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INTRODUCTION Factors underlying discordant visual and quantitative amyloid beta–positron emission tomography (Aβ‐PET) results and their clinical implications are not well understood. METHODS Participants from the 1Florida Alzheimer's Disease Research Center (1FLADRC) underwent Aβ‐PET, blood draw, brain magnetic resonance imaging (MRI), and neuropsychological testing. We evaluated differences in demographics, apolipoprotein E (APOE) status, biomarkers, and cognition among older adults with concordant and discordant visual‐quantitative Aβ‐PET. Discordance was defined as positive visual read (V) of Aβ‐PET with below‐threshold Centiloid quantification (Q; CL <25; V+/Q–) or negative visual read with CL ≥25 (V–/Q+). RESULTS We studied 386 participants (mean age ± SD: 70.7 ± 7.8, 55.2% female, 44.6% Hispanic White). Compared to V+/Q–, V–/Q+ had a higher frequency of APOE ε4 carriers (40%). Black/African American participants were overrepresented in V–/Q+ (40.9%). Both discordant groups had higher plasma phosphorylated tau 217 (p‐tau217) and glial fibrillary acidic protein (GFAP) than V–/Q– but lower than V+/Q+. Discordant groups had greater gray matter volume and better cognitive performance than V+/Q+. DISCUSSION Discordant Aβ‐PET findings likely hold clinical significance and may reflect early stages of neuropathological progression. Highlights Groups with concordant/discordant visual‐quantitative amyloid beta–positron emission tomography (Aβ‐PET) results were compared. Visual–/quant+ were more likely than visual+/quant– to be apolipoprotein E (APOE) ε4 carriers and Black/African American. Discordant groups had higher plasma phosphorylated tau 217 (p‐tau217) and glial fibrillary acidic protein (GFAP) than concordant negative. Discordant groups had less atrophy and better cognition than concordant positive. Centiloid quantification should supplement visual reads in clinical settings.

To determine whether the DCTclock can detect differences across groups of patients seen in the memory clinic for suspected dementia. Patients ( = 123) were classified into the following groups: cognitively normal (CN), subtle cognitive impairment (SbCI), amnestic cognitive impairment (aMCI), and mixed/dysexecutive cognitive impairment (mx/dysMCI). Nine outcome variables included a combined command/copy total score and four command and four copy indices measuring drawing efficiency, simple/complex motor operations, information processing speed, and spatial reasoning. Total combined command/copy score distinguished between groups in all comparisons with medium to large effects. The mx/dysMCI group had the lowest total combined command/copy scores out of all groups. The mx/dysMCI group scored lower than the CN group on all command indices (  < .050, all analyses); and lower than the SbCI group on drawing efficiency (  = .011). The aMCI group scored lower than the CN group on spatial reasoning (  = .019). Smaller effect sizes were obtained for the four copy indices. These results suggest that DCTclock command/copy parameters can dissociate CN, SbCI, and MCI subtypes. The larger effect sizes for command clock indices suggest these metrics are sensitive in detecting early cognitive decline. Additional research with a larger sample is warranted.

INTRODUCTION This study aimed to investigate whether sleep quality predicts cognitive/functional decline, and whether Alzheimer's disease (AD) pathology modifies these relationships. METHODS The Pittsburgh Sleep Quality Index was administered to 326 older adults (113 cognitively normal, 192 mild cognitive impairment, 21 dementia; mean age = 66.4 ± 8.0 years) enrolled in the 1Florida Alzheimer's Disease Research Center. The Clinical Dementia Rating Sum of Boxes (CDR‐SB) assessed cognitive/functional decline at baseline and over time. Moderators included hippocampal volume (HV), amyloid beta (Aβ) positron emission tomography, and plasma phosphorylated tau (p‐tau)217. RESULTS Cross‐sectionally, longer sleep duration and later wake time were associated with worse CDR‐SB, with stronger associations observed among individuals with higher Aβ and p‐tau217 levels, and smaller HV. Longitudinally, prolonged sleep duration was associated with faster cognitive decline, particularly in individuals with elevated Aβ or p‐tau217 levels and smaller hippocampal volumes at baseline. DISCUSSION Prolonged sleep duration and later wake times predicted worsening cognitive performance, and these effects were strengthened by greater AD pathology. Highlights Longer sleep duration and later wake times were associated with higher Clinical Dementia Rating Sum of Boxes scores at baseline and over time. The presence of amyloid and phosphorylated tau217 pathology, as well as reduced hippocampal volume, potentiates the effect of sleep disturbances on cognitive/functional impairment. Results suggest that sleep measures may serve as early markers (before cognitive impairment is observed) and potential targets for intervention in cognitive decline associated with aging and Alzheimer's disease.

Sleep apnea is a potential risk factor for Alzheimer's Disease (AD). Associations between sleep apnea and elevated AD biomarkers like amyloid beta (Aβ) and p-tau have been reported, but it is unclear if or how sleep apnea influences the connection between the two. The link between sleep apnea and AD also has not been extensively studied in the context of relevant demographic, sociocultural, and common genetic factors. Therefore, we assessed the moderating effects of sleep apnea on the association between Aβ-PET and plasma p-tau217 and whether this moderation differed based on sex, ethnicity, or APOE e4 carrier status. We studied 1Florida ADRC participants (N = 288) with normal cognition, mild cognitive impairment, or dementia (Table 1). Presence or absence of sleep apnea was determined from the National Alzheimer's Coordinating Center Health History. All participants had plasma samples analyzed for p-tau217 (ALZPath) and completed Aβ-PET with [18F] florbetaben or florbetapir. Global standardized uptake value ratio (SUVR; whole cerebellum reference) was calculated and converted to the Centiloid (CL) scale. We used multiple linear regression to assess the interaction of Aβ-PET and sleep apnea status on plasma p-tau217, controlling for age, sex, and CDR sum of boxes. To determine whether sleep apnea moderator effects differed by APOE e4 carrier status, sex, or ethnicity (Hispanic/Latino vs. non-Hispanic/Latino), we employed three-way interactions. Sleep apnea moderated Aβ-PET associations with p-tau217 (β = 0.26, p = .022; Figure 1), such that greater amyloid burden related more strongly to higher plasma p-tau217 in those with sleep apnea versus without. A significant three-way interaction of Aβ-PET x sleep apnea x ethnicity on plasma p-tau217 (β = -0.52, p = .024; Figure 2) revealed that sleep apnea only moderated this association in non-Hispanic/Latino participants. Sleep apnea moderation was not dependent on sex or APOE e4 carrier status. Addressing sleep apnea as a modifiable risk factor may promote slowing or resistance to AD. Larger and longitudinal studies are needed to comprehensively examine sleep apnea in older adults. Exploring sleep apnea effects in more representative samples with consideration of social and structural determinants of brain health will help clarify the role of sleep on AD onset and progression.

INTRODUCTION Glial fibrillary acidic protein (GFAP) may contribute to Alzheimer's pathology at early disease stages. GFAP moderation of Alzheimer's disease (AD)‐related neurodegeneration and cognition is unclear. METHODS We examined plasma GFAP moderation of AD biomarkers (amyloid beta [Aβ]‐positron emission tomography [PET][A]; plasma phosphorylated tau‐181 [p‐tau181][T1]), neurodegeneration (plasma NfL[Nplasma]; structural magnetic resonance imaging [MRI][NMRI]), and cognition (Cogmemory; Cogexecutive) in two cohorts: University of California San Francisco (UCSF) (N = 212, 91.0% non‐Hispanic/Latino White [NHLW], age = 74.7 [7.6] years, 75.9% cognitively unimpaired [CU]) and 1Florida Alzheimer's Disease Research Centers (1FLADRC; N = 582, 32.8% NHLW, age = 70.7 [8.5] years, 28.9% CU). RESULTS Plasma GFAP consistently moderated A–T1 (UCSF: β = 0.46, p = 0.012; 1FLADRC: β = 0.12, p = 0.029). The association between elevated Aβ‐PET and increased (p‐tau) was strengthened at higher GFAP concentrations. In 1FLADRC, GFAP moderated T1–Nplasma/MRI. In UCSF, GFAP moderated T1–Cogmemory/executive and NMRI–Cogmemory/executive. Higher GFAP consistently related to worse neurodegeneration and cognition (main effects). DISCUSSION Across demographically and clinically heterogeneous cohorts, plasma GFAP is a key moderator of AD and may help identify individuals at greatest risk of AD‐related neurodegeneration and cognitive decline. Highlights AD biomarkers were measured in two demographically and clinically distinct cohorts. Plasma GFAP moderated Aβ‐PET to p‐tau associations in both UCSF and 1FLADRC. Cohort‐dependent, GFAP moderated p‐tau to neurodegeneration and cognition associations. All moderations revealed strengthened disease associations with higher plasma GFAP. Plasma GFAP may help identify individuals at greatest risk of AD‐related decline.

Abstract Background and Objective Prior research with patients with mild cognitive impairment (MCI) suggests that visual versus verbal episodic memory test performance may be more sensitive to emergent illness. However, little research has examined visual versus verbal episodic memory performance as related to MCI subtypes. Research Design and Methods Patients were diagnosed with non-MCI, amnestic MCI (aMCI), and combined mixed/dysexecutive MCI (mixed/dys MCI). Visual and verbal episodic memory were assessed with the Brief Visuospatial Memory Test-Revised (BVMT-R) and the 12-word Philadelphia (repeatable) Verbal Learning Test (P[r]VLT), respectively. Results BVMT-R and P(r)VLT scores yielded similar between-group patterns of performance. Non-MCI patients scored better than other groups on all parameters. aMCI and mixed/dys MCI did not differ on immediate or delayed free recall. Both delayed BVMT-R and P(r)VLT recognition test performance dissociated all three groups. Logistic regression analyses found that BVMT-R delayed free recall and delayed recognition scores correctly classified more patients with MCI (75.40%) than analogous P(r)VLT scores (66.20%). Visual versus verbal memory within-group analyses found no differences among non-MCI patients; P(r)VLT immediate free recall was worse among aMCI patients, but BVMT-R immediate free recall and delayed recognition were worse among mixed/dys MCI patients. Discussion and Implications Between-group analyses found convergent patterns of performance such that both tests identified elements of amnesia. However, logistic and within-group analyses found differing performance patterns suggesting that impaired visual episodic memory performance may be specific to emergent illness in mixed/dys MCI. Complementary but divergent neurocognitive networks may underlie visual versus verbal episodic memory performance in some patients with MCI.

Objective:Widespread musculoskeletal pain disorders like fibromyalgia are often accompanied by varying levels of cognitive dysfunction. Fibromyalgia research suggests that around the time of diagnosis, typically 30-50 years of age, many patients are already showing cognitive difficulties on various neuropsychological assessments. It is unknown, however, how older adults with fibromyalgia perform on rapid cognitive screeners in clinical settings. The present study compared older adults with and without fibromyalgia on a digitized version of a classic neuropsychological screener, the clock drawing test.Participants and Methods:Participants aged 65+ were recruited as part of a larger IRB-approved and federally funded investigation within the preoperative surgical center at the University of Florida (UF) and UF Health. Participant data were obtained with Health Insurance Portability and Accountability Act (HIPAA) waiver and honest broker medical extraction from January 2018 to December 2019 (N=14,807). Based on medical record diagnostic code, participants were categorized into fibromyalgia or non-fibromyalgia groups, then propensity score matched based on age, ethnicity, race, sex, and years of education. The final sample contained 718 older adults (mean age= 71.3±4.89, education years= 13.7±2.62, female= 98.1%, white= 87.9%) (n=359 in each group). All participants completed the command and copy condition of the digital Clock Drawing Test (dCDT). Variables of interest for both conditions included: total completion time (TCT), pre-first hand latency (PFHL), clock face area (CFA), and digit misplacement. These variables were chosen to represent two latency and two graphomotor variables. A natural log transformation was applied to all dCDT variables to achieve normality of the distribution.Results:We confirmed that there was no significant group difference in age, ethnicity, race, sex, and years of education following the propensity match. Fibromyalgia patients had higher comorbidity scores on American Society of Anesthesiologists Classification (ASA) (p= 0.003). Analysis of variance (ANOVA) showed a significant group difference in TCT for both command [F(1,637)= 5.13, p= 0.024, d=0.178] and copy conditions [F(1,466)= 4.03, p= 0.045, d=0.179j. Controlling for ASA, a repeated measures analysis of covariance (ANCOVA) showed that groups still differed in TCT in the command condition [F(1,630)= 4.21, p= 0.041, n2= 0.007; Fibromyalgia > Non-Fibromyalgia], but not in the copy condition.Conclusions:In our sample, older adults with fibromyalgia showed slower TCT to command by approximately three seconds compared to non-fibromyalgia peers. Since TCT to command taps into multiple domains of cognitive functioning, our results are consistent with previous work demonstrating poorer performance across many cognitive domains in fibromyalgia. Future research should continue investigating digital cognitive assessments to identify older adults with fibromyalgia who may be at higher risk for cognitive change. Data acquired through NIH R01 AG055337.

Objective:Research shows that highly educated individuals have at least 20 graphomotor features associated with clock drawing with hands set for '10 after 11' (Davoudi et al., 2021). Research has yet to understand clock drawing features in individuals with fewer years of education. In the current study, we compared older adults with < 8 years of education to those with > 9 years of education on number and pattern of graphomotor feature relationships in the clock drawing command condition.Participants and Methods:Participants age 65+ from the University of Florida (UF) and UF Health (N= 10,491) completed both command and copy conditions of the digital Clock Drawing Test (dCDT) as a part of a federally-funded investigation. Participants were categorized into two education groups: < 8 years of education (n= 304) and > 9 years of education (n= 10,187). Propensity score matching was then used to match participants from each subgroup (n= 266 for each subgroup) on the following demographic characteristics: age, sex, race, and ethnicity (n= 532, age= 74.99±6.21, education= 10.41±4.45, female= 42.7%, non-white= 32.0%). Network models were derived using Bayesian Structure Learning (BSL) with the hill-climbing algorithm to obtain optimal directed acyclic graphs (DAGs) from all possible solutions in each subgroup for the dCDT command condition.Results:Both education groups retained 13 of 91 possible edges (14.29%). For the < 8 years of education group (education= 6.65±1.74, ASA= 3.08±0.35), the network included 3 clock face (CF), 7 digit, and 3 hour hand (HH) and minute hand (MH) independent, or “parent,” features connected to the retained edges (BIC= -7395.24). In contrast, the > 9 years of education group (education= 14.17±2.88, ASA= 2.90±0.46) network retained 1 CF, 6 digit, 5 HH and MH, and 1 additional parent features representing the total number of pen strokes (BIC= -6689.92). Both groups showed that greater distance from the HH to the center of the clock also had greater distance from the MH to the center of the clock [ßz(< 8 years)= 0.73, ßz(> 9 years)= 0.76]. Groups were similar in the size of the digit height relative to the distance of the digits to the CF [ßz(< 8 years)= 0.27, ßz(> 9 years)= 0.56]. Larger HH angle was associated with larger MH angle across groups [ßz(< 8 years)= 0.28, ßz(> 9 years)= 0.23].Conclusions:Education groups differed in the ratio of dCDT parent feature types. Specifically, copy clock production in older adults with < 8 years of education relied more heavily on CF parent features. In contrast, older adults with > 9 years of education relied more heavily on HH and MH parent features. Individuals with < 8 years of education may more infrequently present the concept of time in the clock drawing command condition. This study highlights the importance of considering education level in interpreting dCDT scores and features.

Objective:Research shows that highly educated individuals have at least 20 graphomotor features associated with clock drawing with hands set for '10 after 11' (Davoudi et al., 2021). Research has yet to understand clock drawing features in individuals with fewer years of education. In the current study, we compared older adults with < 8 years of education to those with > 9 years of education on number and pattern of graphomotor feature relationships in the clock drawing copy condition.Participants and Methods:Participants age 65+ from the University of Florida (UF) and UF Health (N= 10,491) completed command and copy digital Clock Drawing Tests (dCDT) as a part of a federally-funded investigation. Participants were categorized into two groups: < 8 years of education (n= 304) and > 9 years of education (n= 10,187). Propensity score matching was used to match participants from each subgroup (n= 266 for each subgroup) on the following: age, sex, race, and ethnicity (n= 532, age= 74.99±6.21, education= 10.41±4.45, female= 42.7%, non-white= 32.0%). Network models were derived using Bayesian Structure Learning (BSL) with the hill-climbing algorithm to obtain optimal directed acyclic graphs (DAGs) from all possible solutions in each subgroup for the dCDT copy condition.Results:The < 8 years of education group (education= 6.65±1.74, ASA= 3.08±0.35), retained 12 of 91 possible edges (13.19%, BIC= -7775.50). The network retained 2 clock face (CF), 5 digit, and 5 hour hand (HH) and minute hand (MH) independent, or “parent,” features connected to the retained edges. In contrast, the > 9 years of education group (education= 14.17±2.88, ASA= 2.90±0.46) network retained 15 of 91 possible edges (16.48%, BIC= -8261.484). The network retained 2 CF, 6 digit, 4 HH and MH, and an additional 3 total stroke parent features. Both groups showed that greater distance from the HH to the clock center also had greater distance from the MH to the clock center (ßz= 0.73, both). Groups were similar in digit width size relative to digit height [ßz(< 8 years)= 0.72, ßz(> 9 years)= 0.74]. Digit height size related to CF area [ßz(< 8 years)= 0.44, ßz(> 9 years)= 0.62] and CF area related to the digit distance to the CF across groups [ßz(< 8 years)= 0.39, ßz(> 9 years)= 0.46]. Greater distance from the MH to the clock center was associated with smaller MH angle [ßz(< 8 years)= -0.35, ßz(> 9 years)= -0.31], whereas greater digit misplacement was associated with larger MH angle across groups [ßz(< 8 years)= 0.14, ßz(> 9 years)= 0.29].Conclusions:Education groups differed in the ratio of dCDT parent feature types. Specifically, copy clock production in older adults with < 8 years of education relied more evenly across CF, digit, and MH and HH parent features. In contrast, those with > 9 years of education differed in the additional reliance on total stroke parent features. Individuals with < 8 years of education may more heavily rely upon visual referencing when copying a clock. This study highlights the importance of considering education level in interpreting dCDT scores and features.

Background Traumatic encephalopathy syndrome (TES) is a proposed framework for the clinical syndrome resulting from chronic traumatic encephalopathy and other neurodegenerative effects of repetitive head impacts (RHI). TES symptoms can mirror Alzheimer's disease (AD) despite absence of hallmark AD pathology. We investigated whether GFAP, NfL, and IL‐6 correlated with cognition and brain volume changes within TES relative to AD. Method We studied 96 participants from the UCSF Memory and Aging Center (N=35 RHI/TES; 24 of whom were AD biomarker‐negative, TESAD‐; N=61 biomarker‐confirmed AD phenotype, no RHI; Table 1). Plasma was analyzed for GFAP, NfL, and IL‐6 (age‐ and sex‐adjusted). Cognitive measures included composite memory and executive functioning scores (demographically‐adjusted). MRI was obtained concurrent to blood draws and several regions of interest were analyzed (demographic‐ and total intracranial volume‐adjusted): frontal, temporal, parietal, occipital, hippocampus, subcortical. Spearman’s rho assessed associations between plasma biomarkers, cognition, and brain volume. A priori alpha was p<.05, but associations with at least medium effect size (rho ≥0.3) were interpreted as potentially meaningful given small N in TES and TESAD‐ subgroups. Result In TES, higher GFAP was associated with lower hippocampal volume (rho=‐0.33, p=.09) and worse memory (rho=‐0.44, p=.02). Results were similar in TESAD‐ subgroup (GFAP‐hippocampus: rho=‐0.45, p=.07; GFAP‐memory: rho=‐0.42, p=.07). IL‐6 appeared most related to brain volume in the TESAD‐ subgroup, where higher IL‐6 correlated with lower volumes in all regions (rho’s ‐.43 ‐ ‐.63, p’s=.004 ‐ .06), but not with cognition. In AD, both higher NfL and GFAP were associated with lower brain volume in several regions and with worse cognition but, notably, neither related to hippocampal volume (NfL: rho=‐.11, p=.47; GFAP: rho=.02, p=.91). IL‐6 did not relate to brain volume or cognition in AD (Figure 1). Conclusion Plasma biomarkers reflect different regions of atrophy and cognitive change in TES vs. AD. Inflammation (IL‐6) may play a distinctive role in the pathophysiology underlying atrophy in TES. While recent work highlights astroglial activation (GFAP) is a putative AD‐related biomarker, it may uniquely relate to hippocampal changes in TES. Ongoing work is needed to unravel the clinical utility of plasma biomarkers for characterizing the neurodegenerative effects of RHI and underlying TES symptoms.