Amyloid PET Research Articles

Machine Learning Models of Polygenic Risk for Enhanced Prediction of Alzheimer Disease Endophenotypes.

Alzheimer disease (AD) has a polygenic architecture, for which genome-wide association studies (GWAS) have helped elucidate sequence variants (SVs) influencing susceptibility. Polygenic risk score (PRS) approaches show promise for generating summary measures of inherited risk for clinical AD based on the effects of APOE and other GWAS hits. However, existing PRS approaches, based on traditional regression models, explain only modest variation in AD dementia risk and AD-related endophenotypes. We hypothesized that machine learning (ML) models of polygenic risk (ML-PRS) could outperform standard regression-based PRS methods and therefore have the potential for greater clinical utility. We analyzed combined data from the Mayo Clinic Study of Aging (n = 1,791) and the Alzheimer's Disease Neuroimaging Initiative (n = 864). An AD PRS was computed for each participant using the top common SVs obtained from a large AD dementia GWAS. In parallel, ML models were trained using those SV genotypes, with amyloid PET burden as the primary outcome. Secondary outcomes included amyloid PET positivity and clinical diagnosis (cognitively unimpaired vs impaired). We compared performance between ML-PRS and standard PRS across 100 training sessions with different data splits. In each session, data were split into 80% training and 20% testing, and then five-fold cross-validation was used within the training set to ensure the best model was produced for testing. We also applied permutation importance techniques to assess which genetic factors contributed most to outcome prediction. ML-PRS models outperformed the AD PRS (r2 = 0.28 vs r2 = 0.24 in test set) in explaining variation in amyloid PET burden. Among ML approaches, methods accounting for nonlinear genetic influences were superior to linear methods. ML-PRS models were also more accurate when predicting amyloid PET positivity (area under the curve [AUC] = 0.80 vs AUC = 0.63) and the presence of cognitive impairment (AUC = 0.75 vs AUC = 0.54) compared with the standard PRS. We found that ML-PRS approaches improved upon standard PRS for prediction of AD endophenotypes, partly related to improved accounting for nonlinear effects of genetic susceptibility alleles. Further adaptations of the ML-PRS framework could help to close the gap of remaining unexplained heritability for AD and therefore facilitate more accurate presymptomatic and early-stage risk stratification for clinical decision-making.

Amyloid beta-independent sleep markers associated with early regional tau burden and cortical thinning.

Sleep is crucial for memory consolidation and the clearance of toxic proteins associated with Alzheimer's disease (AD). We examined the association between sleep characteristics and imaging biomarkers of early amyloid beta (Aβ) and tau pathology as well as neurodegeneration in brain regions known to be affected in the incipient stages of AD. Thirty-nine cognitively unimpaired (CU) participants of the Harvard Aging Brain Study underwent at-home polysomnography as well as tau positron emission tomography (flortaucipir-PET), amyloid PET (Pittsburgh compound B [PiB]-PET), and magnetic resonance imaging-derived assessment of cortical thickness (CT). Increased N1 sleep was associated with a higher tau PET signal (β=0.009, p=0.001) and lower CT in the temporal composite region of interest (β=-0.017, p=0.007). Decreased slow-wave sleep (SWS) was associated with higher tau burden in the temporal composite (β=-0.008, p=0.005) and lower CT (β=0.008, p=0.002), even after controlling for global PiB-PET. In CU older adults, lower SWS and higher N1 sleep were associated with higher tau burden and lower CT in brain regions associated with early tau deposition and vulnerable to AD-related neurodegeneration through mechanisms dissociable from amyloid deposition. We report the results of an observational study, which leveraged -a well-characterized cohort of healthy aging (Harvard Aging Brain Study) by adding in-home full polysomnograms.By adding at-home polysomnograms to this unique and deeply phenotyped cohort, we examined variations in sleep architecture that are associated with Alzheimer's disease (AD) pathologic changes.Our results confirmed the association of sleep changes with early tau and cortical neurodegenerative changes that were independent of amyloid.The results will be of importance in monitoring sleep-related variations in relation to the natural history of AD pathology and in designing sleep-focused clinical trials.

Plasma p-tau181 as an outcome and predictor of multidomain intervention effects: a secondary analysis of a randomised, controlled, dementia prevention trial.

It is unknown whether multidomain interventions, which might preserve late-life cognition, affect Alzheimer's disease pathology. Previous studies measured cerebrospinal fluid and imaging Alzheimer's disease biomarkers in small subsamples of multidomain trial participants. Newly developed assays enable the measurement of blood-based Alzheimer's disease biomarkers in larger samples. We aimed to assess whether plasma tau phosphorylated at threonine 181 (p-tau181) was able to detect or predict 3-year multidomain intervention effects. This is a secondary analysis of the randomised, controlled, Multidomain Alzheimer Prevention Trial (MAPT) testing a 3-year multidomain intervention, omega-3 fatty acid supplementation, or both versus placebo, in individuals aged 70 years and older in 13 memory centres in France and Monaco. Plasma p-tau181 was measured in stored blood samples in a subsample of 527 participants on an intention-to-treat basis. Changes in cognitive score were calculated as a composite measure using the average of Z scores for the following tests: Mini Mental State Examination orientation items, Free and Cued Selective Reminding Test (sum of free and total recall scores), category fluency, and Digit Symbol Substitution Test. Intervention effects on 3-year change in p-tau181 concentration were estimated by use of a linear mixed model with centre-specific random intercepts. Recruitment took place between May 30, 2008, and Feb 24, 2011. Median baseline plasma p-tau181 was 8·8 pg/mL (IQR 6·7-11·9) in the total sample, and significantly higher in older individuals, men, APOE ε4 carriers, and participants with renal dysfunction or a positive PET amyloid scan. During 3-year follow-up, individuals with raised baseline p-tau181 underwent greater cognitive decline (eg, mean difference in 3-year change on the composite cognitive score between control group participants with normal and abnormal baseline levels of p-tau was -0·34 [effect size -0·52; 95% CI -0·61 to 0·07] in the fully adjusted model using a 12·4 pg/mL cutoff for abnormal baseline p-tau181), but there were no intervention effects on change in p-tau181 either in this subgroup or the total population, and no effect on cognitive change in individuals with raised baseline p-tau181 (eg, in the fully adjusted model using the 12·4 pg/mL cutoff for p-tau181 abnormality, the mean difference [95% CI] in this subgroup in 3-year decline on the composite cognitive score between the control group and the multidomain + omega-3 group, the omega-3 group, and the multidomain intervention group, was, respectively: 0·13 [-0·21 to 0·47], 0·03 [-0·30 to 0·36], and 0·10 [-0·26 to 0·46]). Surprisingly, individuals with raised baseline p-tau181 showed a decrease in p-tau181 during follow-up (eg, unadjusted mean [95% CI] 3-year change was -3·01 pg/mL (-4·45 to -1·56) in control group subjects with abnormal baseline p-tau181 [using the 12·4 pg/mL abnormal p-tau cutoff]). Our results support the utility of p-tau181 as a prognostic biomarker, but it did not predict or detect intervention effects in this study. Further investigation of its usefulness as a prevention trial outcome measure is required. Toulouse Gérontopôle, French Ministry of Health and Pierre Fabre Research Institute.

Different aspects of failing to recover from proactive semantic interference predicts rate of progression from amnestic mild cognitive impairment to dementia.

This study investigated the role of proactive semantic interference (frPSI) in predicting the progression of amnestic Mild Cognitive Impairment (aMCI) to dementia, taking into account various cognitive and biological factors. The research involved 89 older adults with aMCI who underwent baseline assessments, including amyloid PET and MRI scans, and were followed longitudinally over a period ranging from 12 to 55 months (average 26.05 months). The findings revealed that more than 30% of the participants diagnosed with aMCI progressed to dementia during the observation period. Using Cox Proportional Hazards modeling and adjusting for demographic factors, global cognitive function, hippocampal volume, and amyloid positivity, two distinct aspects of frPSI were identified as significant predictors of a faster decline to dementia. These aspects were fewer correct responses on a frPSI trial and a higher number of semantic intrusion errors on the same trial, with 29.5% and 31.6 % increases in the likelihood of more rapid progression to dementia, respectively. These findings after adjustment for demographic and biological markers of Alzheimer's Disease, suggest that assessing frPSI may offer valuable insights into the risk of dementia progression in individuals with aMCI.

Modified RCTU Score: A Semi-Quantitative, Visual Tool for Predicting Alzheimer's Conversion from aMCI.

This research evaluated the modified RCTU score, derived from amyloid PET scans, for predicting the progression from amnestic Mild Cognitive Impairment (aMCI) to Alzheimer's Disease (AD). aMCI patients underwent baseline evaluations, including amyloid PET. AD conversion was identified through neuropsychological tests after observation. The RCTU was modified by segmenting frontal, parietal, and temporal lobes into left and right, resulting in seven areas. Scores from both modified and conventional RCTU were analyzed and compared. Among 45 patients, 12 progressed to AD (over 17.8 ± 6.8 months). AD converters showed higher scores in modified RCTU scores. Modified RCTU score had strong correlations with amyloid SUVR (r > 0.7). Modified RCTU sum score was the significant covariate of AD conversion. Modified RCTU could determine the asymmetry of amyloid deposits. We demonstrated that symmetric deposits of amyloid showed a higher risk for AD conversion when analyzed using modified RCTU. The modified RCTU score is a promising method for predicting AD conversion, correlating strongly with amyloid SUVR.

Brain activation during scene encoding fMRI in the Alzheimer’s disease continuum: Association with amyloid and tau burden in PE

Background and Hypothesis:This project assessed brain activation during a scene encoding task in 4 groups: older adults who were cognitively normal (CN), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia due to Alzheimer’s disease (AD). Associations between scene encoding related brain activation and tau, amyloid, and other biomarkers were analyzed. Our hypothesis was that higher levels of cerebral tau and amyloid would be associated with reduced scene encoding activation. In addition, we hypothesized that scene encoding activation would be significantly different between cognitively normal and cognitively impaired groups.
 Methods:234 individuals from the Indiana Memory and Aging Study (79 CN, 67 SCD, 70 MCI, and 18 AD) completed structural and functional MRI, clinical/cognitive assessment and biomarkers; 155 underwent amyloid ([18F]florbetapir/[18F]florbetaben) PET, while 111 also underwent [18F]flortaucipir PET. For the fMRI scene encoding task, participants were asked to view and remember a set of images. A one-way ANOVA test was used to analyze scene encoding related activation differences among the 4 groups. Regression was used to identify associations between scene encoding activation and tau and amyloid deposition.
 Results:Significant differences in activation were observed between the MCI and CN groups, including less activation in widespread regions during the task and reduced deactivation in the default mode network (DMN) in MCI participants relative to CN. Significant associations between higher amyloid and tau deposition and altered scene encoding activation were also observed.
 Conclusion and Potential Impact:Cognitive decline is associated with activation changes during scene encoding, as well as reduced deactivation in the DMN, especially in the posterior cingulate region. Higher cerebral amyloid and tau deposition predicted decreased scene encoding related activation. These findings are consistent with models linking cognitive status, functional brain activation during episodic encoding, and pathophysiological processes in the AD continuum.

Value of Knowing: Health-Related Behavior Changes following Amyloid PET Results Disclosure in Mild Cognitive Impairment.

Growing evidence supports the clinical utility of amyloid PET, however, whether patients at risk for dementia use knowledge of their brain amyloid status to alter their health behaviors remains unclear. To explore the effect of amyloid PET results disclosure on self-reported health behaviors in patients with mild cognitive impairment. Self-reported health behaviors were a secondary outcome of the Return of Amyloid Imaging Scan Results (RAISR) randomized clinical trial of amyloid PET results disclosure for individuals with mild cognitive impairment. Academic medical center. RAISR study participants included 82 patients with mild cognitive impairment who were 92% non-Hispanic white, 59% male, and, on average, 73 ± 8.61 years old with 16.25 ± 2.49 years of education. Participants were assigned to a scan group with the opportunity to have an amyloid PET scan and learn their results or to a control group consisting only of a mild cognitive impairment education session and no opportunity for an amyloid PET scan. A 14-item health behavior questionnaire supplemented with qualitative data from the open-ended text entries to describe "other" health behaviors and follow-up semi-structured interviews. Baseline assessments were conducted prior to group assignment. For the present analysis, 71 participants had available data and scan group participants were divided by amyloid status, creating three groups for comparison: amyloid positive, amyloid negative, and control (no scan). Over 12 months of follow-up, no significant differences were observed in lifestyle, vitamin/supplement use, stress reduction activities, cognitive stimulation, or advance directive completion. Amyloid-negative participants were less likely than controls to consider long-term care insurance (63.6% vs. 89.2%; P = .025), and to endorse behaviors classified as "other" (36.4% vs. 64.9%; P = 0.037). After adjusting for education level, gender, and Mini-Mental State Exam score, logistic regression showed that amyloid-negative patients were 74% less likely than controls to report "other" behaviors (OR = 0.26, 95% CI [0.08, 0.85], P = 0.025), and 78% less likely to consider long-term care insurance (OR= 0.22, 95% CI [0.06, 0.86], P = 0.03). Qualitative analysis of open-ended questionnaire data and supplemental interviews with scan group participants revealed "other" activities to include changes in areas like employment, driving, and residential status, and engagement in other non-medical activities (e.g., pursuing bucket lists). This exploratory analysis of health-related behavior changes following amyloid PET disclosure suggests that the value of knowing one's brain amyloid status may differ by scan result and encompass actions that focus more on maximizing quality of life than promoting cognitive health.

At-Home Administration of Gantenerumab by Care Partners to People with Early Alzheimer's Disease: Feasibility, Safety and Pharmacodynamic Impact.

Monoclonal antibodies that target amyloid-beta and remove amyloid plaques can slow cognitive and functional decline in early Alzheimer's disease. Gantenerumab is a subcutaneously administered fully-human anti-amyloid-beta monoclonal antibody with highest affinity for aggregated amyloid-beta. Since the phase 3 GRADUATE trials did not meet the primary endpoint (change from baseline to Week 116 in Clinical Dementia Rating scale - Sum of Boxes), development of gantenerumab in sporadic Alzheimer's disease was stopped and all ongoing trials were terminated early due to sponsor decision. Subcutaneous administration at the clinic or at home by care partner would be an important option for other therapies in this class in order to increase flexibility and reduce overall burden. The insights obtained from the experience with gantenerumab home administration by care partner in the phase 2 GRADUATION trial will serve to guide the ongoing efforts with other anti-amyloid-beta antibodies. To evaluate the pharmacodynamic effects on brain amyloid load of once weekly subcutaneous administration of gantenerumab and the safety and feasibility of home administration by care partners. Phase 2, open-label, single arm study. Multicenter trial conducted in 33 sites in 8 countries from November 2020 to March 2023. Participants aged 50 to 90 with early symptomatic Alzheimer's disease (mild cognitive impairment/mild dementia due to Alzheimer's disease), and evidence of amyloid positron emission tomography positivity. Participants could receive up to 255 mg gantenerumab once-weekly, administered subcutaneously at site or at home by healthcare professionals or non-healthcare-professional care partners. The primary endpoint was the change from baseline to Week 52 and to Week 104 in brain amyloid load as measured by PET centiloid levels. The secondary endpoints were responses to the home administration questionnaire, plasma concentrations and safety. The overall number of participants enrolled was 192, with a mean (standard deviation) amyloid PET load at baseline of 101.80 (29.80) centiloids. At the time of early study termination by sponsor, 149 participants had valid Week 52 amyloid PET data (primary endpoint), and 12 participants had an early termination PET within the pre-defined time range of Week 104. The mean change in amyloid PET from baseline to Week 52 and Week 104 was -26.19 centiloids (range: -75.6-15.8; n=149) and -35.48 centiloids (range: -63.2--7.0; n=12), respectively. Responses to the home administration questionnaire at Week 52 (n=148) indicated that the majority of care partners (88-97%) considered administration of study drug at home easy (30.4%) or very easy (57.4%), and convenient (25.7%) or very convenient (70.9%). Care partners felt confident (31.1%) or very confident (62.2%) and satisfied (29.7%) or very satisfied (64.9%) with giving the injection at home. Responses by care partners at Week 36 (n=72), Week 76 (n=126) and Week 104 (n=29) and participant (patient) assessment of convenience and satisfaction at these time points were similar. There were no new safety findings associated with gantenerumab administered subcutaneously once weekly at 255 mg or safety issues associated with at-home injections by non-healthcare professional care partners. Once-weekly subcutaneous home administration of the anti-amyloid-beta antibody gantenerumab by non-healthcare-professional care partners to participants with early Alzheimer's disease was feasible, safe, well tolerated, and considered as a convenient option by both the care partners and participants with Alzheimer's disease. Although gantenerumab's development has been stopped due to lack of efficacy, this approach has the potential to reduce the frequency of hospital/outpatient clinic visits required for treatment with other anti-amyloid-β antibodies and can increase flexibility of drug administration for people living with Alzheimer's disease and their families.

Alzheimer Disease Pathology and Neurodegeneration in Midlife Obesity: A Pilot Study.

Obesity and excess adiposity at midlife are risk factors for Alzheimer disease (AD). Visceral fat is known to be associated with insulin resistance and a pro-inflammatory state, the two mechanisms involved in AD pathology. We assessed the association of obesity, MRI-determined abdominal adipose tissue volumes, and insulin resistance with PET-determined amyloid and tau uptake in default mode network areas, and MRI-determined brain volume and cortical thickness in AD cortical signature in the cognitively normal midlife population. Thirty-two middle-aged (age: 51.27±6.12 years, 15 males, body mass index (BMI): 32.28±6.39 kg/m2) cognitively normal participants, underwent bloodwork, brain and abdominal MRI, and amyloid and tau PET scan. Visceral and subcutaneous adipose tissue (VAT, SAT) were semi-automatically segmented using VOXel Analysis Suite (Voxa). FreeSurfer was used to automatically segment brain regions using a probabilistic atlas. PET scans were acquired using [11C]PiB and AV-1451 tracers and were analyzed using PET unified pipeline. The association of brain volumes, cortical thicknesses, and PiB and AV-1451 standardized uptake value ratios (SUVRs) with BMI, VAT/SAT ratio, and insulin resistance were assessed using Spearman's partial correlation. VAT/SAT ratio was associated significantly with PiB SUVRs in the right precuneus cortex (p=0.034) overall, controlling for sex. This association was significant only in males (p=0.044), not females (p=0.166). Higher VAT/SAT ratio and PiB SUVRs in the right precuneus cortex were associated with lower cortical thickness in AD-signature areas predominantly including bilateral temporal cortices, parahippocampal, medial orbitofrontal, and cingulate cortices, with age and sex as covariates. Also, higher BMI and insulin resistance were associated with lower cortical thickness in bilateral temporal poles. In midlife cognitively normal adults, we demonstrated higher amyloid pathology in the right precuneus cortex in individuals with a higher VAT/SAT ratio, a marker of visceral obesity, along with a lower cortical thickness in AD-signature areas associated with higher visceral obesity, insulin resistance, and amyloid pathology.

A Pragmatic, Investigator-Driven Process for Disclosure of Amyloid PET Scan Results to ADNI-4 Research Participants.

Prior studies of Alzheimer's disease (AD) biomarker disclosure have answered important questions about individuals' safety after learning and comprehending their amyloid PET results; however, these studies have typically employed highly structured disclosure protocols and focused on the psychological impact of disclosure (e.g., anxiety, depression, and suicidality) in homogeneous populations. More work is needed to develop flexible disclosure protocols and study outcomes in ethnoculturally representative samples. The Alzheimer's Disease Neuroimaging Initiative (ADNI) is formally incorporating amyloid PET disclosure into the newest protocol (ADNI-4). Participants across the cognitive spectrum who wish to know their amyloid PET results may learn them. The pragmatic disclosure process spans four timepoints: (1) a pre-disclosure visit, (2) the PET scan and its read, (3) a disclosure visit, and (4) a post-disclosure check-in. This process applies to all participants, with slight modifications to account for their cognitive status. In designing this process, special emphasis was placed on utilizing investigator discretion. Participant measures include perceived risk of dementia, purpose in life, and disclosure satisfaction. Investigator assessment of the disclosure visit (e.g., challenges encountered, topics discussed, etc.) is also included. Data collection is ongoing. Results will allow for more robust characterization of the impact of learning amyloid PET results on individuals and describe the perspectives of investigators. The pragmatic design of the disclosure process in ADNI-4 coupled with the novel participant and investigator data will inform future disclosure practices. This is especially important as disclosure of biomarker results expands in research and care.

A case of left posterior cortical atrophy presenting with kana-predominant reading impairment

The patient was an 85-year-old man with a one-year history of difficulty reading kana. Neuropsychological evaluation revealed kana (phonogram)-selective reading impairment and kanji (ideogram)-dominant writing impairment. MRI revealed significant cerebral atrophy in the left occipital cortex, leading to the clinical diagnosis of posterior cortical atrophy (PCA). Cerebrospinal fluid amyloid β1-42 levels were reduced, and amyloid PET showed accumulation in the posterior cingulate cortex, precuneus, and frontal lobe. In contrast, tau PET showed no accumulation in the atrophied brain areas. Episodes of REM sleep behavior disorder and decreased uptake on meta-iodobenzylguanidine (MIBG) myocardial scintigraphy suggested the involvement of Lewy body pathology. PCA with distinct laterality has been rarely reported, and ‍this is the first case to present Kana-selective reading impairment and Kanji-dominant writing impairment with neurodegenerative background.

Significance of a positive tau PET scan with a negative amyloid PET scan.

The implications of positive tau positron emission tomography (T) with negative beta amyloid positron emission tomography (A) are not well understood. We investigated cognitive performance in participants who were T+ but A-. We evaluated 98 participants from the Mayo Clinic who were T+ and A-. Participants were matched 2:1 to A- and T- cognitively unimpaired (CU) controls. Cognitive test scores were compared between different groups. The A-T+ group demonstrated lower performance than the A-T- group on the Mini-Mental Status Exam (MMSE) (p<0.001), Wechsler Memory Scale-Revised Logical Memory I (p<0.001) and Logical Memory II (p<0.001), Auditory Verbal Learning Test (AVLT) delayed recall (p=0.004), category fluency (animals p=0.005; vegetables p=0.021), Trail Making Test A and B (p<0.001), and others. There were no significant differences in demographic features or apolipoprotein E (APOE) e4 genotype between CU A-T+ and CI A-T+. A-T+ participants show an association with lower cognitive performance.

EFFECT OF AMYLOID PET RESULTS DISCLOSURE ON HEALTH-RELATED BEHAVIORS IN PERSONS WITH MILD COGNITIVE IMPAIRMENT

Abstract Mounting evidence supports the clinical utility of amyloid PET. However, whether patients use knowledge of their amyloid status to alter health behaviors remains unclear. We describe health-related actions taken by Mild Cognitive Impairment patients following amyloid PET disclosure (n=34) vs. a comparison group (n=37). Patients were 92% non-Hispanic white, 59% male, 73±8.61 years old with 16.25±2.49 years of education. Over 12 months of follow-up, all participants reported at least one behavior change from baseline on a 14-item health behavior questionnaire. Amyloid positive patients reported the most behavior changes (mean=4.67±1.83) while amyloid negative patients reported the fewest (mean=3.72±1.58). Across groups, no significant differences were observed in: lifestyle, vitamin/supplement use, stress reduction activities, cognitive stimulation, or advance directive completion. Amyloid negative participants were significantly less likely than controls to consider long-term care insurance (63.6% vs. 89.2%; P=.025), and to endorse changes classified as “other” (36.4% vs. 64.9%; P=0.037). After adjusting for education level, gender, and MMSE, logistic regression showed that amyloid negative patients were 74% less likely than controls to report “other” changes (OR=0.26, 95% CI [0.08, 0.85], P=0.025), and 78% less likely to consider long-term care insurance (OR=0.22, 95% CI [0.06, 0.86], P=0.03). Qualitative analysis of supplemental interviews with scan group participants revealed “other” activities to include changes in employment, driving, and residential status, and engagement in other non-medical activities (pursuing bucket lists and mending strained relationships). Health-related behavior changes following amyloid PET disclosure may differ by scan result and encompass actions to enhance not only cognition but quality of life.

EFFECTS OF DISCLOSING DIAGNOSES AND BIOMARKER RESULTS FOR ALZHEIMER’S DISEASE AND RELATED DISORDERS

Abstract Early diagnosis of mild cognitive impairment (MCI) and Alzheimer’s disease and related dementias (ADRD) has been recognized as a key strategy to improve health-related outcomes. However, given that these conditions are highly stigmatized, receiving a diagnostic label or knowing about biomarkers related to MCI or ADRD may have a profound impact on the person’s life. As the impacts of disclosure of diagnostic information related to MCI and ADRD on the well-being of people living with these conditions are not well understood, this symposium attempts to address this knowledge gap. The first presenter will describe a study that examined racial/ethnic variations in the effects of diagnostic labeling of ADRD on social aspects of the person’s life. The second presenter will discuss findings from a systematic review of the effects of ADRD and cognitive impairment on social engagement. The third presenter will present the findings of the study on the effect of amyloid PET results disclosure on health-related behaviors of people with MCI. The fourth presenter will describe the results of an online vignette study on the outcomes of a preclinical Alzheimer disease diagnosis. The fifth presenter will discuss the use of blood biomarkers to aid in the diagnosis of ADRD in primary care (PC). At the end of the presentation, the discussant will highlight implications for future research and policy development to alleviate negative impacts and maximize the positive impacts of a diagnostic label of MCI and ADRD.

PATIENT AGE AND SEX DO NOT APPEAR TO INFLUENCE DECISION MAKING AROUND BIOMARKER TESTING FOR COGNITIVE IMPAIRMENT

Abstract The QUIP I Study (ClinicalTrials.gov Identifier: NCT05477056) was a prospective, single-arm study which included 347 older persons (average age 74, 56% women) presenting with signs and symptoms of cognitive impairment. In a subgroup analysis, we measured the effect of a person’s age and sex on clinical decision making around the PrecivityAD® blood biomarker (BBM) test result. The test result was reported as the Amyloid Probability Score (APS), which measures the likelihood of a positive result on an amyloid PET scan. Clinical decision making was recorded by clinician survey pre- and post-BBM testing. Clinician-reported probability of Alzheimer’s disease (“AD”) changed pre-test to post-test from 58% to 23% (Low APS group) and from 71% to 89% (High APS group) (p &amp;lt; 0.0001 for all APS groups). The relationships between APS and change in diagnostic certainty were not significantly different as analyzed by age (p=0.344 for Low APS, p=0.292 for High APS) or sex (p=0.167 for Low APS, p=0.213 for High APS). Overall use of AD drug therapy decreased from 48% to 26% (Low APS group) and increased from 56% to 88% (High APS group) (p &amp;lt; 0.0001 for all APS groups). The relationships between APS and change in medication prescribing were not significantly different as analyzed by age (p=0.4534 for Low APS, p=0.9939 for High APS) or sex (p=1 for Low APS, p=0.931 for High APS). We believe that the current study results help to underscore the usefulness and generalizability of this BBM among older adults in clinical care pathways.

Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease

Background“Brain-predicted age” estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology.MethodsWe modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans. We then tested whether BAG differed as a function of mutation and cognitive status, or estimated years until symptom onset, and whether it was associated with established markers of amyloid (PiB PET, CSF amyloid-β-42/40), phosphorylated tau (CSF and plasma pTau-181), neurodegeneration (CSF and plasma neurofilament-light-chain [NfL]), and cognition (global neuropsychological composite and CDR-sum of boxes). We compared BAG to other MRI measures, and examined heterogeneity in BAG as a function of ADAD mutation variants, APOE ε4 carrier status, sex, and education.ResultsAdvanced brain aging was observed in mutation-carriers approximately 7 years before expected symptom onset, in line with other established structural indicators of atrophy. BAG was moderately associated with amyloid PET and strongly associated with pTau-181, NfL, and cognition in mutation-carriers. Mutation variants, sex, and years of education contributed to variability in BAG.ConclusionsWe extend prior work using BAG from sporadic AD to ADAD, noting consistent results. BAG associates well with markers of pTau, neurodegeneration, and cognition, but to a lesser extent, amyloid, in ADAD. BAG may capture similar signal to established MRI measures. However, BAG offers unique benefits in simplicity of data processing and interpretation. Thus, results in this unique ADAD cohort with few age-related confounds suggest that brain aging attributable to AD neuropathology can be accurately quantified from minimally-processed MRI.

Association of Sleep Duration and Change Over Time With Imaging Biomarkers of Cerebrovascular, Amyloid, Tau, and Neurodegenerative Pathology.

Both short and long sleep duration were previously associated with incident dementia, but underlying mechanisms remain unclear. We evaluated how self-reported sleep duration and its change over time associate with (A)myloid, (T)au, (N)eurodegeneration, and (V)ascular neuroimaging markers of Alzheimer disease. Two Framingham Heart Study overlapping samples were studied: participants who underwent 11C-Pittsburg Compound B amyloid and 18F-flortaucipir tau PET imaging and participants who underwent an MRI. MRI metrics estimated neurodegeneration (total brain volume) and cerebrovascular injuries (white matter hyperintensities [WMHs] volume, covert brain infarcts, free-water [FW] fraction). Self-reported sleep duration was assessed and split into categories both at the time of neuroimaging testing and approximately 13 years before: short ≤6 hours. average 7-8 hours, and long ≥9 hours. Logistic and linear regression models were used to examine sleep duration and neuroimaging metrics. The tested cohort was composed of 271 participants (age 53.6 ± 8.0 years; 51% male) in the PET imaging sample and 2,165 participants (age 61.3 ± 11.1 years; 45% male) in the MRI sample. No fully adjusted association was observed between cross-sectional sleep duration and neuroimaging metrics. In fully adjusted models compared with consistently sleeping 7-8 hours, groups transitioning to a longer sleep duration category over time had higher FW fraction (short to average β [SE] 0.0062 [0.0024], p = 0.009; short to long β [SE] 0.0164 [0.0076], p = 0.031; average to long β [SE] 0.0083 [0.0022], p = 0.002), and those specifically going from average to long sleep duration also had higher WMH burden (β [SE] 0.29 [0.11], p = 0.007). The opposite associations (lower WMH and FW) were observed in participants consistently sleeping ≥9 hours as compared with people consistently sleeping 7-8 hours in fully adjusted models (β [SE] -0.43 [0.20], p = 0.028; β [SE] -0.019 [0.004], p = 0.020). Each hour of increasing sleep (continuous, β [SE] 0.12 [0.04], p = 0.003; β [SE] 0.002 [0.001], p = 0.021) and extensive increase in sleep duration (≥2 hours vs 0 ± 1 hour change; β [SE] 0.24 [0.10], p = 0.019; β [SE] 0.0081 [0.0025], p = 0.001) over time was associated with higher WMH burden and FW fraction in fully adjusted models. Sleep duration change was not associated with PET amyloid or tau outcomes. Longer self-reported sleep duration over time was associated with neuroimaging biomarkers of cerebrovascular pathology as evidenced by higher WMH burden and FW fraction. A longer sleep duration extending over time may be an early change in the neurodegenerative trajectory.

Association between results of an amyloid PET scan and healthcare utilization in individuals with cognitive impairment.

The Imaging Dementia Evidence for Amyloid Scanning (IDEAS) study reports that amyloid PET scans help providers diagnose and manage Alzheimer's disease and related dementias (ADRD). Using CARE-IDEAS, an IDEAS supplemental study, we examined the association between amyloid PET scan result (elevated or non-elevated amyloid), patient characteristics, and participant healthcare utilization. We linked respondents in CARE-IDEAS study to their Medicare fee-for-service records (n = 1333). We examined participants' cognitive impairment-related, outpatient, emergency department (ED), and inpatient encounters in the year before compared with the 2 years after the amyloid PET scan. Individuals with a non-elevated amyloid scan had more healthcare encounters throughout the overall study period than those with an elevated amyloid scan. Regardless of the amyloid scan result, cognitive impairment-related and outpatient encounters overall decreased, but ED and inpatient encounters increased in the 2 years after the scan compared with the year prior. There was minimal evidence of differences in healthcare utilization between participants with an elevated and non-elevated amyloid scan. There is no difference in change in healthcare utilization between people with scans showing elevated and non-elevated beta-amyloid.

Here's How Coverage for Amyloid PET Is Changing

Here's How Coverage for Amyloid PET Is Changing

Comparison of plasma Ab42, Ab40, and p‐tau181 assessed on two different platforms with CSF AD biomarkers and amyloid (PiB) PET

AbstractBackgroundAs blood‐based biomarkers of Alzheimer’s disease enter clinical diagnostic use, key considerations remain including the concordance with CSF or amyloid PET and the comparability of results between different assay platforms.MethodParticipants (n = 42) from the Clinical Core of the Wake Forest ADRC, were selected using CSF Aβ42/Aβ40 values which clearly indicated amyloid pathology status (‐ or +). A subset of 29 participants had amyloid (PiB) PET measures within one year of CSF. Participants were considered amyloid positive when CSF Aβ42/40 ≤0.058 and/or amyloid PET was adjudicated as “positive”. CSF and plasma Aβ42, Aβ40, and pTau181 were assessed using the Lumipulse platform at the Wake Forest ADRC; plasma Aβ42, Aβ40, and pTau181 were also assessed using the Quanterix SIMOA platform at the National Centralized Repository for Alzheimer’s disease. CSF and plasma from each participant were collected on the same day.ResultAmyloid positive and negative groups differed significantly in age and APOE‐ε4 status (Table 1). Although raw values between plasma platforms differed significantly, biomarkers were highly correlated (Table 2). The correlation between CSF and plasma was: Lumipulse for Aβ42/Aβ40 (ρS = 0.76, p&lt;0.0001) and pTau181 (ρS = 0.64, p&lt;0.0001) and SIMOA Aβ42/Aβ40 (ρS = 0.63, p&lt;0.0001) and pTau181 (ρS = 0.50, p = 0.0009). When comparing groups positive or negative for either CSF or PET, the ROC AUC for plasma Aβ42/Aβ40 was 0.94 for Lumipulse and 0.92 for SIMOA. Ptau181 AUC was 0.80 for Lumipulse and 0.82 for SIMOA. Figure 1 shows a clear relationship between decreasing Aβ42/Aβ40 and increasing pTau181 in the CSF which is present but diminished in Lumipulse plasma and largely absent in SIMOA plasma data.ConclusionRaw values from both platforms differed significantly which may limit generalizability and translatability of plasma data across platforms, but results were correlated. CSF values correlated marginally with both Lumipulse and SIMOA plasma. Plasma indices performed better than previously reported in other AD cohorts, likely due to our stringent CSF‐based selection criteria, and AUC did not differ between Lumipulse and SIMOA for either Aβ42/Aβ40 or pTau181. Further work is underway to expand the dataset and define population‐based cutoffs which also consider comorbidities, such as chronic kidney disease.