = 1.1 × 10-5) and in those with only maternal history (n = 1772; mean [SD] SUVR = 1.10 [0.19]; Wilcoxon P = 2.70 × 10-5) compared with those with only paternal history (n = 632; mean [SD] SUVR = 1.08 [0.18]; Wilcoxon P = 1.1 × 10-5) or no family history (n = 1554; mean [SD] SUVR = 1.08 [0.19]; Wilcoxon P = 1.1 × 10-5). Paternal history of early-onset memory impairment (age <65 years) but not late-onset (age ≥65 years) was associated with elevated participant Aß-PET (mean [SD] SUVR = 1.19 [0.21]; P = 3.00 × 10-6) in comparison with no paternal history (mean [SD] SUVR = 1.09 [0.19]) whereas maternal history was associated with elevated Aß in both early-onset and late-onset groups. There was no association with cognition. Conclusions and Relevance: In this study, maternal history (at any age) and paternal history of early-onset memory impairment were associated with Aß burden among asymptomatic older individuals. Sex-specific parental history may help inform clinicians on likelihood of Aß burden in offspring and help identify high-risk individuals at the earliest stages of disease for prevention.

The Parkinson's Disease Composite of Executive Functioning: A Measure for Detecting Cognitive Decline in Clinical Trials.

BACKGROUND AND OBJECTIVES: Executive functioning is one of the first domains to be impaired in Parkinson disease (PD), and the majority of patients with PD eventually develop dementia. Thus, developing a cognitive endpoint measure specifically assessing executive functioning is critical for PD clinical trials. The objective of this study was to develop a cognitive composite measure that is sensitive to decline in executive functioning for use in PD clinical trials. METHODS: We used cross-sectional and longitudinal follow-up data from PD participants enrolled in the PD Cognitive Genetics Consortium, a multicenter setting focused on PD. All PD participants with Trail Making Test, Digit Symbol, Letter-Number Sequencing, Semantic Fluency, and Phonemic Fluency neuropsychological data collected from March 2010 to February 2020 were included. Baseline executive functioning data were used to create the Parkinson's Disease Composite of Executive Functioning (PaCEF) through confirmatory factor analysis. We examined the changes in the PaCEF over time, how well baseline PaCEF predicts time to cognitive progression, and the required sample size estimates for PD clinical trials. PaCEF results were compared with the Montreal Cognitive Assessment (MoCA), individual tests forming the PaCEF, and tests of visuospatial, language, and memory functioning. RESULTS: A total of 841 participants (251 no cognitive impairment [NCI], 480 mild cognitive impairment [MCI], and 110 dementia) with baseline data were included, of which the mean (SD) age was 67.1 (8.9) years and 270 were women (32%). Five hundred forty five PD participants had longitudinal neuropsychological data spanning 9 years (mean [SD] 4.5 [2.2] years) and were included in analyses examining cognitive decline. A 1-factor model of executive functioning with excellent fit (comparative fit index = 0.993, Tucker-Lewis index = 0.989, and root mean square error of approximation = 0.044) was used to calculate the PaCEF. The average annual change in PaCEF ranged from 0.246 points per year for PD-NCI participants who remained cognitively unimpaired to -0.821 points per year for PD-MCI participants who progressed to dementia. For PD-MCI, baseline PaCEF, but not baseline MoCA, significantly predicted time to dementia. Sample size estimates were 69%-73% smaller for PD-NCI trials and 16%-19% smaller for PD-MCI trials when using the PaCEF rather than MoCA as the endpoint. DISCUSSION: The PaCEF is a sensitive measure of executive functioning decline in PD and will be especially beneficial for PD clinical trials.

Medial amygdalar tau is associated with anxiety symptoms in preclinical Alzheimer's disease.

BACKGROUND: While the amygdala receives early tau deposition in Alzheimer's disease (AD) and is involved in social and emotional processing, the relationship between amygdalar tau and early neuropsychiatric symptoms in AD is unknown. We sought to determine whether focal tau binding in the amygdala and abnormal amygdalar connectivity were detectable in a preclinical AD cohort and identify relationships between these and self-reported mood symptoms. METHODS: We examined n=598 individuals (n=347 amyloid-positive (58% female), n=251 amyloid-negative (62% female); subset into tau PET and fMRI cohorts) from the A4 Study. In our tau PET cohort, we used amygdalar segmentations to examine representative nuclei from three functional divisions of the amygdala. We analyzed between-group differences in division-specific tau binding in the amygdala in preclinical AD. We conducted seed-based functional connectivity analyses from each division in the fMRI cohort. Finally, we conducted exploratory post-hoc correlation analyses between neuroimaging biomarkers of interest and anxiety and depression scores. RESULTS: Amyloid-positive individuals demonstrated increased tau binding in medial and lateral amygdala (F(4,442)=14.61, p=0.00045; F(4,442)=5.83, p=0.024, respectively). Across amygdalar divisions, amyloid-positive individuals had relatively increased regional connectivity from amygdala to other temporal regions, insula, and orbitofrontal cortex. There was an interaction by amyloid group between tau binding in the medial and lateral amygdala and anxiety. Medial amygdala to retrosplenial connectivity negatively correlated with anxiety symptoms (rs=-0.103, p=0.015). CONCLUSIONS: Our findings suggest that preclinical tau deposition in the amygdala may result in meaningful changes in functional connectivity which may predispose patients to mood symptoms.

Plasma pTau181 Reveals a Pathological Signature that Predicts Cognitive Outcomes in Lewy Body Disease.

OBJECTIVE: To determine whether plasma phosphorylated-Tau181 (pTau181) could be used as a diagnostic biomarker of concurrent Alzheimer's disease neuropathologic change (ADNC) or amyloidosis alone, as well as a prognostic, monitoring, and susceptibility/risk biomarker for clinical outcomes in Lewy body disease (LBD). METHODS: We studied 565 participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 with Alzheimer's disease, and 274 cognitively normal. Plasma pTau181 levels were measured with the Lumipulse G platform. Diagnostic accuracy for concurrent ADNC and amyloidosis was assessed with Receiver Operating Characteristic curves in a subset of participants with CSF pTau181/Aß42, and CSF Aß42/Aß40 or amyloid-ß PET, respectively. Linear mixed effects models were used to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes. RESULTS: Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In LBD patients with abnormal cognition, higher baseline plasma pTau181 was associated with worse baseline MoCA and CDR-SB, as well as accelerated decline in CDR-SB. Additionally, in this group, rapid increases in plasma pTau181 over 3 years predicted a faster decline in CDR-SB and memory. In LBD patients with normal cognition, there was no association between baseline or longitudinal plasma pTau181 levels and clinical outcomes; however, elevated pTau181 at baseline increased the risk of conversion to cognitive impairment. INTERPRETATION: Our findings suggest that plasma pTau181 is a promising biomarker for concurrent ADNC and amyloidosis in LBD. Furthermore, plasma pTau181 holds potential as a prognostic, monitoring, and susceptibility/risk biomarker, predicting disease progression in LBD. ANN NEUROL 2024;96:526-538.

Sex, racial, and APOE-ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease.

INTRODUCTION: The effects of sex, race, and Apolipoprotein E (APOE) - Alzheimer's disease (AD) risk factors - on white matter integrity are not well characterized. METHODS: Diffusion MRI data from nine well-established longitudinal cohorts of aging were free-water (FW)-corrected and harmonized. This dataset included 4,702 participants (age=73.06 ± 9.75) with 9,671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. RESULTS: Sex differences in FAFWcorr in association and projection tracts, racial differences in FAFWcorr in projection tracts, and APOE-ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced. DISCUSSION: There are prominent differences in white matter microstructure by sex, race, and APOE-ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted.

Temporal tau asymmetry spectrum influences divergent behavior and language patterns in Alzheimer's disease.

Understanding the psychiatric symptoms of Alzheimer s disease (AD) is crucial for advancing precision medicine and therapeutic strategies. The relationship between AD behavioral symptoms and asymmetry in spatial tau PET patterns is not well-known. Braak tau progression implicates the temporal lobes early. However, the clinical and pathological implications of temporal tau laterality remain unexplored. This cross-sectional study investigated the correlation between temporal tau PET asymmetry and behavior assessed using the neuropsychiatric inventory and composite scores for memory, executive function, and language, using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. In the entire cohort, continuous right and left temporal tau contributions to behavior and cognition were evaluated, controlling for age, sex, education, and tau burden on the contralateral side. Additionally, a temporal tau laterality index was calculated to define "asymmetry-extreme" groups (individuals with laterality indices greater than two standard deviations from the mean). 695 individuals (age = 73.9 ± 7.6 years, 372 (53.5 %) females) were included, comprising 281 (40%) cognitively unimpaired (CU) amyloid negative, 185 (27%) CU amyloid positive, and 229 (33%) impaired (CI) amyloid positive participants. In the full cohort analysis, right temporal tau was associated with worse behavior (B = 8.14, p-value = 0.007), and left temporal tau was associated with worse language (B = 1.4, p-value < 0.001). Categorization into asymmetry-extreme groups revealed 20 right- and 27 left-asymmetric participants. Within these extreme groups, there was additional heterogeneity along the anterior-posterior dimension. Asymmetrical tau burden is associated with distinct behavioral and cognitive profiles. Wide multi-cultural implementation of social cognition measures is needed to understand right-sided asymmetry in AD.

Impaired 24-h activity patterns are associated with an increased risk of Alzheimer's disease, Parkinson's disease, and cognitive decline.

BACKGROUND: Sleep-wake regulating circuits are affected during prodromal stages in the pathological progression of both Alzheimer's disease (AD) and Parkinson's disease (PD), and this disturbance can be measured passively using wearable devices. Our objective was to determine whether accelerometer-based measures of 24-h activity are associated with subsequent development of AD, PD, and cognitive decline. METHODS: This study obtained UK Biobank data from 82,829 individuals with wrist-worn accelerometer data aged 40 to 79 years with a mean (± SD) follow-up of 6.8 (± 0.9) years. Outcomes were accelerometer-derived measures of 24-h activity (derived by cosinor, nonparametric, and functional principal component methods), incident AD and PD diagnosis (obtained through hospitalization or primary care records), and prospective longitudinal cognitive testing. RESULTS: One hundred eighty-seven individuals progressed to AD and 265 to PD. Interdaily stability (a measure of regularity, hazard ratio [HR] per SD increase 1.25, 95% confidence interval [CI] 1.05-1.48), diurnal amplitude (HR 0.79, CI 0.65-0.96), mesor (mean activity; HR 0.77, CI 0.59-0.998), and activity during most active 10 h (HR 0.75, CI 0.61-0.94), were associated with risk of AD. Diurnal amplitude (HR 0.28, CI 0.23-0.34), mesor (HR 0.13, CI 0.10-0.16), activity during least active 5 h (HR 0.24, CI 0.08-0.69), and activity during most active 10 h (HR 0.20, CI 0.16-0.25) were associated with risk of PD. Several measures were additionally predictive of longitudinal cognitive test performance. CONCLUSIONS: In this community-based longitudinal study, accelerometer-derived metrics were associated with elevated risk of AD, PD, and accelerated cognitive decline. These findings suggest 24-h rhythm integrity, as measured by affordable, non-invasive wearable devices, may serve as a scalable early marker of neurodegenerative disease.

Speech patterns during memory recall relates to early tau burden across adulthood.

INTRODUCTION: Early cognitive decline may manifest in subtle differences in speech. METHODS: We examined 238 cognitively unimpaired adults from the Framingham Heart Study (32-75 years) who completed amyloid and tau PET imaging. Speech patterns during delayed recall of a story memory task were quantified via five speech markers, and their associations with global amyloid status and regional tau signal were examined. RESULTS: Total utterance time, number of between-utterance pauses, speech rate, and percentage of unique words significantly correlated with delayed recall score although the shared variance was low (2%-15%). Delayed recall score was not significantly different between ß-amyoid-positive (Aß+) and -negative (Aß-) groups and was not associated with regional tau signal. However, longer and more between-utterance pauses, and slower speech rate were associated with increased tau signal across medial temporal and early neocortical regions. DISCUSSION: Subtle speech changes during memory recall may reflect cognitive impairment associated with early Alzheimer's disease pathology. HIGHLIGHTS: Speech during delayed memory recall relates to tau PET signal across adulthood. Delayed memory recall score was not associated with tau PET signal. Speech shows greater sensitivity to detecting subtle cognitive changes associated with early tau accumulation. Our cohort spans adulthood, while most PET imaging studies focus on older adults.

Post-translational modifications linked to preclinical Alzheimer's disease-related pathological and cognitive changes.

INTRODUCTION: In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults. METHODS: We constructed a protein co-expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically-relevant outcomes. RESULTS: We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p-tau181 (M4: ß = 2.44, p < 0.001, M7: ß = 2.57, p < 0.001) and executive function performance (M4: ß = -2.00, p = 0.005, M7: ß = -2.39, p < 0.001). DISCUSSION: In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post-translational modifications for early cognitive and pathological changes.

Reliability of remote National Alzheimer's Coordinating Center Uniform Data Set data.

INTRODUCTION: The National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) neuropsychological battery is being used to track cognition in participants across the country, but it is unknown if scores obtained through remote administration can be combined with data obtained in person. METHODS: The remote UDS battery includes the blind version of the Montreal Cognitive Assessment (MoCA), Number Span, Semantic and Phonemic Fluency, and Craft Story. For these tests, we assessed intraclass correlation coefficients (ICCs) between in-person and remote scores in 3838 participants with both in-person and remote UDS assessments, and we compared annual score changes between modalities in a subset that had two remote assessments. RESULTS: All tests exhibited moderate to good reliability between modalities (ICCs = 0.590-0.787). Annual score changes were also comparable between modalities except for Craft Story Immediate Recall, Semantic Fluency, and Phonemic Fluency. DISCUSSION: Our findings generally support combining remote and in-person scores for the majority of UDS tests.

Temporal tau asymmetry spectrum influences divergent behavior and language patterns in Alzheimer`s disease.

Understanding psychiatric symptoms in Alzheimer`s disease (AD) is crucial for advancing precision medicine and therapeutic strategies. The relationship between AD behavioral symptoms and asymmetry in spatial tau PET patterns is unknown. Braak tau progression implicates the temporal lobes early. However, the clinical and pathological implications of temporal tau laterality remain unexplored. This cross-sectional study investigated the correlation between temporal tau PET asymmetry and behavior assessed using the neuropsychiatric inventory, and composite scores for memory, executive function, and language; using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. In the entire cohort, continuous right and left temporal tau contributions to behavior and cognition were evaluated controlling for age, sex, education, and tau burden on the contralateral side. Additionally, a temporal tau laterality index was calculated to define "asymmetry-extreme" groups (individuals with laterality indices greater than two standard deviations from the mean). 858 individuals (age=73.9±7.7 years, 434(50%) females) were included, comprising 438 cognitively unimpaired (CU) (53.4%) and 420 impaired (CI) participants (48.9%). In the full cohort analysis, right temporal tau was associated with worse behavior (B(SE)=7.19 (2.9), p-value=0.01) and left temporal tau was associated with worse language (B(SE)=1.4(0.2), p-value<0.0001). Categorization into asymmetry-extreme groups revealed 20 right- and 27 left-asymmetric participants. Within these extreme groups, four patterns of tau PET uptake were observed: anterior temporal, typical AD, typical AD with frontal involvement, and posterior. Asymmetrical tau burden is associated with distinct behavioral and cognitive profiles. Behavioral and socioemotional measures are needed to understand right-sided asymmetry in AD.

The link between static and dynamic brain functional network connectivity and genetic risk of Alzheimer's disease.

Apolipoprotein E (APOE) polymorphic alleles are genetic factors associated with Alzheimer's disease (AD) risk. Although previous studies have explored the link between AD genetic risk and static functional network connectivity (sFNC), to the best of our knowledge, no previous studies have evaluated the association between dynamic FNC (dFNC) and AD genetic risk. Here, we examined the link between sFNC, dFNC, and AD genetic risk with a data-driven approach. We used rs-fMRI, demographic, and APOE data from cognitively normal individuals (N = 886) between 42 and 95 years of age (mean = 70 years). We separated individuals into low, moderate, and high-risk groups. Using Pearson correlation, we calculated sFNC across seven brain networks. We also calculated dFNC with a sliding window and Pearson correlation. The dFNC windows were partitioned into three distinct states with k-means clustering. Next, we calculated the proportion of time each subject spent in each state, called occupancy rate or OCR and frequency of visits. We compared both sFNC and dFNC features across individuals with different genetic risks and found that both sFNC and dFNC are related to AD genetic risk. We found that higher AD risk reduces within-visual sensory network (VSN) sFNC and that individuals with higher AD risk spend more time in a state with lower within-VSN dFNC. We also found that AD genetic risk affects whole-brain sFNC and dFNC in women but not men. In conclusion, we presented novel insights into the links between sFNC, dFNC, and AD genetic risk.

Computerized cognitive practice effects in relation to amyloid and tau in preclinical Alzheimer's disease: Results from a multi-site cohort.

Scalable cognitive paradigms that provide metrics such as the Computerized Cognitive Composite (C3) may be sensitive enough to relate to Alzheimer's disease biomarkers in the preclinical clinically unimpaired (CU) stage. We examined CU older adults (n = 3287) who completed alternate versions of the C3 approximately 51 days apart. A subset of CU with abnormal amyloid also completed tau positron emission tomography (PET) imaging. C3 initial performance and practice effects were examined in relation to amyloid status and continuous regional tau burden. Initial C3 performance was associated with amyloid status across all participants, and with tau burden in the medial temporal lobe and early cortical regions in CU with abnormal amyloid. Short-term practice effects were associated with reduced tau in these regions in CU with abnormal amyloid, but were not associated with amyloid status. Thus, computerized cognitive testing repeated over a short follow-up period provides additional insights into early Alzheimer's disease processes.

APOE effects on regional tau in preclinical Alzheimer's disease.

BACKGROUND: APOE variants are strongly associated with abnormal amyloid aggregation and additional direct effects of APOE on tau aggregation are reported in animal and human cell models. The degree to which these effects are present in humans when individuals are clinically unimpaired (CU) but have abnormal amyloid (Aß+) remains unclear. METHODS: We analyzed data from CU individuals in the Anti-Amyloid Treatment in Asymptomatic AD (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies. Amyloid PET data were available for 4486 participants (3163 Aß-, 1323 Aß+) and tau PET data were available for a subset of 447 participants (55 Aß-, 392 Aß+). Linear models examined APOE (number of e2 and e4 alleles) associations with global amyloid and regional tau burden in medial temporal lobe (entorhinal, amygdala) and early neocortical regions (inferior temporal, inferior parietal, precuneus). Consistency of APOE4 effects on regional tau were examined in 220 Aß + CU and mild cognitive impairment (MCI) participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: APOE2 and APOE4 were associated with lower and higher amyloid positivity rates, respectively. Among Aß+ CU, e2 and e4 were associated with reduced (-12 centiloids per allele) and greater (+15 centiloids per allele) continuous amyloid burden, respectively. APOE2 was associated with reduced regional tau in all regions (-0.05 to -0.09 SUVR per allele), whereas APOE4 was associated with greater regional tau (+0.02 to +0.07 SUVR per allele). APOE differences were confirmed by contrasting e3/e3 with e2/e3 and e3/e4. Mediation analyses among Aß+ s showed that direct effects of e2 on regional tau were present in medial temporal lobe and early neocortical regions, beyond an indirect pathway mediated by continuous amyloid burden. For e4, direct effects on regional tau were only significant in medial temporal lobe. The magnitude of protective e2 effects on regional tau was consistent across brain regions, whereas detrimental e4 effects were greatest in medial temporal lobe. APOE4 patterns were confirmed in Aß+ ADNI participants. CONCLUSIONS: APOE influences early regional tau PET burden, above and beyond effects related to cross-sectional amyloid PET burden. Therapeutic strategies targeting underlying mechanisms related to APOE may modify tau accumulation among Aß+ individuals.