Rosie E. Curiel Cid

Background: Plasma biomarkers for Alzheimer's disease (AD), including pTau217, are increasingly used to identify individuals at risk for underlying AD pathology. However, biomarkers alone do not capture the cognitive expression of disease, underscoring the need for brief cognitive measures capable of distinguishing impairment across biologically defined groups. Objective: To evaluate the discriminative validity of the Brief Semantic Paired Associates Test (B-SPAT), a novel three-minute computerized cognitive screening test, among cognitively unimpaired and cognitively impaired older adults stratified by plasma pTau217 status. Methods: Participants included 35 cognitively unimpaired (CU) older adults with negative plasma pTau217 (pTau217−), 22 cognitively impaired (CI) participants with pTau217−, and 20 CI participants with positive plasma pTau217 (pTau217+). All participants completed the B-SPAT, a fully digitized six-item semantic paired-associate learning task, along with a comprehensive neuropsychological battery. Results: After adjustment for age, education, sex, and Mini-Mental State Examination scores, significant group differences in B-SPAT performance remained [F(2,70) = 8.28, p < 0.001]. Post-hoc analyses indicated that the CU pTau217− group performed significantly better than both cognitively impaired groups. Importantly, no significant differences were observed between the CI pTau217 + and CI pTau217− groups following covariate adjustment. Receiver operating characteristic analysis comparing CI pTau217 + and CU pTau217− participants yielded an area under the curve of 0.902 (SE = 0.041), with 95% sensitivity and 77.1% specificity. Conclusions: The B-SPAT is a promising exploratory brief digital cognitive screening tool that differentiates cognitively impaired from cognitively unimpaired older adults across biomarker-defined groups and may have utility in community and primary care settings.

Emerging evidence suggests that systemic physiological factors may influence plasma biomarker concentrations of Alzheimer’s disease (AD) and related neurodegenerative processes, potentially affecting their specificity for central nervous system pathology. This study examined the relationship of demographic factors and medical comorbidities with plasma biomarkers of AD and neurodegeneration in a community-dwelling cohort of Black/African American (B/AA) older adults (N = 141). Participants underwent plasma assessment of phosphorylated tau at threonine 217 (p-Tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Results showed associations between plasma p-Tau217 and amyloid PET positivity, and significant intercorrelations among p-Tau217, GFAP, and NfL. Stepwise regression models incorporated demographics, amyloid PET status, and laboratory measures of renal, metabolic, and lipid function as predictors for each biomarker. p-Tau217 was primarily predicted by amyloid PET and renal function; GFAP by age and sex; and NfL by renal function, age, and sex. Findings indicate plasma biomarker concentrations in B/AA older adults reflect both central AD-related pathology and systemic physiological factors, particularly renal function, and demographic influences. Results underscore the importance of accounting for comorbid medical conditions and demographic characteristics when interpreting blood-based biomarkers and highlight the need for comprehensive medical phenotyping to improve diagnostic specificity and clinical utility.

Background: The impact of Alzheimer's Disease (AD) and Alzheimer's Disease‐Related Dementias (ADRD) is projected to rise significantly among Hispanic/Latino (H/L) and Black/African American (B/AA) populations. However, these groups remain underrepresented in clinical research and trials, resulting in critical gaps in understanding the effectiveness of early‐stage detection and monitoring methods for AD/ADRD. The lack of representation in studies focused on the earliest stages of these diseases limits the ability to assess the diagnostic, prognostic, and clinical utility of promising biomarkers and their effects on cognition, making it difficult to establish generalizable findings. Method: The MADRE (Mobile Alzheimer's Disease Research and Evaluation) study was designed to provide comprehensive evaluations in participants' homes or community centers, specifically targeting B/AA and H/L populations. This approach reduces participant burden, increases the standardization of evaluations, and ensures efficient and accurate data capture. By meeting participants in familiar settings, the study minimizes the stress of traveling to medical centers, improving accessibility for individuals in underserved regions who may not be aware of research opportunities. Results: In an ongoing longitudinal study aimed at deep‐phenotyping B/AA older adults, we successfully recruited 159 participants over 18 months. The cohort consisted of 72 males and 84 females, with an average age of 67.32 years (SD = 5.5; range = 52–88). The annual retention rate exceeded 93%. The sample included 33% with mild cognitive impairment (MCI), 30% with mild impairments but not meeting MCI criteria (“impaired, not MCI”), 3% with subjective cognitive complaints, and 34% cognitively unimpaired (CU). The mean MMSE score was 27.18 (SD = 3.1). Educational levels varied, with 6.3% having ≤8 years of education, 57.7% with a high school diploma, 25.3% with higher degrees, and 10.7% with a master's degree or higher. Blood draws were collected to examine AD/ADRD plasma biomarkers and common comorbidity markers. Additionally, 31.2% carried one or more APOE ε4 alleles. Conclusions: These findings demonstrate the success of our innovative MADRE initiative in recruiting and retaining B/AA participants for comprehensive in‐home evaluations, emphasizing the effectiveness of culturally relevant, accessible research methods for underserved populations.

Objective: There are diagnostic disparities in dementia across ethno-racial communities. The potential contribution of measurement bias in cognitive assessments was investigated by examining the factor structure and measurement invariance of the Uniform Data Set neuropsychological battery (UDS3-NB) across ethno-racial groups as well as Spanish and English speakers along a cognitive continuum. Methods: Data were from the National Alzheimer's Coordinating Center (NACC) and the 1Florida Alzheimer's Disease Research Center (1FLADRC). Confirmatory factor analyses were conducted in NACC (n = 29,462; M age = 71.0, SD = 10.4; 58.5% female, M education = 15.8, SD = 3.0; 68.6% non-Hispanic White, 5.3% -primary Spanish speaking) to determine the UDS3-NB factor structure. Measurement invariance was tested in NACC and separately within 1FLADRC (n = 829; M age = 69.9, SD = 8.5; 56.5% female; M education = 14.6, SD = 3.5 years; 33.3% non-Hispanic White, 33.8% primary Spanish speaking), across ethno-racial (non-Hispanic White, Hispanic White, Black/African American), primary language (English, Spanish), and cognitive status (cognitively normal, mild cognitive impairment, dementia). Invariance was assessed at configural, metric, scalar, and strict levels. Results: A 4-factor model (memory, processing speed/executive functioning, language, attention) demonstrated acceptable to good fit in NACC (CFI = 0.97, TLI = 0.96, RMSEA = 0.07, SRMR = 0.03) and 1FLADRC (CFI = 0.97, TLI = 0.96, RMSEA = 0.05, SRMR = 0.04). Standardized factor loadings ranged from 0.43-0.87. Metric invariance was supported across all contrasts in both cohorts. Higher levels of invariance were cohort-dependent: CN vs. MCI achieved strict invariance in both cohorts, whereas non-Hispanic White vs. Hispanic White and English vs. Spanish only achieved strict invariance in NACC. Conclusions: The UDS3-NB demonstrates structural validity and metric equivalence across ethno-racial, linguistic, and cognitive status groups.

Background: Semantic intrusion errors (SIEs) are associated with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). It is unknown whether accounting for maximum learning capacity still leads to an increase in SIEs when elevated plasma p-tau₂₁₇, a biological indicator of underlying AD, is present.Methods: One hundred fifty-eight older adult participants completed the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), a sensitive cognitive challenge test designed to elicit SIEs. Of these, 108 were clinically diagnosed with amnestic MCI (aMCI). Fifty-eight individuals met or exceeded a plasma p-tau₂₁₇ positivity of >0.55 pg/ml, while 50 individuals scored below this threshold.Results: After adjusting for demographic covariates and maximum learning capacity, the aMCI p-tau₂₁₇+ group evidenced more SIEs compared to aMCI p-tau₂₁₇- on the first (list B1; p = 0.035) and second trials of the competing list (list B2; p = 0.006). Biological predictors such as ApoE ε4 status, higher p-tau₂₁₇, and older age were predictors of an elevated number of SIEs [list B2: F (3,104) = 10.92; p = 0.001; R = 0.489)].Conclusions: Unlike previous studies that used amyloid PET or other plasma biomarkers, individuals with aMCI p-tau₂₁₇+ evidenced more SIEs, even after adjusting for their initial learning capacity, a covariate that has not been studied previously. These findings support that SIEs are more prevalent in the presence of underlying AD pathology and occur independent of learning deficits.

Alzheimer’s disease (AD) disproportionately affects Black/African American (B/AA) older adults, yet this group remains underrepresented in research. Traditional neuropsychological assessments, often developed on predominantly White populations, may not be reliable for B/AA individuals. The Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) have been shown to effectively differentiate individuals with amnestic mild cognitive impairment (aMCI) from cognitively unimpaired (CU) individuals. This study examines the relationship between LASSI-L performance and plasma p-tau₂₁₇ levels to explore early detection methods for AD in B/AA populations. Fifty-six older adults received clinical and cognitive evaluations and were deemed cognitively unimpaired (CU) and p-tau₂₁₇ negative (n = 35) or met criteria for amnestic mild cognitive impairment (aMCI) and p-tau₂₁₇ positive (n = 21). All participants were administered the LASSI-L to compare groups, but it was not used for group allocation to avoid circularity. After adjusting for age and MMSE score, the aMCI p-tau₂₁₇+ group performed significantly worse than the CU p-tau₂₁₇− group on both free recall on List B (Free B1 Recall) and frPSI (correct responses on Cued B2). These differences remained statistically significant after covariate adjustment (p < 0.001). In addition, four other outcomes remained statistically significant following covariate adjustment: the aMCI p-tau₂₁₇+ group exhibited a higher percentage of intrusion errors (PIE) on both Cued B1 and Cued B2, along with poorer performance on maximal learning ability (Cued A2) and PSI (correct responses on Cued B1). However, after applying the Bonferroni correction, only PIE on Cued B2 remained statistically significant among these measures. Notably, performance on LASSI-L Free B1 Recall and PIE for List Cued B2 were significant predictors distinguishing aMCI p-tau₂₁₇+ from CU p-tau₂₁₇− groups, with high sensitivity (80%) and specificity (91.7%). ROC analysis of these predictors yielded an area under the curve of 0.872 (SE = 0.055; p < 0.001), with a 95% confidence interval ranging from 0.765 to 0.979. The study highlights the utility of the LASSI-L in conjunction with plasma biomarkers, particularly p-tau₂₁₇, for early AD detection in B/AA older adults. The LASSI-L demonstrated strong sensitivity to cognitive impairment, effectively differentiating between CU and aMCI groups based on plasma p-tau₂₁₇ levels. These findings suggest that combining cognitive assessments with plasma biomarkers can enhance early diagnosis and improve timely interventions, addressing health disparities in AD diagnosis and care.

Background: The early detection of mild cognitive impairment is crucial for providing treatment before further decline. Cognitive challenge tests such as the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L) can identify individuals at highest risk for cognitive deterioration. Performance on elements of the LASSI-L, particularly proactive interference, correlate with the presence of critical Alzheimer disease biomarkers. However, in-person paper tests require skilled testers and are not practical in many community settings or for large-scale screening in prevention. Objective: This study reports on the development and initial validation of a self-administered computerized version of the Loewenstein-Acevedo Scales for Semantic Interference (LASSI), the digital LASSI (LASSI-D). A self-administered digital version, with an artificial intelligence–generated avatar assistant, was the migrated assessment. Methods: Cloud-based software was developed, using voice recognition technology, for English and Spanish versions of the LASSI-D. Participants were assessed with either the LASSI-L or LASSI-D first, in a sequential assessment study. Participants with amnestic mild cognitive impairment (aMCI; n=54) or normal cognition (NC; n=58) were also tested with traditional measures such as the Alzheimer Disease Assessment Scale-Cognition. We examined group differences in performance across the legacy and digital versions of the LASSI, as well as correlations between LASSI performance and other measures across the versions. Results: Differences on recall and intrusion variables between aMCI and NC samples on both versions were all statistically significant (all P<.001), with at least medium effect sizes (d>0.68). There were no statistically significant performance differences in these variables between legacy and digital administration in either sample (all P<.13). There were no language differences in any variables (P>.10), and correlations between LASSI variables and other cognitive variables were statistically significant (all P<.01). The most predictive legacy variables, proactive interference and failure to recover from proactive interference, were identical across legacy and migrated versions within groups and were identical to results of previous studies with the legacy LASSI-L. Classification accuracy was 88% for NC and 78% for aMCI participants. Conclusions: The results for the digital migration of the LASSI-D were highly convergent with the legacy LASSI-L. Across all indices of similarity, including sensitivity, criterion validity, classification accuracy, and performance, the versions converged across languages. Future studies will present additional validation data, including correlations with blood-based Alzheimer disease biomarkers and alternative forms. The current data provide convincing evidence of the use of a fully self-administered digitally migrated cognitive challenge test.

Background: Semantic intrusion errors (SIEs) are both sensitive and specific to PET amyloid-β (Aβ) burden in older adults with amnestic mild cognitive impairment (aMCI). Objective: Plasma Aβ biomarkers including the Aβ42/40 ratio using mass spectrometry are expected to become increasingly valuable in clinical settings. Plasma biomarkers are more clinically informative if linked to cognitive deficits that are salient to Alzheimer’s disease (AD). Methods: This study included 119 older adults enrolled in the 1Florida Alzheimer’s Disease Research Center (ADRC), 45 aMCI participants scored below the established Aβ42/40 ratio cut-off of 0.160 using the Quest AD-Detect™ assay indicating Aβ positivity (Aβ+), while 50 aMCI participants scored above this cut-off indicating Aβ negative status (Aβ–). Additionally, 24 cognitively unimpaired (CU) persons scored above the cut-off of 0.160 (Aβ–). Results: The aMCI plasma Aβ+ group evidenced the greatest percentage of SIEs, followed by the aMCI Aβ–. The CU Aβ– group exhibited the lowest percentage of SIEs. After adjustment for global cognitive impairment, aMCI plasma Aβ+ continued to demonstrate greater SIEs on tests tapping the failure to recover from proactive semantic interference (frPSI) as compared to the aMCI Aβ–group. Using pre-established cut-offs for frPSI impairment, 8.3% of CU Aβ– participants evidenced deficits, compared to 37.8% of aMCI Aβ–, and 74.0% of aMCI Aβ+. Conclusions: SIEs reflecting frPSI were associated with aMCI Aβ+ status based on the Aβ42/40 ratio. Results suggest the importance of SIEs as salient cognitive markers that map onto underlying AD pathology in the blood.