US forces used Agent Orange (AO) during the Vietnam War and continued to store/test it at other locations after the war. AO is a powerful herbicide including dioxin, a highly toxic ingredient classified as a human carcinogen. The National Academies of Sciences, Engineering, and Medicine periodically review the literature on the health effects of AO exposure (AOE) and concluded in 2018 that there is sufficient evidence linking AO with a wide range of adverse health outcomes, including neurologic disorders (e.g., Parkinson’s disease). The VA has a list of medical disorders considered presumptive conditions related to AOE. More recently, AOE has been linked to a nearly double risk compared to those without AOE for receiving a dementia diagnosis. To our knowledge, no one has investigated the association of AOE to mild cognitive impairment (MCI), a condition thought to precede dementia.

We examined men in three waves of the Vietnam Era Twin Study of Aging (VETSA). In wave 3, participants self-reported yes/no to the question of whether they ever had prolonged or serious AOE. MCI was diagnosed by the Jak-Bondi approach. Impairment was defined as 2+ tests within a cognitive domain that were more than 1.5 standard deviations below normative means after adjusting for premorbid cognitive ability. In mixed effects models, we tested the effect of AOE on MCI status. Models were adjusted for age, ethnicity, and non-independence within twin pairs.

In wave 3, 12.6% (230) of 1167 participants reported AOE. Those with AOE data had mean ages of 51.1 (wave 1), 56.0 (wave 2), and 61.4 (wave 3). Those with data on both AOE and MCI numbered 861 (wave 1), 900 (wave 2), 1121 (wave 3), and 766 had AOE and MCI at all waves. AOE was significantly related to wave 2 MCI (p < .001), but not to waves 1 and 3 MCI. AOE was significantly associated with the number of time points at which someone met criteria for MCI (p = .011). Analyses were conducted on six cognitive domains used to diagnose MCI, using available participants per wave. At all 3 waves, AOE was significantly associated with lower scores in processing speed (p = .003, p = .004, p = .005, respectively), working memory (p < .001, p = .002, p = .008) and nearly significant at all waves for executive dysfunction (p < .001, p < .001, p = .050). There were two other significant associations [wave 2 memory (p = .038), wave 3 fluency (p = .024)]. The semantic fluency cognitive domain was unrelated to AOE in all waves.

AOE was consistently associated with lower processing speed, working memory, and executive dysfunction in males ages 51-61. It was also associated with the number of time points at which one met criteria for MCI in that age range, and with MCI in the mid-fifties. Findings support the idea of a risk for greater cognitive decline in those exposed to AO earlier in their lives, and with a risk for developing MCI.

Subjective Cognitive Decline (SCD), the perception of deteriorating cognition in the absence of apparent impairment on objective testing, has gained momentum in recent literature as a risk marker for AD. Traditional neuropsychological assessments, while typically inclusive of a word list learning task, often do not include a comparable figure learning task. Growing evidence suggests that nonverbal assessments may be particularly sensitive to the earliest cognitive changes associated with Alzheimer’s disease. The Biber Figure Learning Test (BFLT), a visuospatial analogue to verbal list learning tasks, has been shown to associate with brain-based biomarkers of Alzheimer’s disease (AD; hippocampal volume, amyloid load). This study investigates the utility of the BFLT in capturing SCD above and beyond other cognitive measures sensitive to AD progression.

50 community-dwelling, cognitively normal individuals (78% White, 16% Black, 6% Other; 92% Non-Hispanic; 64% Female; Education M=17.1, SD=2.1; Age M=72.7, SD=6.2) participated in a study of SCD. All participants performed >-1.5 SD on clinical neuropsychological testing including a word list learning task. SCD was assessed using a 20-item scale querying individuals’ perception of difficulty across a range of memory and non-memory abilities in relation to others of the same age. Participants completed the BFLT, Loewenstein-Acevedo Scales of Semantic Interference and Learning (LASSI-L), Short-Term Memory Binding (STMB), and Face-Name Associative Memory Exam (FNAME), previously established as being sensitive to pre-clinical AD, were examined as predictors of SCD. A multiple regression adjusted for demographics (age, gender, education) was used to investigate the extent to which BFLT Trial 1 (T1) predicted SCD above and beyond these other cognitive measures sensitive to AD progression. Trial 1 of the BFLT was used based on a separate abstract examining which BFLT score was most highly associated with SCD (Kann et al., pending acceptance).

Adjusting for demographics, the present model accounts for 42% of the variance in SCD, while Biber T1 alone accounts for 20% and is the only significant individual predictor of SCD (β=-0.55, p=0.004). In contrast, other variables in the model independently accounted for less than 1% to 4% each (age β=-0.23, p=0.15; gender β=-0.15, p=0.34; education β=0.06, p=0.66; LASSI-L β=-0.11, p=0.55; STMB β=-0.03, p=0.85; FNAME β=-0.10, p=0.64).

The present study demonstrates the usefulness of the first learning trial of the BFLT as an independent predictor of SCD above and beyond other verbal and nonverbal measures sensitive to AD pathology. It also highlights the value of including even one trial of figure learning (< 5 minutes) in both clinical and research assessments seeking to capture cognitive changes which may be the earliest indicators of a neurodegenerative process. Ongoing longitudinal research is examining the predictive utility of the BFLT for future cognitive decline and transition to Mild Cognitive Impairment. Further research should explore the association between Biber T1, specifically, and neuropathological biomarkers of AD to further establish its utility as a portent of AD.

Subjective cognitive decline (SCD) is increasingly being considered one of the earliest clinical signs of Alzheimer’s Disease (AD). Certain characteristics of early life, such as childhood socioeconomic status (SES), have been associated with late life cognitive performance. Here we examine the extent to which childhood SES predicts SCD.

The current sample consisted of 55 healthy older adults (17 Male, 39 Female), aged 51 to 88 (M=73.14, SD=6.23) with a mean education of 16 years (SD=2.1 years). 21.5% of the sample self-reported as race/ethnic minorities (e.g., Hispanic or Non-Hispanic African American, Asian, Other.) Participants completed a 20-item SCD questionnaire assessing perceived cognitive difficulties in comparison to same aged peers, and objective cognitive testing. Childhood SES was assessed using two items. The first item asked the participant to utilize a modified MacArthur Scale of Subjective Social Status to identify where on the ladder they felt their family would have been placed during their childhood relative to others in the United States. This ladder has 10 rungs, with rung 1 associated with being the “worst off” and rung 10 associated with being the “best off”. The second item asked the participant to rate their family’s difficulty paying bills during their childhood. Linear regression models were used to examine the extent to which childhood SES predicted SCD. Models were adjusted for education, referral source (clinical versus non-clinical), and objective cognitive testing. Age and gender were not associated with childhood SES or SCD, and as a result were not adjusted for in these models.

On the MacArthur Scale, 20% of participants placed their family at rung 5, 38.2% placed their families at a rung lower than 5, and 41.8% placed their family at a rung higher than 5. When rating the difficulty their family faced paying bills, 3.6% of participants responded “extremely difficult”, 16.4% responded “very difficult”, 20% responded “somewhat difficult”, 23.6% responded “slightly difficult”, and 36.4% responded “not difficult”. Linear regression models revealed a significant effect of childhood SES on SCD (β=-.29, p=.045, SE=.90; β=-.35, p=.015, SE=1.68).

Childhood SES, measured by subjective social status and family’s difficulty paying the bills in childhood, was predictive of SCD in this study of cognitively healthy adults. This result highlights another characteristic of early life that may shape the path of cognitive aging. The predictive utility of childhood SES for SCD may also provide clinicians and researchers with further insight into the populations that may be more susceptible to experiencing SCD in later life. Future studies should utilize a larger sample size among a population with a greater range of childhood SES, to most accurately capture the effectiveness of childhood SES to predict SCD.

Physical inactivity is associated with a greater risk of frailty, neuropsychiatric symptoms, worse quality of life, and increased risk for Alzheimer’s disease. Little is known about how physical activity engagement of older adults during the COVID-19 pandemic relates to subjective cognitive concerns and management of emotional distress. This study aimed to examine whether there were changes in physical activity during the pandemic in older adults at baseline and 3 months compared to before the pandemic and whether these changes varied based on age, sex, income level, and employment status. Further, we examined whether individuals who reported engaging in less physical activity experienced greater subjective cognitive difficulties and symptoms of depression and anxiety than those who maintained or increased their physical activity levels.

301 participants (73% non-Hispanic whites) completed an online survey in either English or Spanish between May and October 2020 and 3 months later. The Everyday Cognition Scale was used to measure subjective cognitive decline, the CES-D-R-10 scale to measure depressive symptoms, and the GAD-7 scale to measure anxiety symptoms. Changes in physical activity were measured with the question “Since the coronavirus disease pandemic began, what has changed for you or your family in regard to physical activity or exercise levels?” with options “less physical activity,” “increase in physical activity,” or “same activity level.” Income was self-reported as high, middle, or low. Analyses of chi-squared tests were used to examine differences in physical activity maintenance by age, income level, sex, and employment status.

Most individuals (60%) reported having decreased their physical activity levels during the pandemic, at baseline and 3-month followup. There were differences in physical activity levels based on income and age: participants with a high income reported engaging in more physical activity than those with low income (X^2=4.78, p =.029). At the 3-month follow-up, middle-income participants reported being less active than the high-income earners (X^2=8.92, p=.003), and younger participants (55-65 years, approximately) reported being less active than older participants (X^2=5.28, p =.022). Those who reported an increase in their physical activity levels had fewer cognitive concerns compared to those who were less active at baseline, but this difference was not seen in the 3-month follow-up. Participants of all ages who reported having maintained or increased their physical activity levels had fewer depressive symptoms than those who were less active (p < 0.0001). Those who reported maintaining their physical activity levels exhibited fewer anxiety symptoms than those who were less active (p < 0.01).

Older adults reported changes in physical activity levels during the pandemic and some of these changes varied by sociodemographic factors. Further, maintaining physical activity levels was associated with lower symptoms of depression, anxiety, and cognitive concerns. Encouraging individuals and providing resources for increasing physical activity may be an effective way to mitigate some of the pandemic’s adverse effects on psychological wellbeing and may potentially help reduce the risk for cognitive decline. Alternately, it is possible that improving emotional distress could lead to an increase in physical activity levels and cognitive health.

Fear of falling is an anxiety-related phenomenon that is associated with increased risk of morbidity and mortality in older adults. Furthermore, a growing body of research has established the relationship between fear of falling and decreased cognitive functioning within various populations (i.e., older adult, multiple sclerosis, stroke survivors). Yet there is little information on the relationship between fear of falling and cognition outside of a geriatric context, with no publications investigating this relationship within informal caregivers. It is important to understand this relationship within caregiver populations because fear of falling may negatively impact caregivers’ ability to take care of themselves and their care recipients. The present study examines the relationship between fear of falling and cognitive function in informal caregivers.

Fifty informal caregivers (86% female; 58% White; 10% Hispanic or Latino; 82% married; 53% with at least a bachelor’s degree; mean age = 57.76 ± 16.60 years) were assessed at the VA Palo Alto Health Care System in Palo Alto, CA. Fear of falling was measured via the Short Falls Efficacy Scale. Areas of cognitive functioning included verbal attention (Rey Auditory Verbal Learning Task [RAVLT] Trial 1), learning and memory (RAVLT Trials 1-5), delayed memory (RAVLT Delayed Recall), visual attention (Stroop Color, Stroop Word), and executive function (Stroop Color Word). Analyses included linear regressions with age as a covariate in all models.

Analyses revealed that fear of falling was significantly associated with decreased verbal attention (RAVLT Trial 1: ß=-0.34, p = 0.02, t = -2.35, CI = [-0.659, -0.051]) and with decreased executive functioning (Stroop Color Word: ß = -0.35, p < 0.001, t = -3.10, CI = [-4.097, -0.874]). Fear of falling was not significantly associated with learning and memory or visual attention.

Fear of falling negatively impacts verbal attention and executive functioning, regardless of age. To our knowledge, this is the first study to examine the relationship between fear of falling and cognition outside of a geriatric population and within a caregiver sample. Findings suggest a need for additional assessment, research, and treatment of fear of falling within informal caregivers. Caregivers may need to be assessed for anxiety-related symptoms such as fear of falling on a more regular basis. A caregiver experiencing fear of falling, as well as difficulties with attention and executive functioning, can result in increased risk of functional and cognitive decline for both the caregiver and their care recipient. It is integral that future research investigates this relationship longitudinally to identify if the negative impact of fear of falling on cognition is reversible.

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.

As the US population ages, the prevalence of Alzheimer’s disease and related dementias (AD/RD) is on the rise. This is especially true in rural America, where mortality rates due to AD/RD are rising faster than in metropolitan areas. To date, however, people living in rural communities are severely underrepresented in aging research. The Nevada Exploratory Alzheimer’s Disease Research Center (NVeADRC) seeks to address this gap. Here, we present preliminary cognitive data from our rural-dwelling cohort, as well as relevant demographic and clinical characteristics.

Individuals with normal cognition (NC), mild cognitive impairment (MCI), and dementia due to Alzheimer’s disease (AD) living in rural communities, defined as a rural-urban commuting area (RUCA) code of 4 or higher, were enrolled through either clinic or community outreach. Eligibility for the observational cohort required: age >55 years, primarily English-speaking, primary residence in a rural community, and availability of a study partner. Measures included the Uniform Data Set (v3), blood-based biomarkers, structural brain MRI, and portions of the PhenX Social Determinants of Health toolkit. Participants are seen at baseline and followed annually, with interim remote visits every 6 months. A multidisciplinary consensus diagnosis is rendered after each visit. Where feasible, a harmonized urban cohort followed by the Nevada Center for Neurodegeneration and Translational Neuroscience (CNTN) was used for comparison.

Fifty-six rural-dwelling (age=70.4±7.1 years; edu=15.2±2.6 years; 61% female) and 148 urban-dwelling (age=72.9±6.8 years; edu=15.8±2.7 years; 46% female) older adults were included; age significantly differed between cohorts but education did not. The rural cohort was 46% NC (MoCA=26.8±2.3; CDRsob=0.3±0.6), 32% MCI (MoCA=22.8±3.1; CDRsob=1.2±1.0), and 22% AD (MoCA=16.9±5.5; CDRsob=5.2±3.0). The urban cohort was 39% NC (MoCA=26.4±2.6; CDRsob=0.3±0.8), 44% MCI (MoCA=22.3±3.1; CDRsob=2.0±1.5) and 17% AD (MoCA=18.6±3.9; CDRsob=4.7±2.3). Rural communities were significantly more disadvantaged, as measured by the Area Deprivation Index (ADI), than urban communities (rural ADI=6.3±2.6; urban ADI=3.4±2.3; p<.001). Fifty-percent of the rural cohort lives in a moderate to severely disadvantaged neighborhood (ADI Decile>7) compared to 12% of the urban cohort, and 11% of individuals in the rural cohort reported living more than 30 miles from the nearest medical facility. Across the combined cohort, education was significantly correlated with ADI deciles (r=-.30, p<.001), with people in the areas of highest disadvantage having the lowest education. Verbal memory was also inversely associated with ADI. There were no differences in clinical diagnosis as a function of ADI rank.

Living in a rural community conveys a multifaceted array of risks and benefits, some of which differ from urban settings. The literature to date suggests that older adults living in rural communities are at significantly increased risk for morbidity and mortality due to AD/RD, though it is unclear why. Preliminary data from the NVeADRC show that increasing levels of neighborhood disadvantage were associated with lower levels of education and worse verbal memory in this convenience sample. The combined effect of low education and increased disadvantage account for some of the urban-rural differences in mortality that have been reported, though additional research on representative samples in this underrepresented population is critical.

Differences in adaptive functioning present early in development for many children with monogenic (Down Syndrome, Fragile X) and neurodevelopmental disorders. At this time, it is unclear whether children with ACC present with early adaptive delays, or if difficulties emerge later as functional tasks become more complex. While potential delays in motor development are frequently reported, other domains such as communication, social and daily living skills are rarely described. We used a prospective, longitudinal design to examine adaptive behavior from 6-24 months in children with ACC and compared their trajectories to those with monogenic and neurodevelopmental conditions.

Our sample included children with primary ACC (n= 27-47 depending on time point) whose caregivers completed the Vineland Adaptive Behavior Scales-Interview 3rd Edition, via phone at 6, 12, 18 and 24 months. Comparison samples (using the Vineland-2) included children with Down Syndrome (DS; n = 15-56), Fragile X (FX; n = 15-20), children at high familial likelihood for autism (HL-; n=192-280), and low likelihood (LL; no family history of autism and no developmental/behavioral diagnosis; n = 111196). A subset of the HL children received an autism diagnosis (HL+; n = 48-74). The DS group did not have an 18-month Vineland.

A series of linear mixed model analyses (using maximum likelihood) for repeated measures was used to compare groups on three Vineland domains at 6, 12, 18 and 24 month timepoints). All fixed factors (diagnostic group, timepoint, and group X timepoint interaction) accounted for significant variance on all Vineland domains (p < .001). Post hoc comparisons with Bonferroni-correction examined ACC Vineland scores compared to the other diagnostic groups at each timepoint. At 6 months, parent-ratings indicated the ACC group had significantly weaker skills than the LL group in Communication and Motor domains. At 12, 18 and 24 months, ratings revealed weaker Communication, Daily Living and Motor skills in the ACC group compared to both the LL and HL- groups. Compared to the other clinical groups, the ACC group had stronger Socialization and Motor skills than Fragile X at 6 months, and at 24 months had stronger Communication and Socialization skills than both the DS and FX groups, as well as stronger Socialization than the HL+ group.

Compared to children with low likelihood of ASD, children with primary ACC reportedly have weaker Communication and Motor skills from 6 to 24 months, with weakness in Daily Living Skills appearing at 12 months and all differences increase with age. Compared to Fragile X, the ACC exhibited relative strengths in socialization and motor skills starting at 6 months. By 24 months, the ACC group was outperforming the monogenic groups on Socialization and Communication. In general, the ACC scores were consistent with the HL+ sample, except the ACC group had stronger Social skills at 18 and 24 months. The results clearly inform the need for early intervention in the domains of motor and language skills. Additionally, as we know that children with ACC are at increased risk for social difficulties, research is needed both using more fine-grained social-communication tools, and following children from infancy through middle childhood.

Agenesis of the Corpus Callosum (ACC), a congenital disorder in which the corpus callosum partially or completely fails to develop properly, occurs in ∼1 in 4,000 live births. ACC has been identified as a major risk factor for receiving an Autism Spectrum Disorder (ASD) diagnosis (∼10% diagnosis rate, as compared to 2.3% in the general population), but little is currently known about behavioral and social development during infancy and early childhood in this disorder. In this study we aim to 1) characterize the manifestation of autistic features in 24-month-old children (a common age for early diagnosis of ASD) with ACC and a convenience sample of age matched comparison children from the community, and 2) determine if parent reports of autistic features during the first year of life are associated with reciprocal social behavior and autistic traits at 24-months of age in children with ACC.

Parents of infants who had received a diagnosis of ACC completed the Parent Rating of Communication, Emotion, and Social Skills (PROCESS) for their child at 6, 12, and 24-months of age, and the video-referenced rating of reciprocal social behavior (vrRSB) at 24-months of age. Comparison data were obtained from a convenience community sample in Minnesota. Aim 1). The distributions of PROCESS total scores at 24-months were compared between the ACC group (n=43) and control group (n=1058) via a 2-tailed t-test. Likewise, distributions of reciprocal social behavior (RSB) scores at 24 months were compared between ACC (n=72) and controls (n=1438) via a 2-tailed t-test. Aim 2). A partial Pearson Correlation was conducted between ACC participants’ 6-month PROCESS scores and 24-month RSB (n=18) scores, as well as between their 12-month PROCESS and 24-month vrRSB (n=37) scores, controlling for child sex.

Aim 1). At 24 months of age, children with ACC are reported to have significantly higher PROCESS scores (t = 3.73, df = 42.67, p < .001), and RSB (t = 4.89, df = 88.38, p < .001) scores than comparison toddlers, indicating an elevated presentation of behaviors associated with autistic features. Aim 2). No correlation was found between participants’ 6-month PROCESS and 24-month RSB scores (r(16) = .39, p = .12). A relatively strong correlation (r(35) = .60, p < .001) was found between participants’ 12-month PROCESS and 24-month RSB scores.

As early as two years of age, children with ACC display a heightened presentation of autistic features compared to typically developing controls. Additionally, reports of social behaviors related to ASD at 24-months are correlated with reports of autistic features at 12-months of age. This evidence indicates that children with ACC who are at a higher likelihood for being diagnosed with ASD may be identified as early as 12-months old. Formulating and leveraging an early identification methodology is imperative for this population with an already elevated risk for ASD, as providing early interventions leads to improved outcomes later in life.

Accumulating evidence suggests that corpus callosum development is critically involved in the emergence of behavioral and cognitive skills during the first two years of life and that structural abnormalities of the corpus callosum are associated with a variety of neurodevelopmental disorders. Indeed by adulthood ∼30% of individuals with agenesis of the corpus callosum (ACC), a congenital condition resulting in a partial or fully absent corpus callosum, exhibit phenotypic features consistent with autism spectrum disorder (ASD). However, very little is known about developmental similarities and/or differences among infants with ACC and infants who develop ASD. This study describes temperament in infants with ACC during the first year of life in comparison with a neurotypical control group. Additionally, it examines the potential contribution of disrupted callosal connectivity to early expression of temperament in ASD through comparison to children with high familial likelihood of ASD.

Longitudinal ratings of positive and negative emotionality were acquired at 6 and 12 months on the Infant Behavior Questionnaire-Revised across four groups of infants: isolated complete and partial ACC (n=104), high familial likelihood of ASD who do and do not have a confirmed ASD diagnosis (HL+ n=81, HL- n=282), and low-likelihood controls (LL- n=152).

Overall, the ACC group demonstrated blunted affect, with significantly lower positive and negative emotionality than LL controls at both timepoints. Specifically, the ACC group exhibited lower activity and approach dimensions of positive emotionality at both timepoints, with lower high-intensity pleasure at 6 months and lower vocal reactivity at 12 months. On negative emotionality subscales, the ACC group exhibited lower distress to limitations and sadness at both timepoints, as well as lower falling reactivity at 6 months. The ACC and HL groups did not differ significantly on positive emotionality at either timepoint. However, negative emotionality was lower in the ACC group than the HL- group at both timepoints and lower than the HL+ group at 12 months, with lower distress to limitations and sadness ratings than both HL groups at both timepoints.

These findings highlight the importance of interhemispheric connections in facilitating active engagement and pursuit of pleasurable activities during the first year of life, as well as expression of sadness and distress to limitations. Notably, similarities between infants with ACC and infants at elevated familial risk of ASD suggest that disrupted callosal connectivity may specifically contribute to reductions in positive emotionality.

It is unclear how agenesis of the corpus callosum (ACC), a congenital brain malformation defined by complete or partial absence of the corpus callosum, impacts language development. fMRI studies of middle childhood suggest that the corpus callosum plays a role in the interhemispheric language network (Bartha-Doering et al., 2020), and that reduced interhemispheric functional connectivity is correlated with worse language abilities in children with ACC (Bartha-Doering et al., 2021). Additionally, accumulating evidence suggests structural abnormalities of the corpus callosum play a role in neurodevelopmental disorders. While children who go on to receive an autism spectrum disorder (ASD) diagnosis may show early signs of altered word and gesture acquisition (Iverson et al., 2018), the same is not known about ACC. This study examined language development during the second year of life in children with ACC in comparison to neurotypical control participants, as well as other children at elevated risk of ASD.

The MacArthur-Bates Communicative Development Inventories (MCDI): Words and Gestures scales were administered to parents of 74 children with isolated ACC at 12, 18 and 24 months of age. Children whose first language was not English and children who were bilingual were excluded. Comparison groups consisted of individuals with a low familial likelihood of ASD (LL- n=140) and individuals with high familial likelihood of ASD who do and do not have a confirmed ASD diagnosis (HL+ n=68, HL- n=256).

Compared to LL controls, the ACC group produced fewer words at 18 and 24 months of age, and demonstrated fewer words understood at all three timepoints. Similarly, compared to the HL- group, the ACC group demonstrated fewer words produced and understood at 18 months of age, and fewer words produced at 24 months of age. The ACC and HL+ groups did not differ in words produced or words understood at any timepoint.

Overall, infants with ACC demonstrated delayed vocabulary expansion from 12 to 24 months of age. These findings illustrate the role of callosal connectivity in the development of language across the first 2 years of life, and highlight the need for support and interventions that target vocabulary production and comprehension.

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.

Age, sex, education, memory, and the APOE e4 allele are related to Alzheimer’s disease (AD) risk. Recently it was suggested that low body mass index (BMI) contributes to the development of AD. The objective of this study was to examine how delayed recall of a word list was influenced by demographic variables, APOE and BMI in people with memory problems, and to investigate whether the impact of these variables was smaller at higher disease severity levels.

The participants were 1206 patients in the Norwegian NorCog registry diagnosed with either subjective cognitive decline (SCD) (n=274), mild cognitive impairment (MCI) (n=444), or AD (n=488). ANOVAs and hierarchical regression were applied to examine whether the delayed recall part of the 10-word test of the CERAD-WL was associated with age, sex, education, APOE (e4/non-e4) and BMI. Analyses were run separately for SCD, MCI and AD patients.

There were significant bivariate differences (p<.001) between the three patient groups for all variables; the AD patients were older, less educated, more were women, more had APOE e4 alleles, and they had lower BMI. For the SCD group, 34% of the total variance (R2) of the dependent variable was explained. All independent variables except BMI (p=.07) had a significant contribution in the prediction. For MCI, 18% of the total were explained. All variables except education and sex showed significant contribution to R2. For the AD group, R2 was 13%. Sex and BMI did not contribute significantly.

As expected, the performance on CERAD-WML was influenced by age, education and sex in the SCD group, whereas the associations between memory function and the three demographic variables were less clear among patients with MCI and AD. ApoE genotype influenced on the CERAD-WML results among all patients, whereas BMI only influenced on the results among patients with SCD and MCI. Our findings do not support that BMI is associated with delayed recall of memory in AD.

The Stricker Learning Span (SLS) is a computer-adaptive word list memory test specifically designed for remote assessment and self-administration on a web-based multi-device platform (Mayo Test Drive). Given recent evidence suggesting the prominence of learning impairment in preclinical Alzheimer’s disease (AD), the SLS places greater emphasis on learning than delayed memory compared to traditional word list memory tests (see Stricker et al., Neuropsychology in press for review and test details). The primary study aim was to establish criterion validity of the SLS by comparing the ability of the remotely-administered SLS and inperson administered Rey Auditory Verbal Learning Test (AVLT) to differentiate biomarkerdefined groups in cognitively unimpaired (CU) individuals on the Alzheimer’s continuum.

Mayo Clinic Study of Aging CU participants (N=319; mean age=71, SD=11; mean education=16, SD=2; 47% female) completed a brief remote cognitive assessment (∼0.5 months from in-person visit). Brain amyloid and brain tau PET scans were available within 3 years. Overlapping groups were formed for 1) those on the Alzheimer’s disease (AD) continuum (A+, n=110) or not (A-, n=209), and for 2) those with biological AD (A+T+, n=43) vs no evidence of AD pathology (A-T-, n=181). Primary neuropsychological outcome variables were sum of trials for both the SLS and AVLT. Secondary outcome variables examined comparability of learning (1-5 total) and delay performances. Linear model ANOVAs were used to investigate biomarker subgroup differences and Hedge’s G effect sizes were derived, with and without adjusting for demographic variables (age, education, sex).

Both SLS and AVLT performances were worse in the biomarker positive relative to biomarker negative groups (unadjusted p’s<.05). Because biomarker positive groups were significantly older than biomarker negative groups, group differences were attenuated after adjusting for demographic variables, but SLS remained significant for A+ vs A- and for A+T+ vs A-T- comparisons (adjusted p’s<.05) and AVLT approached significance (p’s .05-.10). The effect sizes for the SLS were slightly better (qualitatively, no statistical comparison) for separating biomarker-defined CU groups in comparison to AVLT. For A+ vs A- and A+T+ vs A-T- comparisons, unadjusted effect sizes for SLS were -0.53 and -0.81 and for AVLT were -0.47 and -0.61, respectively; adjusted effect sizes for SLS were -0.25 and -0.42 and for AVLT were -0.19 and -0.26, respectively. In secondary analyses, learning and delay variables were similar in terms of ability to separate biomarker groups. For example, unadjusted effect sizes for SLS learning (-.80) was similar to SLS delay (.76), and AVLT learning (-.58) was similar to AVLT 30-minute delay (-.55) for the A+T+ vs AT- comparison.

Remotely administered SLS performed similarly to the in-person-administered AVLT in its ability to separate biomarker-defined groups in CU individuals, providing evidence of criterion validity. The SLS showed significantly worse performance in A+ and A+T+ groups (relative to A- and A-T-groups) in this CU sample after demographic adjustment, suggesting potential sensitivity to detecting transitional cognitive decline in preclinical AD. Measures emphasizing learning should be given equal consideration as measures of delayed memory in AD-focused studies, particularly in the preclinical phase.

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.

Blood-based biomarkers offer a more feasible alternative to Alzheimer’s disease (AD) detection, management, and study of disease mechanisms than current in vivo measures. Given their novelty, these plasma biomarkers must be assessed against postmortem neuropathological outcomes for validation. Research has shown utility in plasma markers of the proposed AT(N) framework, however recent studies have stressed the importance of expanding this framework to include other pathways. There is promising data supporting the usefulness of plasma glial fibrillary acidic protein (GFAP) in AD, but GFAP-to-autopsy studies are limited. Here, we tested the association between plasma GFAP and AD-related neuropathological outcomes in participants from the Boston University (BU) Alzheimer’s Disease Research Center (ADRC).

This sample included 45 participants from the BU ADRC who had a plasma sample within 5 years of death and donated their brain for neuropathological examination. Most recent plasma samples were analyzed using the Simoa platform. Neuropathological examinations followed the National Alzheimer’s Coordinating Center procedures and diagnostic criteria. The NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Measures of GFAP were log-transformed. Binary logistic regression analyses tested the association between GFAP and autopsy-confirmed AD status, as well as with semi-quantitative ratings of regional atrophy (none/mild versus moderate/severe) using binary logistic regression. Ordinal logistic regression analyses tested the association between plasma GFAP and Braak stage and CERAD neuritic plaque score. 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 autopsy-confirmed AD status. All analyses controlled for sex, age at death, years between last blood draw and death, and APOE e4 status.

Of the 45 brain donors, 29 (64.4%) had autopsy-confirmed AD. The mean (SD) age of the sample at the time of blood draw was 80.76 (8.58) and there were 2.80 (1.16) years between the last blood draw and death. The sample included 20 (44.4%) females, 41 (91.1%) were White, and 20 (44.4%) were APOE e4 carriers. Higher GFAP concentrations were associated with increased odds for having autopsy-confirmed AD (OR=14.12, 95% CI [2.00, 99.88], p=0.008). ROC analysis showed plasma GFAP accurately discriminated those with and without autopsy-confirmed AD on its own (AUC=0.75) and strengthened as the above covariates were added to the model (AUC=0.81). Increases in GFAP levels corresponded to increases in Braak stage (OR=2.39, 95% CI [0.71-4.07], p=0.005), but not CERAD ratings (OR=1.24, 95% CI [0.004, 2.49], p=0.051). Higher GFAP levels were associated with greater temporal lobe atrophy (OR=10.27, 95% CI [1.53,69.15], p=0.017), but this was not observed with any other regions.

The current results show that antemortem plasma GFAP is associated with non-specific AD neuropathological changes at autopsy. Plasma GFAP could be a useful and practical biomarker for assisting in the detection of AD-related changes, as well as for study of disease mechanisms.

The purpose of the present study was to study the clinical significance of fluctuations in cognitive impairment status in longitudinal studies of normal aging and dementia. Several prior studies have shown fluctuations in cognition in longitudinal studies is associated with greater risk of conversion to dementia. The present study defines “reverters” as participants who revert between cognitive normality and abnormality according to the Clinical Dementia Rating (CDRTM). A defining feature of the CDR at the Knight Alzheimer’s Disease Research Center (Knight ADRC) at Washington University in St. Louis is that the CDR is calculated by clinicians blinded to cognitive data and any prior assessments so that conclusions are drawn free of circularity and examiner bias. We hypothesized reverters, when compared to cognitively normal participants who remain unimpaired, would have worse cognition, abnormal biomarkers, and would eventually progress to a stable diagnosis of cognitive impairment.

From ongoing studies of aging and dementia at the Knight ADRC, we selected cognitively normal participants with at least three follow-up visits. Participants fell into three categories: stable cognitively normal (“stable CN”), converters to stable dementia (“converters”), and reverters. Cognitive scores at each visit were z-scored for comparison between groups. A subset of participants had fluid biomarker data available including cerebrospinal fluid (CSF) amyloid and phosphorylated-tau species, and plasma neurofilament light chain (NfL). Mixed effect models evaluated group relationships between biomarker status, APOE £4 status, and CDR progression.

930 participants were included in the study with an average of 5 years of follow-up (Table 1). 661 participants remained cognitively normal throughout their participation while 142 progressed to stable dementia and 127 participants had at least one instance of reversion. Compared to stable CN, reverters had more abnormal biomarkers at baseline, were more likely to carry an APOE £4 allele, and had better cognitive performance at baseline (Table 2, Figure 1). Compared to converters, reverters had less abnormal biomarkers at baseline, were less likely to carry an APOE £4 allele, and had overall better cognitive performance at baseline. In longitudinal analyses, cognitive trajectories of reverters exhibited a larger magnitude of decline compared to stable CNs but the magnitude of decline was not as steep as converters.

Our results confirm prior studies that showed reversion in cognitive status, when compared to stable cognitive normality, is associated with worse overall genetic, biomarker and cognitive outcomes. Longitudinal analyses demonstrated reverters show significantly more decline than stable participants and a higher likelihood of eventual conversion to a stable dementia diagnosis. Reverters’ cognitive trajectories appear to occupy a transitional phase in disease progression between that of cognitive stability and more rapid and consistent progression to stable dementia. Identifying participants in the preclinical phase of AD who are most likely to convert to symptomatic AD is critical for secondary prevention clinical trials. Our results suggest that examining intraindividual variability in cognitive impairment using unbiased, longitudinal CDR scores may be a good indicator of preclinical AD and predict eventual conversion to symptomatic AD.

Cognitive problems, both complaints and objective impairments, are frequent and disabling in patients with multiple sclerosis (MS) and profoundly affect daily living. However, intervention studies that focus on cognitive problems that patients experience in their daily lives are limited. This study therefore aimed to investigate the effectiveness of cognitive rehabilitation therapy (CRT) and mindfulness-based cognitive therapy (MBCT) on patient-reported cognitive complaints in MS.

In this randomized-controlled trial, MS patients with cognitive complaints completed questionnaires and underwent neuropsychological assessments at baseline, post-treatment and 6-month follow-up. Patient-reported cognitive complaints were primarily investigated. Secondary outcomes included personalized cognitive goals and objective cognitive function. CRT and MBCT were compared to enhanced treatment as usual (ETAU) using linear mixed models.

Patients were randomized into CRT (n=37), MBCT (n=36) or ETAU (n=37), of whom 100 completed the study. Both CRT and MBCT positively affected patient-reported cognitive complaints compared to ETAU at post-treatment (p<.05), but not 6 months later. At 6-month follow-up, CRT had a positive effect on personalized cognitive goals (p=.028) and MBCT on processing speed (p=.027). Patients with less cognitive complaints at baseline benefited more from CRT on the Cognitive Failures Questionnaire (i.e. primary outcome measuring cognitive complaints) at post-treatment (p=.012-.040), and those with better processing speed at baseline benefited more from MBCT (p=.016).

Both CRT and MBCT alleviated cognitive complaints in MS patients immediately after treatment completion, but these benefits did not persist. In the long term, CRT showed benefits on personalized cognitive goals and MBCT on processing speed. These results thereby provide insight in the specific contributions of available cognitive treatments for MS patients.