Alzheimer’s Disease (AD) and dementia present major and escalating public health concerns for the U.S., especially among ethnoculturally diverse (e.g., Latinx, non-Latinx Black [NLB]) populations who represent an increasing percentage of the older adult population in the US and bear greater AD burden compared to non-Latinx Whites (NLWs). Notably, neurocognition and functional status are highly correlated in those with AD. However, little has been done to understand these associations and validate functional measures across geographically diverse, multiethnic samples. The aims of this study were to characterize the neurocognition and functional status of a large, multiethnic sample and subsequently examine any associations between neurocognition and functional status among Latinx, NLB, and NLW older adults.

This cross-sectional, retrospective study utilized archival data drawn from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). ADNI is a national, longitudinal, multi-site, observational study aiming to measure the progression of AD (see https://adni-info.org). Study measures included the: 1) Alzheimer’s Disease Assessment Scale Cognitive subscale (ADAS-cog; 13-items), a global neurocognitive battery evaluating neurocognition in people with AD; 2) Functional Activities Questionnaire (FAQ; 10-item questionnaire) to assess functional status; 3) Geriatric Depression Scale (GDS; 15-item questionnaire) for depression; and 4) American National Adult Reading Test (ANART; 50-word test) for reading level. The sample included 1537 older adults who completed baseline visits for the ADNI study, 1333 of whom were NLW, 123 NLB, and 81 Latinx. The average age of the sample was 73 years, average 16 years of education, and 53% male. Compared to the NLW group, the NLB and Latinx groups were significantly younger and had a higher percentage of female participants. Compared to NLW and Latinx groups, the NLB group also had significantly fewer years of education and lower reading scores. Potential confounds (i.e., demographic variables, depression) were identified a priori based on the literature and subsequently analyzed for inclusion as covariates in the primary analyses. Analyses revealed variables were non-normally distributed, therefore Independent Samples Kruskal-Wallis tests and Spearman’s Correlations were computed to examine differences and correlations between ethnocultural groups.

After controlling for age and education, Latinx and NLB groups had significantly higher ADAS-cog and FAQ scores than the NLW group (Hs = 9.50-21.53, ps < .05). Spearman’s partial correlations controlling for age, education, gender, and depression revealed that higher ADAS-cog scores were associated with higher FAQ scores within Latinx (p=.49, p<.001), NLB (p=.66, p<.001), and NLW (p=.60, p<.001) groups.

Findings indicate that neurocognition is positively associated with functional status and support the ecological and external validity of the ADAS-cog and FAQ for use with NLB and Latinx older adults, in addition to previously established work with more homogenous samples. Study strengths include the overall sample size, geographic diversity, and standardization of research approaches. Study limitations include high education level and low comorbidity rates present in the sample, limiting the generalizability of the results, in addition to the unbalanced ethnocultural groups, further emphasizing the need for increased inclusion efforts of ethnoculturally diverse older adults into brain health research studies.

As the older adult population increases in the coming decades, the number of persons that develop dementia of the Alzheimer’s type (DAT) will increase accordingly. Though curative treatment for Alzheimer’s disease remains elusive, early detection of cognitive decline allows for initiation of pharmacological treatment to slow disease progression and non-pharmacological approaches to support quality of life and well-being of affected individuals and their care partners. Streamlined approaches that bridge the gap between brief screenings and comprehensive neuropsychological evaluation are needed. The NIH Toolbox Cognition Battery (NIHTB-CB) is a brief, easily administered, computerized cognitive battery that assesses various aspects of both fluid and crystallized cognitive abilities. ARMADA (Advancing Reliable Measurement in Alzheimer’s Disease and Cognitive Aging) is a multi-site study that aims to validate the NIHTB across the spectrum from normal aging to DAT. The current study utilized longitudinal data from ARMADA to determine whether performance on the NIHTB-CB detects cognitive decline in persons with normal cognition (NC), mild cognitive impairment (MCI), and mild DAT over the span of two years. We predicted that scores would decline for the MCI and DAT groups, but not for the NC group.

Participants were 191 participants drawn from the larger ARMADA cohort aged 65-84 (nNC = 118, nMCI = 47, nDAT = 26) that completed the NIHTB-CB at baseline and 12 months. The clinical groups were significantly older than the NC group at baseline (MNC = 72.72, MMCI = 76.63, MDAT = 75.42; p < .001) and the NC and MCI groups had significantly more years of education than the DAT group (MNC = 17.03, MMCI = 16.83, MDAT = 15.54; p = .008).

Mixed model ANOVAs determined differences in uncorrected NIHTB-CB scores between clinical groups at baseline and 12 months, controlling for age and education. There were significant interactions between time and clinical group for Flanker (p < .001), Pattern Comparison (p < .001), and Picture Vocabulary (p = .001), such that the DAT group demonstrated a more negative slope of change than the NC and MCI groups. For Oral Reading, the MCI group demonstrated a more negative slope of change than the NC and DAT groups (p = .01).

Differential score trajectories were found for the Flanker task, with a more negative pattern of change in scores in the DAT group compared to the NC and MCI groups. Contrary to expectation, scores decreased for the two crystallized subtests across groups, which may reflect regression to the mean given high baseline scores, especially for Picture Vocabulary; however, these results were also moderated by group with less decline in scores in the NC group, which may indicate involvement of non-crystallized abilities in executing a single word comprehension task. Group differences were subtle, which may in part reflect the relatively short period of follow up. The Flanker task appears to be most sensitive to decline in mild DAT compared to MCI and NC. Results provide preliminary support for the utility of NIHTB-CB in detecting cognitive decline along the cognitive aging to DAT spectrum.

Using a humanized APOE3/4 (Alzheimer’s disease genetic risk allele) mouse model we investigated the potential modulating effects of exercise on systemic risk factors and the ability of this mouse model to translate to active or sedentary, midlife, human participants. We present preliminary results of an ongoing, translational pilot study.

26 Midlife individuals, ages 40-65, were recruited from the community and dichotomized into active or sedentary groups following health screening and cognitive assessment. Blood samples were drawn from human participants for lipid assessment and other general health measures as well as peripheral growth factors concentrations (VEGF, BDNF and FGF21). Traditional, transgenic mouse models have helped the scientific community to understand biological mechanisms of Alzheimer’s disease (AD), but they do not develop significant neuronal loss, a hallmark of AD pathology. The MODEL-AD consortium has created a new “humanized” APOE4 model that has the human APOE4 allelic sequence in place of the mouse APOE gene; the model has shown known human phenotypes including deficits in cholesterol trafficking, amyloid clearance and BBB integrity. Of upmost importance, this model does not develop a full AD phenotype indicating that additional genetics and/or environmental factors are required as would be seen in human populations. We used males and females of this model to complete identical sedentary and active measures of each APOE genotype.

Lipid and general health marker assessment between mouse and human were similar and reproduced published literature. In both humans and mice we saw increased total cholesterol and HDL in active females and decreased total cholesterol and HDL in active males. We also saw similar relationships between APOE genotype, sex, and activity with regards to triglycerides. Although total cholesterol, HDL and LDL measures are the primary lipids needed to confirm or deny translation, other lipid measurements were not equivalent between the two models. Growth factor assessment in both species are also similar and reproduce published literature with regards to VEGF and BDNF as we see trending elevated levels in the active group. Less published on is the finding seen between active females and these elevated growth factors levels; our results indicates that although elevated as a result of exercise, this increase may be more prominent in females.

Based on the results found here we conclude that The Jackson Laboratory’s humanized APOE3/4 mouse model is a translatable model of vascular dysfunction, dementia and Alzheimer’s disease. We also conclude that exercise modulates these aspects by growth factor activation and increases resulting in downstream effects that reduce peripheral vascular risk factors and therefore reduce the risk of Alzheimer’s disease as a result of neuroinflammation. Complete, APOE genotype results from human participants are still ongoing. Descriptive analysis is limited by human samples size.

Women have a greater lifetime risk of developing Alzheimer’s disease (AD) dementia than men, a sex/gender disparity that cannot be explained by female longevity alone. There is substantial evidence for sex differences in the effects of APOE £4 on risk for AD. While APOE e4 increases AD risk in both sexes, women who carry APOE e4 are disproportionately vulnerable to cognitive impairment and AD compared to their counterpart men. In contrast to APOE e4, APOE £2 is associated with slower cognitive decline and a lower risk of AD. Although a less robust literature, APOE e2 may also have sex-specific effects. Because APOE e2 is the rarest major APOE allele, well-powered studies are needed to examine sex-specific effects. The objective of the present study was to examine sex-specific associations of APOE e2 carriage with longitudinal cognitive decline in a large cohort of clinically unimpaired adults.

We used observational data from two sources: the National Alzheimer’s Coordinating Center (NACC) and the Rush Alzheimer’s Disease Center (ROS/MAP/MARS) studies. We included data from clinically unimpaired adults who were >50 years old at baseline who self-identified as non-Hispanic White (NHW) or non-Hispanic Black (NHB). Participants were categorized as APOE £2, £4, or £3/e3 carriers. APOE e2/e4 carriers were excluded. The same battery of neuropsychological tests was used to assess global cognition in participants from both data sources. Linear mixed models examined interactive associations of genotype (£2 or £4 vs. £3/£3), sex, and time on longitudinal cognition in NHW and NHB participants separately. Analyses were first performed in a pooled sample of NACC and ROS/MAP/MARS participants and if significant they were repeated separately in each data source.

Across both data sources, 9,766 NHW (mean (SD) age=73.0(9.00) years, mean (SD) education=16.3(2.83) years, n(%) women=6,344(65.0)) and 2,010 NHB participants (mean(SD) age=71.3(7.59) years, mean(SD) education=14.9(3.10) years, n(%) women=1,583(78.8)) met inclusion criteria. Sex modified the association between APOE £2 and cognitive decline in NHW (ß=0.097, 95% CI: 0.023-0.172, pint=.01) but not NHB participants (ß=-0.011, 95% CI: -0.153-0.131, pint=.9). In sex-stratified analyses of NHW participants, APOE £2 (vs. £3/£3) carriage was associated with attenuated cognitive decline in men (ß=0.096, 95% CI: 0.037-0.155, p=.001), but not women (ß=-0.001, 95% CI: -0.044-0.043, p=.97). In analyses comparing men and women APOE £2 carriers, men exhibited slower cognitive decline than women (ß=0.120, 95% CI: 0.051-0.190, p=.001). Analyses performed separately in NACC and ROS/MAP revealed the same pattern of male-specific APOE £2 protection in NHW participants in both data sources.

In light of the longstanding view that APOE £2 protects against AD and dementia, our results provide evidence that APOE £2 is associated with attenuated cognitive decline in men but not women among NHW adults. This male-specific protection may contribute to sex differences in AD-related cognitive decline. Our findings have important implications for understanding the biological drivers of sex differences in AD risk, which is crucial for developing sex-specific strategies to prevent and treat AD dementia.

Associative memory is impacted early in Alzheimer’s disease (AD). Poorer performance on associative memory tests has been related to greater amyloid and regional tau burden in preclinical AD. Our group previously examined the association of brain pathology and performance on the Free and Cued Selective Reminding Test (FCSRT) in Autosomal Dominant Alzheimer’s Disease (ADAD), finding that associative memory summary scores distinguished non-demented mutation carriers from non-carriers several years before clinical onset of cognitive impairment. In the current study, we examined whether FCSRT learning slopes were associated with brain pathology in a sample of ADAD carriers and non-carriers.

There were 119 participants including 57 non-demented carriers of the Colombian kindred with the Presenilin1 E280A mutation and 62 non-carrier family members (mean age= 36.3, 60% female). Participants were administered the Mini-Mental State Examination (MMSE), a measure of global cognitive status, and the FCSRT, which consists of three trials in which participants are asked to freely recall the same list of 16 items. It is a well-established measure known to be sensitive to early changes in AD. A subsample of 69 participants (32 carriers and 37 non-carriers) underwent positron emission tomography (PET) to measure in vivo cortical amyloid-beta (Pittsburgh compound B, PiB), and regional tau (Flortaucipir, FTP) burden in entorhinal and precuneus regions, which are among the earliest sites of tau accumulation in this ADAD population. Mann Whitney U tests, Spearman correlations, and chi-square tests were used to examine group differences and relations among variables of interest. Learning slope was calculated by subtracting the number of items freely recalled in FCSRT Trial 1 from the number of items freely recalled in Trial 3.

Compared to non-carriers, carriers had greater cortical amyloid-ß and regional tau burden, lower MMSE scores (mean [SD]: carriers= 27.5 [2.7]; non-carriers= 28.8 [1.0]), and lower scores on total immediate/ delayed free/ cued recall scores on the FCSRT (all p<.01). The groups did not differ on age, sex, or education level (all p> 0.05). In the whole sample and in carriers only, we found that higher MMSE scores were associated with higher learning slope, meaning faster learning (whole group p= 0.25, p= 0.006; carriers p= 0.30, p=0.029). In the whole sample, we found that lower learning slope was associated with higher levels of amyloid (p=-.34, p=.006) and tau in the left, right, and bilateral precuneus region (p=-.43, p<.001; p=-.46, p<.001; p=-.45, p<.001). In carriers only, lower learning slope was associated with higher tau burden in the left, right, and bilateral precuneus specifically (p=-.43, p=.017; p=-.48, p=.008; p=-.46, p=.010, respectively). No significant associations were found in non-carriers.

These findings suggest that learning curves on an associative memory test may be sensitive to preclinical pathological changes in AD, specifically within the precuneus, a brain region known to be involved in cue reactivity, episodic memory retrieval, and mental imagery strategies. Future studies with larger samples are warranted to further examine associations between the FCSRT learning curves and regional tau accumulation in individuals with ADAD.

The Biber Figure Learning Test (BFLT) is a serial figure learning assessment previously been shown to be sensitive to various biomarkers of the aging brain. BFLT is an extensive assessment requiring about 30 minutes for administration. In this study, we investigated BFLT’s associations with subjective cognitive decline (SCD), an early marker for preclinical Alzheimer’s Disease (AD), and examined whether alternative BFLT indices could be utilized to considerably shorten the length of assessment without decreasing its sensitivity to SCD.

Participants were 50 cognitively normal older adults (8% Hispanic, 92% Non-Hispanic; 78% White, 16% Black; 64% female; mean age =72.7 (SD =6.2); mean education =17.05 (SD =2.09)). SCD was measured using a 20-item age-anchored dichotomous questionnaire that assessed complaints of cognitive functioning, and the BFLT was administered in full. Pearson correlations were conducted between SCD and BFLT scores including: Trial 1 Learning (T1), Trials 1 to 2 Total Learning (T1T2), Trials 1 to 3 Total Learning (T1T3), Trials 1 to 5 Total Learning (Total Learning), Immediate Recall, Delayed Recall, Proactive Interference (Trial B – Trial 1), Retroactive Interference (Immediate Recall – Trial 5), and Total Discrimination (calculated as [Recognition Total Correct + 0.5]/16) − ([Total False Alarms + 0.5]/31]). A Fishers Exact Test was utilized to compare the correlational strength between SCD and each of the BFLT scores. Lastly, demographically adjusted (age, gender, and education) regression models were conducted to examine SCD as an individual predictor for the various BFLT scores.

SCD was negatively associated with BFLT T1 (r =-0.406, p =0.003), T1T2 (r =-0.331, p =0.019), T1T3 (r =-0.323, p =0.022), Total Learning (r =-0.283, p =0.046), Immediate Recall (r =-0.322, p =0.023), Delayed Recall (r =-0.318, p =0.025), and Retroactive Interference (r =-0.388, p =0.005) and positively associated with Proactive Interference (r =0.308, p =0.029). There was no significant difference in correlational strength between any of these BFLT scores and SCD. Adjusting for demographics, SCD predicted Immediate Recall (B =-0.273, p =0.029), Total Learning (B =- 0.253, p =0.040), T1 (B =-0.412, p =0.002), T1T2 (B =-0.326, p =0.010), T1T3 (B =-0.299, p =0.017), Proactive Interference (B =0.292, p =0.050), and Retroactive Interference (B =- 0.330, p =0.025).

Eight of the nine assessed BFLT scores were strongly correlated with age-anchored SCD and age-anchored SCD predicted seven of the nine assessed BFLT indices when adjusted for demographics. Although additional work is needed, these findings suggest SCD’s sensitivity to changes in visuospatial learning and memory, supporting its use as an early marker for preclinical AD. Likewise, our results suggest that an abbreviated version of the BFLT could be utilized that shortens testing time and reduces participant fatigue without a decrease in clinical relevance. Through ongoing longitudinal work, we hope to further disentangle the relationship between SCD and visuospatial learning and memory as measured through the BFTL and to examine how associations between SCD and the BFLT assessment change over time.

Caregiver burden tends to worsen as severity of dementia increases, and elevated burden can lead to negative consequences for dementia caregivers. In contrast, positive aspects of caregiving, such as feelings of being useful, needed, or appreciated as a caregiver, are associated with better outcomes. Caregivers reporting fewer positive experiences robustly demonstrate greater burden, suggesting that a lack of positive aspects of caregiving could be a key component of the relationship between dementia severity and burden. This study investigated whether an indirect effect of positive aspects of caregiving would be observed on the association between dementia severity and burden.

Data were extracted from the medical records of 724 patients enrolled for services at an outpatient memory clinic. Caregiver-care recipient dyads were included based on a clinically supported patient diagnosis on the dementia spectrum following a comprehensive geriatric evaluation and having fully completed assessments from an informal caregiver. Caregivers completed the Zarit Burden Interview (ZBI) and the Positive Aspects of Caregiving (PAC) measures. The Montreal Cognitive Assessment and Mini-Mental State Exam were used to estimate dementia severity, standardized to create a single variable. Multiple potential covariates (e.g., age, gender, education, nature of dyadic relationship) were considered for inclusion in the model. A cross-sectional mediation analysis using the Hayes PROCESS macro explored presence of an indirect effect of PAC on the relationship between dementia severity and ZBI using 5000 bootstrap samples.

Of the proposed covariates, only caregiver age was correlated with any of the primary variables; this variable was controlled in subsequent analyses. Significant relationships emerged between dementia severity and ZBI (r=-.12, p<.001), between PAC and ZBI (r=-.23, p<.001), and between dementia severity and PAC (r=-.07, p<.05). An indirect effect of positive aspects of caregiving on the relationship between dementia severity and ZBI was statistically significant (B= .0092, BC 95% CI [.0008, .0185]), accounting for 14.4% of the variance in the model.

A small but significant indirect effect of positive aspects of caregiving was observed on the association between dementia severity and burden. Results suggest that as dementia severity worsens, a caregiver who experiences greater positive aspects of caregiving will sustain less burden. Longitudinal examination of these relationships is needed to fully understand causality. Findings may help healthcare providers tailor treatment to alleviate caregiver burden.

History of traumatic brain injury (TBI) is associated with increased risk of dementia, but few studies have evaluated whether TBI history alters the course of neurocognitive decline, and existing literature on this topic is limited to short follow-up and smaller samples. The primary aim of this study was to evaluate whether a history of TBI (TBI+) influences neurocognitive decline later-in-life among older adults with or without cognitive impairment [i.e., normally aging, Mild Cognitive Impairment (MCI), or dementia].

Participants included individuals from the National Alzheimer’s Coordinating Center (NACC) who were at least 50 years old and with 3 to 6 visits (M number of visits = 4.43). Participants with any self-reported history of TBI (n = 1,467) were matched 1:1 to individuals with no reported history of TBI (TBI-) from a sample of approximately 45,000 participants using case-control matching based on age (+/- 2 years), sex, education, race, ethnicity, cognitive diagnosis [cognitively normal (CN), MCI, or all-cause dementia], etiology of cognitive impairment, functional decline (Clinical Dementia Rating Scale, CDR), number of Apolipoprotein E4 (APOE ε4) alleles, and number of annual visits (3 to 6). Mixed linear models were used to assess longitudinal neuropsychological test composites (using NACC normative data) of executive functioning/attention/speed (EFAS), language, and memory in TBI+ and TBI- participants. Interactions between TBI and demographics, APOE ε4 status, and cognitive diagnosis were also examined.

Following matching procedures, TBI+ (n=1467) and TBI- (n=1467) groups were nearly identical in age (TBI+ M = 71.59, SD = 8.49; TBI- M = 71.63, SD = 8.44), education (TBI+ M = 16.12, SD = 2.59; TBI- M = 16.10, SD = 2.52), sex (both 55% male), race (both 90% White), ethnicity (both 98% non-Hispanic), APOE ε4 alleles (both 0 = 62%, 1 = 33%, 2 = 5%), baseline cognitive diagnoses (both CN = 60%, MCI = 18%, dementia = 12%), and global CDR (TBI+ M = 0.30, SD = 0.38, TBI- M = 0.30, SD = 0.38). At baseline, groups had similar Z-scores of in EFAS (TBI+ Mefas = -0.02, SD = 1.21; TBI- Mefas = -0.04, SD = 1.27), language (TBI+ MLanguage = -0.48, SD = 0.98; TBI- MLanguage = -0.55, SD = 1.05), and memory (TBI+ MMemory = -0.45, SD = 1.28; TBI- MMemory = -0.45, SD =1.28). The course of change in neuropsychological functioning worsened longitudinally, but did not differ between TBI groups (p’s > .110). There were no significant interactions between TBI history and age, sex, education, race/ethnicity, number of APOE ε4 status, or cognitive diagnosis (all p’s > .027).

In this matched case-control design, our findings suggest that a history of TBI, regardless of demographic factors, APOE ε4 status, and cognitive diagnosis, does not significantly alter the course of neurocognitive functioning later-in-life in older adults with and without cognitive impairment. Future clinicopathological longitudinal studies with well characterized TBI histories and the associated clinical course are needed to help clarify the mechanism by which TBI may increase dementia risk for some individuals, without affecting course of decline.

Blood-based biomarkers represent a scalable and accessible approach for the detection and monitoring of Alzheimer’s disease (AD). Plasma phosphorylated tau (p-tau) and neurofilament light (NfL) are validated biomarkers for the detection of tau and neurodegenerative brain changes in AD, respectively. There is now emphasis to expand beyond these markers to detect and provide insight into the pathophysiological processes of AD. To this end, a reactive astrocytic marker, namely plasma glial fibrillary acidic protein (GFAP), has been of interest. Yet, little is known about the relationship between plasma GFAP and AD. Here, we examined the association between plasma GFAP, diagnostic status, and neuropsychological test performance. Diagnostic accuracy of plasma GFAP was compared with plasma measures of p-tau181 and NfL.

This sample included 567 participants from the Boston University (BU) Alzheimer’s Disease Research Center (ADRC) Longitudinal Clinical Core Registry, including individuals with normal cognition (n=234), mild cognitive impairment (MCI) (n=180), and AD dementia (n=153). The sample included all participants who had a blood draw. Participants completed a comprehensive neuropsychological battery (sample sizes across tests varied due to missingness). Diagnoses were adjudicated during multidisciplinary diagnostic consensus conferences. Plasma samples were analyzed using the Simoa platform. Binary logistic regression analyses tested the association between GFAP levels and diagnostic status (i.e., cognitively impaired due to AD versus unimpaired), controlling for age, sex, race, education, and APOE e4 status. Area under the curve (AUC) statistics from receiver operating characteristics (ROC) using predicted probabilities from binary logistic regression examined the ability of plasma GFAP to discriminate diagnostic groups compared with plasma p-tau181 and NfL. Linear regression models tested the association between plasma GFAP and neuropsychological test performance, accounting for the above covariates.

The mean (SD) age of the sample was 74.34 (7.54), 319 (56.3%) were female, 75 (13.2%) were Black, and 223 (39.3%) were APOE e4 carriers. Higher GFAP concentrations were associated with increased odds for having cognitive impairment (GFAP z-score transformed: OR=2.233, 95% CI [1.609, 3.099], p<0.001; non-z-transformed: OR=1.004, 95% CI [1.002, 1.006], p<0.001). ROC analyses, comprising of GFAP and the above covariates, showed plasma GFAP discriminated the cognitively impaired from unimpaired (AUC=0.75) and was similar, but slightly superior, to plasma p-tau181 (AUC=0.74) and plasma NfL (AUC=0.74). A joint panel of the plasma markers had greatest discrimination accuracy (AUC=0.76). Linear regression analyses showed that higher GFAP levels were associated with worse performance on neuropsychological tests assessing global cognition, attention, executive functioning, episodic memory, and language abilities (ps<0.001) as well as higher CDR Sum of Boxes (p<0.001).

Higher plasma GFAP levels differentiated participants with cognitive impairment from those with normal cognition and were associated with worse performance on all neuropsychological tests assessed. GFAP had similar accuracy in detecting those with cognitive impairment compared with p-tau181 and NfL, however, a panel of all three biomarkers was optimal. These results support the utility of plasma GFAP in AD detection and suggest the pathological processes it represents might play an integral role in the pathogenesis of AD.

Alzheimer’s disease (AD), a leading cause of dementia worldwide, affected an estimated 47 million people in 2015, placing a burden of over $1 trillion on health systems. Subclinical markers of AD pathology are seen many years before the clinical onset of dementia, suggesting that steps could be taken to prevent progression to disease in healthy individuals. Sleep optimizes cognition by creating a window of opportunity to consolidate memories, prune synaptic networks, and clear waste products. Studies that characterize the relationship between sleep and cognitive function prior to the onset of clinical AD could guide research into effective methods of delaying AD onset or preventing it altogether. The objective of our study is to describe how sleep quality and quantity correlate with performance on cognitive assessments within a healthy, aging population.

Seventeen participants, between 62-82 years of age enrolled in an ongoing clinical trial assessing the effects of melatonin (5mg daily) versus placebo, were included in our study. Participants were observed over a 2-month period, during which no experimental interventions were administered. At study entry, participants underwent a comprehensive neuropsychological evaluation evaluating cognitive domains of attention, memory, speed of information processing, language, executive functioning, and mood. Afterwards, all participants wore a watch that measured actigraphy and light data (Philips Actiwatch Spectrum Pro actigraphy monitor) for 8 weeks to evaluate their sleep habits. Pearson and Spearman partial correlations were used to evaluate relationships between objective sleep parameters and baseline cognitive function test scores.

Aberrations of sleep length, sleep fragmentation, and daytime activity measures significantly correlated with cognitive performance on memory, language, visuospatial skills, and speed of processing tests (p = <0.05). Greater variability of awakenings at nighttime associated with better scores on memory tests but worse scores on language tests. Longer sleep times associated with worse language scores, while greater variability in daily activity correlated with poorer scores on visuospatial skills tests and speed of processing tests.

This study establishes a framework for obtaining longitudinal sleep data in conjunction with serial cognitive function testing, encouraging further exploration into how sleep metrics affect specific domains of cognitive function. Findings suggest that having a less consistent sleep routine correlates with poorer cognitive function across multiple domains. The authors recommend broader analysis of actigraphy and cognitive function testing as objective measures of sleep and cognition in research and clinical practice.

In the field of neurocognitive disorders, the perspective offered by new disease-modifying therapy increases the importance of etiological diagnosis. The prescription of cerebrospinal fluid analysis (CSF) and imaging biomarkers is a common practice in the clinic but is often driven more by personal expertise and local availability of diagnostic tools than by evidence of efficacy and cost-effectiveness analysis. This leads to a widely heterogeneous dementia care across Europe. Therefore, a European initiative is currently being conducted to establish a consensus for biomarker-based diagnosis of patients with mild cognitive impairment (MCI) and mild dementia.

Since November 2020, a European multidisciplinary task force of 22 experts from 11 scientific societies have been defining a diagnostic workflow for the efficient use of biomarkers. The Delphi consensus procedure was used to bridge the gaps of incomplete scientific evidence on biomarker prioritization. The project has been in two phases. During Phase 1, we conducted a literature review on the accuracy of imaging, CSF, neurophysiological and blood biomarkers in predicting the clinical progression or in defining the underpinning aetiology of main neurocognitive disorders. Evidence was provided to support the panelists’ decisions. In phase 2, a modified Delphi procedure was implemented, and consensus was reached at a threshold of 70% agreement, or 50%+1 when a question required rediscussion.

In phase 1, 167 out of 2,200 screened papers provided validated measures of biomarker diagnostic accuracy compared with a gold standard or in predicting progression or conversion of MCI to the dementia stage (i.e., MRI, CSF, FDG-PET, DaT-imaging, amyloid-PET, tau-PET, and myocardial MIBG-scintigraphy and EEG). During phase 2, panelists agreed on the clinical workspace of the workflow, the stage of application, and the patient age window. The workflow is patient-centered and features three levels of assessment (W): W1 defines eleven clinical profiles based on integrated results of neuropsychology, MRI atrophy patterns, and blood tests; W2 describes the first-line biomarkers according to W1 versus clinical suspicion; and W3 suggests the second-line biomarkers when the results of first-line biomarkers are inconsistent with the diagnostic hypothesis, uninformative or inconclusive. CSF biomarkers are first-line in the suspect of Alzheimer’s disease (AD) and when inconsistent neuropsychological and MRI findings hinder a clear diagnostic hypothesis; dopamine SPECT/PET for those leading to suspect Lewy body spectrum. FDG-PET is first-line for the clinical profiles leading to suspect frontotemporal lobar degeneration and motor tauopathies and is followed by CSF biomarkers in the case of atypical metabolic patterns, when an underlying AD etiology is conceivable.

The workflow will promote consistency in diagnosing neurocognitive disorders across countries and rational use of resources. The initiative has some limitations, mainly linked to the Delphi procedure (e.g., kickoff questions were driven by the moderators, answers are driven by the Delphi panel composition, a subtle phrasing of the questions may drive answers, and 70% threshold for convergence is conventional). However, the diagnostic workflow will be able to help clinicians achieve an early and sustainable etiological diagnosis and enable the use of disease-modifying drugs as soon as they become available.

There are numerous adverse health outcomes associated with dementia caregiving, including increased stress and depression. Caregivers often face time-related, socioeconomic, geographic, and pandemic-related barriers to treatment. Thus, implementing mobile health (mHealth) interventions is one way of increasing caregivers’ access to supportive care. The objective of the current study was to collect data from a 3-month feasibility trial of a multicomponent mHealth intervention for dementia caregivers.

40 community-dwelling dementia caregivers were randomized to receive the CARE-Well (Caregiver Assessment, Resources, and Education) App or internet links connected to caregiver education, support, and resources. Caregivers were encouraged to use the App or links at least 4 times per week for 3 months. The App consisted of self-assessments, caregiver and stress reduction education, behavior problem management, calendar reminders, and online social support. Caregivers completed measures of burden, depression, and desire to institutionalize at baseline and post-intervention. Feasibility data included App usage, retention and adherence rates, and treatment satisfaction. Data were analyzed via descriptive statistics.

Caregivers were mostly white (95%), female (68%), in their mid-60s, (M= 66.38, SD= 10.64), and well-educated (M= 15.52 years, SD= 2.26). Caregivers were mainly spouses (68%) or adult children (30%). Care recipients were diagnosed with mild (60%) or moderate (40%) dementia, with 80% diagnosed as having Alzheimer’s disease. Overall, the study had an 85% retention rate (80% for App group; 90% for links group). 58% of caregivers in the App group were considered high users, using the App >120 minutes over the course of 3 months (M= 362.42, SD= 432.68), and an average of 16.44 days (SD= 15.51). 15% of the sample was non-adherent due to time constraints, disinterest, and/or technology issues. Most participants (75%) using the App were mostly or very satisfied, about 87% would be likely or very likely to seek similar programs in the future, and 93% found the App mostly or very understandable. Groups did not significantly differ on clinical outcomes, although the study was not powered for an efficacy analysis. Within groups analysis revealed significant increases in depressive symptoms at post-treatment for caregivers in both groups.

This study demonstrated initial feasibility of the CARE-Well App for dementia caregivers. App use was lower than expected, however, high satisfaction, ease of use, and willingness to use similar programs in the future were endorsed. Some caregivers did not complete the intervention due to caregiving responsibilities, general disinterest, and/or technology issues. Although the study was not designed to assess clinical outcomes, we found that both groups reported higher depressive symptoms at post-treatment. This finding was unexpected and might reflect pandemic-related stress, which has been shown to particularly impact dementia caregivers. Future studies should address the efficacy of multicomponent mHealth interventions for dementia caregivers and the effects of increased dose on clinical outcomes. mHealth interventions should be refined to cater to varying levels of technology literacy among caregivers, and further research should aim to better integrate interventions into caregivers’ routines to enhance treatment engagement.

Patients with early Alzheimer Disease (AD) and Mild Cognitive Impairment of the Amnestic type (MCI-A) have been reported to show large variability of tapping scores. Factors that contribute to that variability remain undetermined. This preliminary study aimed to identify predictors of finger tapping variability in older adults evaluated for a neurodegenerative memory disorder. Based on earlier research with normally functioning adults, we predicted that the number of “invalid” tapping responses (i.e. failure of the index finger to adequately lift off the tapping key once it is depressed to produce the next number on a mechanical counter) and the female gender would predict finger tapping variability, but age and educational level would not predict variability.

This preliminary study included 4 groups of participants, comprised of 8 healthy controls (HC, 3 males; 73±7years); 12 persons with subjective memory complaints (SMC, 3 males; 69±5 years); 12 with MCI-A (7 males; 76±5 years) and 7 early AD (5 males; 75±6years). All participants were administered a modified version of the Halstead Finger Tapping Test (HFTT). Mean, range of tapping score (i.e. a measure of variability), and number of invalid taps across 7 trials in each hand were calculated. ANOVA was performed for the HFTT metrics with the main effect of group. Tukey HSD tests were used for post hoc comparisons between groups. Multiple regression analysis was performed to determine the degree to which the number of invalid tapping responses, sex, age, and educational level predicted finger tapping variability using all 4 groups.

Mean tapping score did not vary significantly across groups in the dominant [F (3, 35) = 0.633, p = 0.599] or non-dominant [F (3, 35) = 2.345, p = 0.090] hand. Range score approached a significant difference between groups in the dominant hand [F (3, 35) = 2.745, p = 0.058], with a clear significant effect of group on range score in the non-dominant hand [F (3, 35) = 4.078, p = 0.014]. Range score in the nondominant hand was significantly higher in the AD compared to SMC (p = 0.018) and HC (p = 0.024). Regression analysis revealed statistically significant findings for the dominant hand (R2 = 0.327, F (4, 34) = 4.130, p = 0.008) and for the non-dominant hand (R2 = 0.330, F (4, 34) = 4.180, p = 0.007). For both the dominant and non-dominant hands, number of invalid taps significantly predicted range score (ß = 0.453, p = 0.044, and ß = 0.498, p = 0.012, respectively). Sex, age, and education years did not predict range scores.

Variability of finger tapping in patients evaluated for neurodegenerative memory disorders and aged matched controls is predicted by the number of invalid tapping responses (comprising over 30% of the variance), but not by demographic variables in this clinical sample. Neurodegenerative disorders may eliminate a sex effect.

The objectives of this study were to investigate family members’ perception of the impact of the neuropsychological evaluation and subsequent feedback session on (1) caregiver understanding of the patient’s diagnosis and symptoms and (2) treatment planning, patient well-being, caregiver stress, and support utilization.

Participants included family members of patients undergoing a neuropsychological dementia evaluation and subsequent oral feedback session at a midwestern university medical center by one of five neuropsychology providers. The average age of patients undergoing dementia evaluation was 73.4 (range = 52 - 92). Patients in the sample were categorized as having dementia (67%), mild cognitive impairment (24%), or no cognitive disorder (9%), with 46% of the sample suspected to have Alzheimer’s disease or mixed Alzheimer’s and vascular disease. Immediately following the feedback session, family members were provided a brief survey, $10 prepaid gift card to keep regardless of survey completion, and a stamped, pre-addressed envelope to return the survey anonymously by mail. A total of 200 surveys were disseminated and 127 (64%) were completed and returned. Family members completing the survey were most often the spouse (60.6%) or the child (29.1%) of the patient. Eighty-two percent of respondents identified as being the patient’s primary caregiver.

Family members were asked to rate their agreement to perceptions held both prior to and following the neuropsychological evaluation. Ninety-seven percent strongly agreed (81%) or agreed (16%) that the neuropsychological evaluation was helpful, and 95% strongly agreed (62%) or agreed (33%) that the neuropsychological evaluation would help the patient get better or more targeted care. Comparison using Wilcoxon signed-rank tests indicated that family members were significantly more likely to agree (p < .001) with the following beliefs after, as opposed to preceding, the neuropsychological evaluation: (1) the patient’s symptoms had been well addressed (z = -7.95), (2) I was explained the diagnosis (z = -8.12), (3) I am confident in my family member’s diagnosis (z = -7.88), and (4) I am more likely to use dementia-related community resources (z = -5.78). Additionally, family members nearly unanimously agreed or strongly agreed that, following the neuropsychological evaluation, their family member’s symptoms had been well addressed (98%), they were explained the patient’s diagnosis (98%), and they were confident in the diagnosis (97%). In instances where dementia was diagnosed, 91% of family members agreed/strongly agreed that they planned to use dementia-related community resources. Furthermore, a majority of family members reported that the neuropsychological evaluation positively impacted the patient’s psychological wellbeing (82%), caregiver stress (74%), caregiver interactions with the patient (76%), treatment plan (82%), and overall patient care (79%).

Results indicate that family members of patients undergoing neuropsychological evaluation for suspected dementia perceive the neuropsychological evaluation as improving diagnostic understanding and confidence. Additionally, family members nearly unanimously agreed that the neuropsychological evaluation had a positive impact on treatment planning, patient well-being, caregiver stress, and utilization of supports.

Neuropsychiatric/behavioral-psychological symptoms of dementia (BPSD) frequently contribute to worse prognosis of patients with neurodegenerative conditions. BPSD are commonly measured via a brief, informant-rated version of the Neuropsychiatric Inventory (NPI), the NPI-Q. Previously (see our other submission to this conference), we established optimal latent structures by comparing different factor models in the literature using confirmatory factor analyses (CFAs). However, questions remain as to why so many different models were found in the literature. One possibility is sampling differences, including different proportions of individuals across cognitive stages (e.g., mild cognitive impairment, moderate dementia) or syndromes (e.g., Alzheimer’s amnestic syndrome, Dementia with Lewy Bodies). We tested this hypothesis by subjecting candidate models to measurement invariance (MI) analyses stratified by cognitive stage and syndrome.

Individuals were included if they had completed an NPI-Q during their first visit at an Alzheimer Disease Research Center reporting to the National Alzheimer Coordinating Center (NACC). This resulted in 20,500 individuals (57% female; 80% White, 13% Black, 8% Hispanic), with a mean age of 71 (SD = 10.41) and 15 average years of education (SD = 3.43). Regarding staging, 75.9% of individuals did not meet criteria for all-cause dementia, whereas 24.1% individuals had all-cause dementia. Regarding syndromes, 35.6% had an Alzheimer’s presentation (“AD-type”) and 5.6% had either a behavioral variant frontotemporal dementia or Lewy-Body dementia presentation (“behavioral-type”). A 3-factor and 4-factor model were subject to MI across these groupings. We conducted MI analyses for equal forms, equal loadings, and equal intercepts using the lavaan R package with a diagonally weighted least squares (DWLS) estimator.

The 3-factor model demonstrated good fit among individuals experiencing (CFI = 0.965, TLI = 0.955) and not experiencing (CFI = 0.984, TLI = 0.979) dementia, as well as among AD-type (CFI = 0.983, TLI = 0.978) presentations, but had borderline poor fit for behavioral-type (CFI = 0.932, TLI = 0.912) presentations. The 4-factor model had better fit among those experiencing (CFI = 0.985, TLI = 0.977) and not experiencing (CFI = 0.995, TLI = 0.992) dementia. Additionally, the 4-factor model demonstrated good of fit for AD-type (CFI = 0.993, TLI = 0.989) and poorer fit for behavioral-type (CFI = 0.949, TLI = 0.922) syndromes. Chi-square differences suggested that equal loading and equal intercept hypotheses should be rejected for both 3- and 4-factor models, for both staging and syndromal groupings. However, relative fit indices suggested that the equal form, equal loading, and equal intercept hypotheses could be adequate for only the 4-factor model.

The variability of factor structures in the BPSD literature appears, at least partially, explained by sampling variability among cognitive stages and dementia syndromes. The best models in the literature appear to have good fit in non-demented individuals and, among those who have dementia, in those with an AD syndrome. Only Sayegh & Knight’s 4-factor model had adequate (albeit, not optimal) fit among those with all-cause dementia and, more specifically, among those with a behavioral-type dementia syndrome. These findings inform BPSD theory and practical implementation of NPI-Q subscales.

Alzheimer’s disease (AD) clinical trials lack diverse representation, limiting their generalizability. In addition, the clinical meaningfulness of observed changes during treatment may vary as a function of participant characteristics. Defining meaningful change in AD within diverse ethnoracial groups is therefore greatly needed. Meaningful change in AD trials can be assessed by three different anchors: participants, informants, or clinicians. Previous research has suggested that estimations of the minimal clinically important difference (MCID) vary by disease severity, choice of anchor, and anchor agreement. These relationships have been studied primarily within non-Hispanic white (NHW) samples. This project evaluates anchor-based MCID within and across the three most prevalent ethnoracial groups in the United States, non-Hispanic White (NHW), Hispanic/Latino (H/L), and Black/African-American (B/AA).

Data from the National Alzheimer’s Coordinating Center Uniform Dataset (NACC UDS) were used to investigate MCID within older adults (ages 50+) diagnosed as cognitively normal or cognitively impaired due to suspected AD. Data were taken from all versions of the UDS and consisted of all available participants with two consecutive annual visits. The identified sample (N=22,043) is approximately 83.6% NHW, 4.7% H/L, and 11.7% B/AA. Participant, informant, and clinician anchor variables were utilized to compare proportions of anchor agreement within and across ethnoracial groups. MCID on the Mini-Mental State Exam (MMSE) was estimated within each ethnoracial group and compared across the independent variables of anchor agreement and disease severity (cognitively normal (CN), mild cognitive impairment (MCI), and dementia) in 2x3 ANOVAs.

Participant age (M = 71.56, SD = 9.03) did not significantly differ across ethnoracial groups; years of education significantly differed across groups, p < .001, with NHW (M=15.83 SD=3.05), H/L (M=12.49, SD=5.01), and B/AA (M=14.42, SD=3.22). Across all three anchors (participant, informant, clinician), unanimous agreement about the presence or absence of a decline in functioning was present in about 75.1% of the full sample. To further explore agreement differences across groups, anchor agreement was classified into a 3-level variable: 1) agreement that the participant remained stable over time, 2) agreement that the participant declined, and 3) disagreement. The proportion of each level within each ethnoracial group was significantly different, (x2(4, n = 22,043) = 179.16, p < .001, phi = .09, NHW (34.5% agreement-stable, 41.4% agreement-declined, 24.1% disagreement), H/L (30.5%, 42.6%, 26.9%, respectively), and B/AA (42.2%, 28.1%, 29.7%, respectively). MCID estimates on the MMSE followed similar trends within each ethnoracial group. There was a significant main effect of disease severity, such that MCID estimates increased in magnitude with increasing disease severity. There were no significant main effects of anchor agreement for any ethnoracial group. Within the NHW sample only, an interaction effect between diagnostic severity and anchor agreement was significant (p = .007).

Across ethnoracial groups, MCID estimates on the MMSE are reliably influenced by the severity of disease. However, the benefit of anchor-based MCID estimates may vary by ethnoracial group with respect to both anchor choice and use of anchor agreement. The origins of anchor disagreement and perceived stability in functioning warrant further exploration.

Mild decline in independent functioning is a core diagnostic criterion for Mild Cognitive Impairment. Performance-based assessments have been considered the gold standard to identify subtle deficits in functioning. Existing assessments were largely designed using demographically homogenous samples (white, highly educated, middle class) and often assume tasks are performed similarly across populations. The current study aimed to validate the utility of the Performance Assessment of Self-Care Skills (PASS) in determining cognitive status in a sample of predominantly African American, low-income older adults.

Cognition and functional capacity were measured in n=245 older participants (aged 50+ years) who were recruited from a larger community study located in Pittsburgh, PA. Cognitive status was defined by a mean split on the Modified Mini Mental Status Examination (3MS) score (84/100). Participants above the cutoff were classified as unlikely cognitive impairment (UCI) and those below classified as potential cognitive impairment (PCI). Functional capacity was assessed using the number of cues provided on three PASS subtasks: shopping, medication management, and critical information retrieval (higher score = worse functioning). Self-reported cognitive and functional decline was assessed via the Everyday Cognition (ECog) questionnaire (higher score = greater decline). Generalized linear models compared performance scores between groups adjusting for literacy (WRAT3), age, and education. Receiver operating characteristic curve (ROC) analyses were run for select functional performance scores to assess their predictive ability in discriminating between PCI and UCI.

Compared to the UCI group (N = 179), the PCI group (N = 66) was older (68 vs. 65 years, p = 0.05), less educated (11 years vs. 12 years, p < 0.01), had lower WRAT3 z-scores (0.19 vs. -0.55, p < .01), and required more cues on the shopping (4.33 vs. 8.54, p < 0.01) and medication management PASS subtasks (2.74 vs. 6.56, p < .01). Both groups reported elevated levels of subjective cognitive complaints on the ECog (1.46 vs. 1.56, p = .09) and performed similarly on the critical information retrieval PASS subtask (0.25 vs 0.54, p = .06). When discerning between UCI and PCI groups, the PASS Shopping subtask had an optimal cut-off score of 4, sensitivity of 0.86, specificity of 0.47, positive predictive value (PPV) of 0.37, and area under the curve (AUC) of 0.71. PASS Medication Management had an optimal cut-off score of 3, sensitivity of 0.77, specificity of 0.56, PPV of 0.39, and AUC of 0.74.

Subjective functional decline and performance on the critical information retrieval subtask were not associated with cognitive groups. PASS shopping and medication management had moderately high AUCs, suggesting they can reliably distinguish between groups. However, both tasks also exhibited low PPVs, low levels of specificity, and high levels of sensitivity, making them strong “rule-out” tests but poor “rule-in” tests in this sample. Because accurate assessment of functioning is useful for MCI and critical to dementia diagnosis, it is imperative we understand how these tasks function across different populations. Future work should 1) validate measures of functional ability across different populations and 2) develop population-appropriate assessments for use in clinical and research settings.

There are critical and perplexing sex/gender differences in Alzheimer’s disease (AD). Women show a more favorable clinical profile in preclinical AD particularly with verbal memory, but a steeper decline post mild cognitive impairment (MCI) diagnosis and, ultimately, higher rates of AD. Longitudinal studies are needed to understand sex differences across the AD trajectory. Using data from the Alzheimer’s Disease Neuroimaging Initiative, we identified profiles of memory trajectories among those with evidence of preclinical AD or MCI at baseline and how these trajectories differ by sex.

In our sample of 659 participants (age range: 55-90, mean age=72.9 [SD=7.4], 95% non-Hispanic White; mean follow-up=41.2 [SD=32.3] months), 233 were labelled “preclinical” AD (51% women) at baseline based on a cognitively normal status but positivity for either the cerebrospinal fluid p-Tau/Aß42, Amyloid PET or Tau PET biomarkers, and 426 participants (44% women) were MCI at baseline based on Jak/Bondi criteria. We applied latent class growth curve modeling to the heterogeneous change in the Rey Auditory Verbal Learning Test (RAVLT) Immediate and Delayed Recall within preclinical and MCI groups separately. Models in MCI group included Non-Linear Spline to account for differential change rates within subgroups. Models were compared on Bayesian Information Criterion, Entropy, and Class distribution to determine a best-fitting model. Effects of sex on trajectories were the primary outcomes. All models included APOE4 carrier status and age.

Women outperformed men on Immediate and Delayed Recall at baseline in the preclinical and MCI groups (ps<.05). Within the preclinical group, 3-class models representing stable, decline, and accelerated decline provided optimal fit for both Immediate and Delayed Recall. Whereas, on average, preclinical women showed more stable Immediate Recall than men (beta=6.24, SE=.82, p<.0001), they were more likely to be in the Immediate Recall accelerated decline class (23.4% vs. 16.25%; female:male; Chi-square=36.29, p<.00001). On average, preclinical women and men did not differ in Delayed Recall trajectories (beta=.31, SE=.30, p=.28); however, preclinical women were more likely to be in the stable Delayed Recall class (11.04% vs. 6.5%; Chi-Square=19.19, p<.0001). Within the MCI group, 2-class models representing a stable decline group and an accelerated decline group provided optimal fit for both outcomes. Whereas, on average, MCI women showed more stable Immediate Recall than men (beta=3.55, SE=.79, p<.0001), they were more likely to be in the Immediate Recall accelerated decline class, although not significantly. Women and men did not differ, on average, in their Delayed Recall trajectories; however, women were significantly more likely to be in the Delayed Recall accelerated decline class (Chi-square=32.24, p<.0001).

Our findings indicate that sex is an important determinant of the variability observed in early-stage AD trajectories; however, sex differences varied by Immediate versus Delayed Recall likely due, in-part, to psychometric test properties. Our results suggest that, when looking at sex differences in AD trajectories on average, women’s superior stability in verbal learning masks their higher likelihood of rapid decline. Our findings have implications for our ability to optimally diagnose and track disease progression in both sexes.

Compared to older men, Alzheimer’s Disease (AD) is more common in older women, who present with higher levels of pathological tau and accelerated memory decline, although it is unclear why. Furthermore, sleep complaints increase with age, with older women reporting worse sleep quality than older men, and past studies have linked sleep disturbances to tau. Because of the life-long “verbal memory advantage” in women over men, nonverbal memory may more accurately reflect tau burden in women since sex differences are not as apparent. Here, in a sample of older women in the Women Inflammation Tau Study (WITS), we examined the associations between subjective sleep quality, tau in temporal regions, and memory, and whether tau would be more strongly related to nonverbal memory than verbal memory.

In WITS, women have elevated AD polygenic hazard scores and have mild cognitive impairment as indicated by the telephone Montreal Cognitive Assessment (range:13-20). This preliminary sample of 20 women (aged 72.0±3.7) completed the Pittsburgh Sleep Quality Index (PSQI) to assess sleep quality in 7 domains of sleep health over the past month. A global score (range:0-21) is calculated, with a score >5 indicative of being a poor sleeper. Participants also underwent positron emission tomography (PET) with the 18F-MK6240 tracer and T1-weighted magnetic resonance imagining (MRI) to determine tau deposition. Standardized uptake value ratio (SUVR) was calculated using the inferior cerebellum grey matter as the reference region, which was created from Automated Anatomic Labeling atlas in native T1 space. The region of interest (ROI) was a composite meta-temporal region. The Rey Auditory Verbal Learning Test (RAVLT) and Logical Memory (LM) Story A and B were administered to assess verbal memory. The Brief Visuospatial Memory Test-Revised (BVMT-R) was administered to assess nonverbal memory. Analysis focused on the delayed recall scores from the memory tests. Partial correlation was used to analyze the associations between PSQI global score, tau-PET SUVR in meta-temporal ROI, and memory delayed recall scores, while adjusting for age and education years.

8 women were poor sleepers indicated by the PSQI global score (mean:4.9±2). Worse subjective sleep quality was associated with greater tau in meta-temporal ROI (r=0.63, p=0.005) and lower BVMT-R delayed recall (r=-0.46, p=0.05). Sleep quality was not significantly related to either RAVLT or LM delayed recall (all p’s>0.40). Tau in meta-temporal ROI was not significantly associated with nonverbal (p=0.23) or verbal memory (all p’s>0.40) delayed recall.

In this preliminary analysis, subjective sleep quality was linked to temporal tau deposition and nonverbal memory delayed recall, which may suggest that poor sleep exacerbates pathogenesis of tau that leads to memory difficulties in older women at increased risk for AD. Although tau was not significantly related to any memory measures, we will explore whether tau will mediate or moderate the relationship between sleep quality and nonverbal memory once we are powered to do so. Continual evaluation and treatment of sleep may be imperative in mitigating AD risk, especially for older women, however, future longitudinal studies will be necessary to investigate this.

Normal pressure hydrocephalus (NPH) is characterized by pathologically enlarged ventricles without elevated cerebrospinal fluid (CSF) pressure along with a triad of clinical symptoms including gait disturbances, urinary incontinence, and cognitive impairment. NPH is evaluated with lumbar drain trials (LDTs) where CSF is removed over several days to determine if patients would benefit from ventricular shunting. Candidate selection and success for these surgeries remains challenging because other diseases such as Alzheimer’s disease (AD) share common features with NPH in cognitive impairment and enlarged ventricles. Prior research has found that 20%-40% of presumed NPH cases have AD pathology as determined by brain biopsy or autopsy. CSF biomarkers of AD can be altered in NPH and are not always conclusive, complicating the interpretation of results when formulating diagnoses and prognoses. Studies to refine the analyses of AD CSF biomarkers in NPH are needed. We aimed to examine the frequency of CSF biomarker results among patients presenting for NPH evaluations with LDTs.

62 patients presented for LDTs upon physician recommendations. CSF specimens were sent to Mayo Clinic Laboratories for Alzheimer Disease Evaluation (ADEVL) that utilizes Elecsys (Lenexa, KS) CSF electrochemiluminescence immunoassays (Roche Diagnostics, Basel, Switzerland) to measure levels of amyloid-beta 42 (Aβ42), total tau (t-tau), and phosphorylatedtau (p-tau), and p-tau:Aβ42 ratio. Results were classified based on interpretation through the Amyloid/Tau/Neurodegeneration (ATN) framework1: 1) AD - biomarker profile consistent with AD pathologic change, 2) non-AD profile - biomarker levels normal or inconsistent with AD pathologic change, or 3) indeterminate - biomarkers were incongruous with only one or two abnormal levels of Aβ42, t-tau, p-tau, or ptau: Aβ42. Indeterminate cases may represent altered protein levels due to CSF dynamics or AD-related pathologic change. In reviewing recent research on CSF dynamics and AD biomarkers in NPH2 a p-tau threshold of 15 pg/mL was derived and implemented such that cases with Aß42 <=1026 pg/mL and p-tau <15 pg/mL were designated as suspected non-AD, and those with Aß42 <=1026 pg/mL and p-tau >15 pg/mL were designated suspected AD.

Of the 62 LDT cases, 12 (19.35%) were classified as AD, 31 (50%) were indeterminate and 22 (35.48%) were non-AD. Of the 31 indeterminate cases, 21 (33.87% of the overall sample) were suspected non-AD and 7 (11.29% of the full sample) were categorized as suspected AD.

Our findings show that 20%-30% of patients presenting for LDT showed evidence for AD-type pathologic change, consistent with prior reports of AD pathology in cases of possible NPH. Half of all LDT cases had indeterminate AD CSF biomarker results, the interpretations of which were confounded by the potential alterations of CSF biomarkers levels due to NPH independent of AD. Our findings emphasize the need to establish better approaches to interpreting CSF AD biomarkers in evaluating NPH. Future research should examine the discriminative utility of CSF AD biomarkers and the selected p-tau threshold in indeterminate cases for predicting response to LDT and shunting.