The Uniform Data Set (UDS) neuropsychological battery, administered across Alzheimer’s Disease Centers (ADC), includes memory tests but lacks a list-learning paradigm. ADCs often supplement the UDS with their own preferred list-learning task. Given the importance of list-learning for characterizing memory, we aimed to develop a harmonized memory score that incorporates UDS memory tests while allowing centers to contribute differing list-learning tasks. We applied item-banking confirmatory factor analysis to develop a composite memory score in 5,287 participants (mean age 67.1; SD = 12.2) recruited through 18 ADCs and four consortia (DiverseVCID, MarkVCID, ALLFTD, LEADS) who completed UDS memory tasks (used as linking-items) and one of five list-learning tasks. All analyses used linear regression. We tested whether memory scores were affected by which list-learning task was administered. To assess construct validity, we tested associations of memory scores with demographics, disease severity (CDR Box Score), an independent memory task (TabCAT Favorites, n = 675), and hippocampal volume (n = 811). We compared performances between cognitively unimpaired (n = 279), AD-biomarker+ MCI (n = 26), and AD-biomarker+ dementia (n = 98). In a subsample with amyloid- and tau-PET (n = 49), we compared memory scores from participants with positive vs negative scans determined using established quantitative cutoffs. Model fit indices were excellent (e.g., CFI = 0.998) and factor loadings were strong (0.43-0.93). Differences in list-learning task had a negligible effect on scores (average Cohen’s d = 0.11). Higher memory scores were significantly ( p ’s<.001) correlated with younger age (β = -0.18), lower CDR Box Scores (β = -0.63), female sex (β = 0.12), higher education (β = 0.19), larger hippocampal volume (β = 0.42), and an independent memory task (β = 0.71, p<0.001). The memory composite declined in a stepwise fashion by diagnosis (cognitively unimpaired>MCI>AD dementia, p<0.001). On average, amyloid-PET positivity was associated with lower composite scores, but was not statistically significant (β = -0.34; p = 0.25; d = 0.40). Tau-PET positivity was associated with worse performance, demonstrating a large effect size (β = -0.75; p<0.002; d = 0.91). The harmonized memory score developed in a large national sample was stable regardless of contributing list-learning task and its validity for cross-cohort ADRD research is supported by expected associations with demographics, clinical measures, and Alzheimer’s biomarkers. A processing script will be made available to enhance cross-cohort ADRD research.

Cerebrovascular disease (CVD) and Alzheimer’s disease (AD) often co-occur and may impact specific cognitive domains. This study’s goal was to determine effects of CVD and AD burden on cross-sectional and longitudinal executive function (EF) and memory in older adults.Longitudinally followed participants from the National Alzheimer Coordinating Center database (n = 3342) were included. Cognitive outcomes were EF and memory composite scores. Baseline CVD presence was defined by moderate-to-severe white matter hyperintensities or lacunar infarct on MRI. Baseline AD pathology was defined by amyloid positivity via PET or CSF. Linear mixed models examined effects of CVD, AD, and time on cognitive outcomes, controlling for sex, education, baseline age, MoCA score, and total number of study visits.At baseline, CVD associated with lower EF (p < 0.001), while AD associated with lower EF and memory (ps < 0.001). Longitudinally only AD associated with faster declines in memory and EF (ps < 0.001).These results extend our understanding of CVD and AD pathology, highlighting that CVD does not necessarily indicate accelerated decline.

Plasma biomarkers have potential to capture features of Alzheimer’s disease (AD)-related pathophysiology, but less is known about how they might associate with an imaging measure of cerebral small vessel disease (cSVD). The present study examined independent and combined associations of plasma markers of AD pathology (Aβ42, P-tau181), axonal damage (neurofilament light [NfL]), and astrocytic activation (glial fibrillary acidic protein [GFAP]) with white matter hyperintensity (WMH) volume in adults without dementia. Plasma Aβ42, P-tau181, NfL, and GFAP (Quanterix Simoa) were measured in 151 older adults without dementia (124 cognitively unimpaired, 27 mild cognitive impairment; aged 52 - 91, 57% female, 95% non-Hispanic white) who underwent MRI with T2-weighted FLAIR. Controlling for age, sex, APOE genotype, and intracranial volume, linear regressions first examined WMH volume as a function of each plasma biomarker separately, and next in a combined model with independent and interactive effects of biomarkers associated with WMH from the individual models. In individual models, higher WMH volumes were associated with lower plasma Aβ42 (β = -0.17, p = 0.032, model R 2 = 19.4%) and higher NfL concentrations (β = 0.21, p = 0.013, model R 2 = 20.3%). Plasma P-tau181 (β = -0.015, p = 0.851) and GFAP (β = 0.05, p = 0.593) were not significantly associated with WMH volume. Aβ42 and NfL did not demonstrate an interaction but both remained independently associated with WMH volume (Aβ42: β = -0.19, p = 0.015; NfL: β = 0.24, p = 0.005; model R 2 = 22.7%). No significant interactions between other biomarkers were found. Plasma Aβ42 and NfL concentrations associate with burden of cSVD as quantified by WMH load on MRI in non-demented older adults. As a non-specific marker of axonal injury, plasma NfL may have utility in studies of brain degeneration related to cSVD. Future studies are warranted to identify factors that may be mediating the effect of plasma amyloid on WMH.

BACKGROUND:Education level is a well-recognized co-factor for cognitive performance and a potential confounder in the application of cognitive evaluations in diverse populations. The Montreal Cognitive Assessment (MoCA) is a widely utilized screening tool for Mild Cognitive Impairment (MCI) composed of 6 domains of cognition: Executive Function (EFC), Attention and Concentration (AC), Language (LANG), Visuospatial (VIS), Memory (MEM), and Orientation (ORIEN). Education is currently accounted for globally by adding 1 point to the total MoCA score. This study considers the impact of education level on a domain-specific scoring of the MoCA. METHOD:We utilized longitudinal subject level data from one site within the MarkVCID Consortium (UCSF) composed of 578 subjects (59.5% female; 82.9% white), mean age 71.5 (+/- 8.7). Mean educational level was 15.3 (+/-4.7) years. Within the cohort, 37 subjects lacked educational level and were omitted (final n = 541). Multivariate linear regression models were used to relate educational level with total and domain specific MoCA score performance at baseline while controlling for the influence of age, sex, and recognized MarkVCID biomarkers that impact cognitive performance including white matter hyperintensity (logWMH), fractional anisotropy (FA), free water (FW), and peak width of skeletonized mean diffusivity (PSMD). RESULTS:An age-, sex-adjusted model replicated a significant association of education level with MoCA total score (p<0.001, b = .336). Among the MoCA domains, EFC was most affected by education level (p<.001, b = .412), followed by AC (p<.001, b = .352). Other MoCA domains were not significantly associated with educational level. Several MoCA domains, namely MEM and ORIEN, showed an association with MarkVCID biomarkers including WMH and FW (p-values <.001). In regression models controlled for MarkVCID imaging biomarkers, educational level remained significantly associated with total and domain-specific MoCA performance. CONCLUSION:Education does not equally contribute to all cognitive domains assessed by the MoCA, mostly affecting EFC and AC. These findings suggest that considering education level in a domain-specific manner could provide a more accurate interpretation of the cognitive impairment.

Physical activity (PA) is linked to better cognitive and brain health, though its mechanisms are unknown. While brain iron is essential for normal function, levels increase with age and, when excessive, can cause detrimental neural effects. We examined how objectively measured PA relates to cerebral iron deposition and memory functioning in normal older adults. Sixty-eight cognitively unimpaired older adults from the UCSF Memory and Aging Center completed neuropsychological testing and brain magnetic resonance imaging, followed by 30-day Fitbit monitoring. Magnetic resonance imaging quantitative susceptibility mapping (QSM) quantified iron deposition. PA was operationalized as average daily steps. Linear regression models examined memory as a function of hippocampal QSM, PA, and their interaction. Higher bilateral hippocampal iron deposition correlated with worse memory but was not strongly related to PA. Covarying for demographics, PA moderated the relationship between bilateral hippocampal iron deposition and memory such that the negative effect of hippocampal QSM on memory performances was no longer significant above 9120 daily steps. PA may mitigate adverse iron-related pathways for memory health.

Education level is a well-recognized co-factor for cognitive performance and a potential confounder in the application of cognitive evaluations in diverse populations. The Montreal Cognitive Assessment (MoCA) is a widely utilized screening tool for Mild Cognitive Impairment (MCI) composed of 6 domains of cognition: Executive Function (EFC), Attention and Concentration (AC), Language (LANG), Visuospatial (VIS), Memory (MEM), and Orientation (ORIEN). Education is currently accounted for globally by adding 1 point to the total MoCA score. This study considers the impact of education level on a domain-specific scoring of the MoCA. We utilized longitudinal subject level data from one site within the MarkVCID Consortium (UCSF) composed of 578 subjects (59.5% female; 82.9% white), mean age 71.5 (+/- 8.7). Mean educational level was 15.3 (+/-4.7) years. Within the cohort, 37 subjects lacked educational level and were omitted (final n = 541). Multivariate linear regression models were used to relate educational level with total and domain specific MoCA score performance at baseline while controlling for the influence of age, sex, and recognized MarkVCID biomarkers that impact cognitive performance including white matter hyperintensity (logWMH), fractional anisotropy (FA), free water (FW), and peak width of skeletonized mean diffusivity (PSMD). An age-, sex-adjusted model replicated a significant association of education level with MoCA total score (p<0.001, b = .336). Among the MoCA domains, EFC was most affected by education level (p<.001, b = .412), followed by AC (p<.001, b = .352). Other MoCA domains were not significantly associated with educational level. Several MoCA domains, namely MEM and ORIEN, showed an association with MarkVCID biomarkers including WMH and FW (p-values <.001). In regression models controlled for MarkVCID imaging biomarkers, educational level remained significantly associated with total and domain-specific MoCA performance. Education does not equally contribute to all cognitive domains assessed by the MoCA, mostly affecting EFC and AC. These findings suggest that considering education level in a domain-specific manner could provide a more accurate interpretation of the cognitive impairment.

Objective:A common assumption in clinical neuropsychology is that cerebrovascular risk is adversely associated with executive function, while Alzheimer’s disease (AD) primarily targets episodic memory. The goal of the present study was to determine the cross-sectional and longitudinal validity of these assumptions using validated markers of cerebrovascular and AD burden.Participants and Methods:19271 longitudinally-followed participants from the National Alzheimer Coordinating Center (NACC) database (Mean age= 72.25; SD age= 10.42; 58% women; 51.6% CDR= 0, 33.7% CDR= 0.5, 14.7% CDR> 1) were included. Cognitive outcomes were a composite memory score and an executive function composite score (UDS3-EF; Staffaroni et al., 2020). Baseline presence of cerebrovascular disease was indexed by the presence of moderate to severe white matter hyperintensities or lacunar infarct on brain MRI (yes/no), while baseline AD pathology was indexed by the presence of a positive amyloid PET scan or elevated CSF AD biomarkers (yes/no). We used linear mixed effect models to assess the effects of baseline cerebrovascular disease, baseline AD pathology, and their interactions with time in study (years post baseline) controlling for baseline age, sex, education, and baseline MoCA score.Results:Baseline cerebrovascular disease was significantly associated with a lower intercept on executive functioning (between-person effect) (p < -0.001, 95% CI -0.37, -0.14) but not memory, while presence of AD biomarkers was associated with a lower memory intercept (p < -0.001, 95% CI -0.52, -0.39) but not executive function. However, only presence of AD pathology at baseline was associated with faster longitudinal decline on both memory and executive functioning over time. Baseline cerebrovascular disease did not independently relate to rate of cognitive decline.Conclusions:Consistent with widely held assumptions, our between-person analyses showed that MRI evidence of cerebrovascular disease was associated with worse executive functioning but not memory, while biomarker evidence of AD pathology was associated with worse memory but not executive function. Longitudinally, however, AD is the primary driver of decline in both executive and memory function. These results extend our understanding of how pathology impacts cognition in aging cohorts and highlight the importance of using longitudinal models.

Cortical function critically depends on inhibitory/excitatory balance. Cortical inhibitory interneurons (cINs) are born in the ventral forebrain and migrate into cortex, where their numbers are adjusted by programmed cell death. Here, we show that loss of clustered gamma protocadherins (Pcdhg), but not of genes in the alpha or beta clusters, increased dramatically cIN BAX-dependent cell death in mice. Surprisingly, electrophysiological and morphological properties of Pcdhg-deficient and wild-type cINs during the period of cIN cell death were indistinguishable. Co-transplantation of wild-type with Pcdhg-deficient interneuron precursors further reduced mutant cIN survival, but the proportion of mutant and wild-type cells undergoing cell death was not affected by their density. Transplantation also allowed us to test for the contribution of Pcdhg isoforms to the regulation of cIN cell death. We conclude that Pcdhg, specifically Pcdhgc3, Pcdhgc4, and Pcdhgc5, play a critical role in regulating cIN survival during the endogenous period of programmed cIN death.