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Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

Background: Subjective cognitive decline (SCD), considered a preclinical dementia stage, is less understood in Hispanics, a high-risk group for dementia. We investigated SCD to mild cognitive impairment (MCI) progression risk, as well as baseline and longitudinal features of depressive symptoms, SCD complaints, and objective cognitive performance among Hispanics compared to non-Hispanic Whites (NHW). Methods: Hispanic (n = 23) and NHW (n = 165) SCD participants were evaluated at baseline and 2-year follow-up. Evaluations assessed function, depressive symptoms, SCD, and objective cognitive performance. Results: Hispanics were at increased risk of progression to MCI (OR: 6.10, 95% CI 1.09-34.20, P =.040). Hispanic participants endorsed more depressive symptoms at baseline (P =.048) that worsened more longitudinally (OR: 3.16, 95% CI 1.18-8.51, P =.023). Hispanic participants had increased SCD complaints on the Brief Cognitive Rating Scale (BCRS) (β =.40 SE:.17, P =.023), and in specific BCRS domains: concentration (β =.13, SE:.07, P =.047), past memory (β =.13, SE:.06, P =.039) and functional abilities (β =.10, SE:.05, P =.037). In objective cognitive performance, Hispanic ethnicity associated with decline in MMSE (β = −.27, SE:.13, P =.039), MoCA (β = −.80 SE:.34, P =.032), Trails A (β = 2.75, SE:.89, P =.002), Trails B (β = 9.18, SE: 2.71, P =.001) and Guild Paragraph Recall Delayed (β = −.80 SE:.28, P =.005). Conclusions: Hispanic ethnicity associated with a significantly increased risk of 2-year progression of SCD to MCI compared to NHW. This increased risk associated with increased depressive symptoms, distinctive SCD features, and elevated amnestic and non-amnestic objective cognitive decline. This supports further research to refine the assessment of preclinical dementia in this high-risk group. [ABSTRACT FROM AUTHOR]

High‐dimensional multinomial regression models are very useful in practice but have received less research attention than logistic regression models, especially from the perspective of statistical inference. In this work, we analyze the estimation and prediction error of the contrast‐based ℓ1$$ {\ell}_1 $$‐penalized multinomial regression model and extend the debiasing method to the multinomial case, providing a valid confidence interval for each coefficient and p$$ p $$ value of the individual hypothesis test. We also examine cases of model misspecification and non‐identically distributed data to demonstrate the robustness of our method when some assumptions are violated. We apply the debiasing method to identify important predictors in the progression into dementia of different subtypes. Results from extensive simulations show the superiority of the debiasing method compared to other inference methods. [ABSTRACT FROM AUTHOR]

Anxiety is highly prevalent in Alzheimer's disease (AD), correlating with cerebrospinal fluid/positron emission tomography biomarkers and disease progression. Relationships to plasma biomarkers are unclear. Herein, we compare levels of plasma biomarkers in research participants with and without anxiety at cognitively normal, mild cognitive impairment, and AD dementia stages. We observed significantly higher plasma tau/amyloid-β42 ratio in AD participants with anxiety versus those without, but did not observe differences at other stages or plasma biomarkers. No such relationships were evident with depression. These results support a unique pathophysiological relationship between anxiety and AD that can be reflected in plasma biomarkers, suggestive of heightened neurodegeneration. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a devastating, age‐associated neurodegenerative disorder and the most common cause of dementia. The clinical continuum of AD spans from preclinical disease to subjective cognitive decline, mild cognitive impairment, and dementia stages (mild, moderate, and severe). Neuropathologically, AD is defined by the accumulation of amyloid β (Aβ) into extracellular plaques in the brain parenchyma and in the cerebral vasculature, and by abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs). Development of treatment approaches that prevent or even reduce the cognitive decline because of AD has been slow compared to other major causes of death. Recently, the United States Food and Drug Administration gave full approval to 2 different Aβ‐targeting monoclonal antibodies. However, this breakthrough disease modifying approach only applies to a limited subset of patients in the AD continuum and there are stringent eligibility criteria. Furthermore, these approaches do not prevent progression of disease, because other AD‐related pathologies, such as NFTs, are not directly targeted. A non‐mutually exclusive alternative is to address lifestyle interventions that can help reduce the risk of AD and AD‐related dementias (ADRD). It is estimated that addressing such modifiable risk factors could potentially delay up to 40% of AD/ADRD cases. In this review, we discuss some of the many modifiable risk factors that may be associated with prevention of AD/ADRD and/or increasing brain resilience, as well as other factors that may interact with these modifiable risk factors to influence AD/ADRD progression. [Color figure can be viewed at www.annalsofneurology.org] ANN NEUROL 2024;96:633–649 [ABSTRACT FROM AUTHOR]

Background: The burden of Alzheimer's disease and related dementias (AD/ADRD) in Costa Rica is expected to become one of the highest in the region. Early detection will help optimize resources and improve primary care interventions. The Montreal Cognitive Assessment (MoCA) has shown good sensitivity for detecting mild cognitive impairment (MCI), but specificity varies depending on the population. This motivated the analysis of different cutoffs to minimize false-positive classifications in a Costa Rican sample for its use in clinical settings. Methods: Data was analyzed from 516 memory clinic outpatients (148 cognitively normal, 260 MCI, 108 mild AD/ADRD; mean age 66.3 ± 10.8 years) who underwent complete neurological and neuropsychological assessment and were diagnosed by consensus. Optimal MoCA cutoff scores were identified using a multiple cutoff approach. Results: Overall, a cutoff score of ≥ 23 showed better accuracy to distinguish between normal cognition (NC) and MCI (sensitivity 73%, specificity 83%). When analyzed by educational levels, a cutoff score of ≥ 21 showed better accuracy for ≤ 6 years (sensitivity 80%, specificity 76%), ≥23 for 7–12 years (sensitivity 86%, specificity 76%) and ≥ 24 for > 12 years (sensitivity 70%, specificity 85%). For distinguishing MCI from mild AD/ADRD, the optimal overall cutoff score was ≥ 15 (sensitivity 66%, specificity 85%). When stratified by years of education, cutoff scores of ≥ 14 showed better accuracy for ≤ 6 years (sensitivity 70%, specificity 88%), ≥15 for 7–12 years (sensitivity 46%, specificity 95%) and ≥ 17 for > 12 years (sensitivity 67%, specificity 93%). Conclusions: A MoCA cutoff score of ≥ 23 in the Costa Rican population showed better diagnostic accuracy for detecting MCI and may reduce the false positive rate. Our findings may be helpful for primary care clinical settings and further referral criteria. [ABSTRACT FROM AUTHOR]

Background: Subjective cognitive decline (SCD) is a preclinical stage of Alzheimer's disease (AD), with correlations to cerebral amyloid and tau and accelerated cognitive decline. Studies have also revealed an association between sleep fragmentation and such AD biomarkers and cognitive decline, suggesting that cognitive function should be monitored in individuals experiencing excessive sleepiness. It is unclear if and how sleep dysfunction relates to SCD apart from AD biomarkers, as well as symptoms related to SCD and sleep dysfunction, such as depression. Furthermore, studies of SCD and sleep dysfunction have primarily focused on non‐Hispanic Whites. Hence, a better understanding of how sleep impacts preclinical AD risk in SCD is needed in more diverse cohorts. We investigated the cross‐sectional relationship between excessive sleepiness in cognitively normal older adults and SCD symptoms linked to cognitive domains in a cohort consisting of NHWs and Black/African Americans (B/AA). Method: This retrospective cross‐sectional study included cognitively normal older participants (n = 147, age> 60 years, 61 B/AA, 86 NHW) evaluated at the NYU Alzheimer's Disease Research Center. Participants underwent Uniform Data Set 3.0 psychometric testing to confirm normal cognition, Epworth Sleepiness Scale (ESS), Geriatric Depression Scale (GDS), and the Cognitive Change Index (CCI) as a measure of SCD. The CCI was further divided into subscores of non‐amnestic (i.e. executive) and amnestic domains (i.e. memory). Participants underwent amyloid (florbetaben) and tau (PI‐2620 or MK‐6240) PET MRI, with composite SUVR calculated by averaging key cortical regions. Multivariable linear regression models tested the association of ESS and covariates (GDS, amyloid SUVR, tau SUVR, race) to the three CCI outcome measures (total, non‐amnestic, amnestic). Result: ESS (excessive sleepiness) was significantly positively associated with total CCI (p = 0.01042) as well as non‐amnestic (0.00771) and amnestic CCI subgroups (0.02583), after full covariate adjustment, as was GDS. Race did not show an independent statistically significant association. Conclusion: These results suggest that excessive sleepiness, independent of depression and amyloid and tau burdens, may be a significant contributor to SCD severity. Furthermore, these contributions impact both amnestic and non‐amnestic domains. Future studies are needed to investigate the longitudinal impact of excessive sleepiness on SCD outcomes. [ABSTRACT FROM AUTHOR]

Background: The lateral entorhinal cortex (LEC), followed by area CA1 of hippocampus, are interconnected brain areas implicated early in Alzheimer's disease (AD). Processing of LEC input by CA1 pyramidal neurons (PNs) is critical for non‐spatial memory, in which deficits are seen in early AD. How this process is affected by tauopathy is unclear. Furthermore, CA1 PNs are divided into molecularly and functionally distinct superficial (sPN) and deep (dPN) subpopulations. It is additionally unclear if and how LEC input processing by these subpopulations are differentially impacted. Method: LEC of female PS19 and WT mice (8‐10 month old) were injected with an AAV expressing channelrhodopsin ChrR2. After two weeks, acute hippocampal slices were prepared and whole cell patch clamp recordings were performed on dPNs/sPNs of distal CA1 in current clamp and voltage clamp mode using a potassium‐ or cesium‐based intracellular solution, respectively. Synaptic responses were measured in current clamp and voltage clamp mode, with LEC axons optogenetically activated by blue LED light. In current clamp, excitatory postsynaptic potentials (EPSPs) were measured with inhibition blocked. In voltage clamp, excitatory postsynaptic currents (EPSCs) were evaluated by holding membrane potential at ‐70mV, and inhibitory postsynaptic currents (IPSCs) were evaluated by holding at 0mV. Result: All data is n = 3‐8/group. Compared to WT, LEC‐driven EPSCs showed significant reductions in PS19 sPNs (18.7pA vs. 8.4pA, p = 0.0016) but were unchanged in dPNs (12.4pA vs. 13.6pA, p = 0.2841). Measurements of LEC‐driven EPSPs showed analogous findings. There was no change in paired pulse ratio, ruling out presynaptic changes. There was no change in EPSP decay time constant or temporal summation of the EPSP, ruling out changes in postsynaptic excitability. In contrast to excitation, LEC‐driven IPSCs were unchanged in PS19 versus WT mice in both sPNs (45.7pA vs. 51.9pA, p = 0.62) and dPNs (25.46pA vs. 22.3pA, p = 0.22). Conclusion: LEC drive of CA1 PNs exhibits a cell type‐specific vulnerability to tauopathy, with sPNs differentially susceptible to a reduction of excitation, without changes in feedforward inhibition. Our results further support a postsynaptic mechanism that may be due to spine loss, changes in spine morphology, or shifts in glutamate receptor expression. [ABSTRACT FROM AUTHOR]

Background: How tauopathy disrupts direct entorhinal cortex (EC) inputs to CA1 and their plasticity is understudied, despite its critical role in memory. Moreover, dysfunction of lateral EC (LEC) input is less clear, despite its relevance to early Alzheimer's disease pathogenesis. Here we examined how tau impacts long‐term potentiation (LTP) of LEC→CA1 input in a transgenic model of tauopathy. Method: Acute hippocampal slices were prepared from PS19 and WT mice (8‐10 mo. old, M/F) in which LEC had been injected with an AAV expressing channelrhodopsin ChR2. Ex vivo recordings were achieved with blue LED light to excite LEC axons and an extracellular field electrode in stratum lacunosum moleculare (SLM) of distal CA1 to record field responses. Input‐output curves were established using 25‐100% LED power for field postsynaptic excitatory potentials (fEPSPs) with inhibition blocked (GABAA: 2mm SR95531, GABAB: 1mm CGP55845). LTP of fEPSPs was elicited after a 10" baseline using an LED theta burst stimulation (TBS). Paired pulse ratio (PPR) of fEPSPs was elicited with LED stimulation of 2 pulses at 20Hz. Fluorescence immunohistochemistry (IHC) was performed in separate mice using antibodies to N‐type calcium channels. Result: All results are based on n = 4‐8/sex/genotype. The LEC fEPSP was of reduced magnitude in female PS19 versus WT mice, while unchanged across genotype in male mice. TBS induced a late‐onset LTP (147% at 45") of the LEC fEPSP in female WT mice, which was significantly reduced in female PS19 mice (p = 0.0051). There was no LTP reduction in male mice. LTP in female WT mice was associated with a PPR reduction that was reversed by the addition of the N‐type calcium channel blocker w‐conotoxin GVIA, all of which did not occur in PS19 mice (p<0.0001). PPR was appropriately reduced in male mice across genotype. IHC of N‐type calcium channels showed reduced fluorescence in the SLM of female PS19 mice versus WT. Conclusion: In PS19 mice, the impact of tau on LEC→CA1 input is sex‐dependent, with reduced LEC‐driven excitation and LTP only in female mice. A reduction in presynaptic N‐type calcium channels in PS19 mice may serve as a presynaptic mechanism for the reduced plasticity. [ABSTRACT FROM AUTHOR]

Background: We examined racial differences between measures of limbic white matter tracts and objective sleep parameters in cognitively unimpaired older‐adults. Method: This cross‐sectional study included 170 community‐dwelling cognitively unimpaired older‐adults (mean±SD: age = 67.2±5.2y) participating in NYU studies of sleep, aging, and memory. Subjects completed polysomnography (NPSG) and brain MRI. Sleep measures of interest included total sleep time (TST), NREM stages 2, 3 and REM sleep duration, sleep latency and fragmentation, slow sleep spindles (SSP), sleep spindle density (SPD), AHI4% and REM AHI4%. Microstructural properties of the cingulum, uncinate fasciculus (UF), and fornix were estimated using diffusional tensor imaging (DTI) metrics including radial kurtosis (RK), radial diffusivity (RD), and fractional anisotropy (FA). Adjusted Linear mixed‐effects regression models examined associations between race, sleep, race*sleep and DTI metrics. Result: Participants were 44.1% Black with 16.8±2.5y of education. Subjects were relatively matched on AHI4%, age, BMI and educational level. In the cingulum, increased fragmentation was associated with higher RD β[Left] = 0.0026, p = 0.022), decreased RK (β[Right] = ‐0.0069, p = 0.039) in Blacks. Additionally, increased sleep latency was associated with reduced FA (β[Right] = ‐0.0010, p = 0.019), higher RD (β [Right] = 0.0010, p = 0.008) in Blacks. In the UF, increased fragmentation was associated with higher RD(β[Left] = 0.0052, p = 0.019) and lower RK (β[Right] = ‐0.0010, p = 0.039) in Blacks; increased AHI4%REM was associated with reduced FA β[Left] = 0.0007, p = 0.041), higher RD (β[Right] = ‐0.0007, p = 0.027) and lower RK (β[AHI4%, Left] = ‐0.0029, p = 0.001) in Blacks. Furthermore, higher SSP (βRight] = 0.00031, p = 0.045 and SPD (β[Right] = 0.045, p = 0.025) was associated with higher RK in Blacks. In the cingulum of white participants, higher AHI4%REM was associated with reduced FA β[right] = ‐0.0006, p = 0.013), higher RD β[Left] = 0.0005, p = 0.051), and reduced RK β[Right] = ‐0.00198, p = 0.008). Additionally, NREM stage‐2 sleep duration was associated with higher FA β[Right] = 0.0010, p = 0.037) and higher RK β[Right] = 0.0031, p = 0.040). In the UF, increased fragmentation was associated with reduced RK β[Left] = ‐0.017, p = 0.047) in Whites. Conclusion: Cognitively‐unimpaired Black and White older‐adults showed sleep disruption associations with limbic white matter integrity, with race‐specific associations observed across various microstructural properties of the cingulum, UF, and fornix. Thus, highlighting possible sleep‐related underpinnings of racial differences in Alzheimer disease‐risk. [ABSTRACT FROM AUTHOR]

Objectives: Subjective cognitive decline (SCD) is a preclinical stage of AD. White matter hyperintensities (WMH), an MRI marker of cerebral small vessel disease, associate with AD biomarkers and progression. The impact of WMH on SCD phenotype is unclear. Methods/Design: A retrospective, cross‐sectional analysis was conducted on a diverse cohort with SCD evaluated at the NYU Alzheimer's Disease Research Center between January 2017 and November 2021 (n = 234). The cohort was dichotomized into none‐to‐mild (n = 202) and moderate‐to‐severe (n = 32) WMH. Differences in SCD and neurocognitive assessments were evaluated via Wilcoxon or Fisher exact tests, with p‐values adjusted for demographics using multivariable logistic regression. Results: Moderate‐to‐severe WMH participants reported more difficulty with decision making on the Cognitive Change Index (1.5 SD 0.7 vs. 1.2 SD 0.5, p = 0.0187) and worse short‐term memory (2.2 SD 0.4 vs. 1.9 SD 0.3, p = 0.0049) and higher SCD burden (9.5 SD 1.6 vs. 8.7 SD 1.7, p = 0.0411) on the Brief Cognitive Rating Scale. Moderate‐to‐severe WMH participants scored lower on the Mini‐Mental State Examination (28.0 SD 1.6 vs. 28.5 SD 1.9, p = 0.0491), and on delayed paragraph (7.2 SD 2.0 vs. 8.8 SD 2.9, p = 0.0222) and designs recall (4.5 SD 2.3 vs. 6.1 SD 2.5, p = 0.0373) of the Guild Memory Test. Conclusions: In SCD, WMH impact overall symptom severity, specifically in executive and memory domains, as well as objective performance on global and domain‐specific tests in verbal memory and visual working/associative memory. Key points: White matter hyperintensities impact subjective cognitive decline in executive and memory domainsWhite matter hyperintensities also affect objective measures of cognition in verbal memory and visual working/associative memory [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer’s disease (AD) and Lewy body disease (LBD) are the two most common neurodegenerative dementias and can occur in combination (AD+LBD). Due to overlapping biomarkers and symptoms, clinical differentiation of these subtypes could be difficult. However, it is unclear how the magnitude of diagnostic uncertainty varies across dementia spectra and demographic variables. We aimed to compare clinical diagnosis and post-mortem autopsy-confirmed pathological results to assess the clinical subtype diagnosis quality across these factors. Methods: We studied data of 1,920 participants recorded by the National Alzheimer’s Coordinating Center from 2005 to 2019. Selection criteria included autopsy-based neuropathological assessments for AD and LBD, and the initial visit with Clinical Dementia Rating (CDR) stage of normal, mild cognitive impairment, or mild dementia. Longitudinally, we analyzed the first visit at each subsequent CDR stage. This analysis included positive predictive values, specificity, sensitivity and false negative rates of clinical diagnosis, as well as disparities by sex, race, age, and education. If autopsy-confirmed AD and/or LBD was missed in the clinic, the alternative clinical diagnosis was analyzed. Findings: In our findings, clinical diagnosis of AD+LBD had poor sensitivities. Over 61% of participants with autopsy-confirmed AD+LBD were diagnosed clinically as AD. Clinical diagnosis of AD had a low sensitivity at the early dementia stage and low specificities at all stages. Among participants diagnosed as AD in the clinic, over 32% had concurrent LBD neuropathology at autopsy. Among participants diagnosed as LBD, 32% to 54% revealed concurrent autopsy-confirmed AD pathology. When three subtypes were missed by clinicians, “No cognitive impairment” and “primary progressive aphasia or behavioral variant frontotemporal dementia” were the leading primary etiologic clinical diagnoses. With increasing dementia stages, the clinical diagnosis accuracy of black participants became significantly worse than other races, and diagnosis quality significantly improved for males but not females. Discussion: These findings demonstrate that clinical diagnosis of AD, LBD, and AD+LBD are inaccurate and suffer from significant disparities on race and sex. They provide important implications for clinical management, anticipatory guidance, trial enrollment and applicability of potential therapies for AD, and promote research into better biomarker-based assessment of LBD pathology. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease and related dementias (AD/ADRD) burden in Costa Rica is expected to become one of the highest in the region. Early detection will help optimize resources and improve primary care interventions. The Montreal Cognitive Assessment (MoCA) has shown good sensitivity for detection of mild cognitive impairment (MCI), but specificity varies depending on the population. This motivates the analysis of different cut‐offs to minimize false‐positive classifications in a Costa Rican sample for its use in clinical settings. Methods: Data was analyzed from 516 memory clinic outpatients (148 cognitively normal, 260 MCI, 108 mild dementia; mean age 66.3 ± 10.8 years) who underwent complete neurological and neuropsychological assessment and were diagnosed by consensus. Optimal MoCA cut‐off scores were identified using the Youden's Index, balanced cut‐offs, and specificity scores. Results: Overall, a cut‐off score of ≥23 showed better accuracy to distinguish between NC and MCI (sensitivity 73%, specificity 83%). When analyzed by educational levels, cut‐off scores of ≥21 showed better accuracy for ≤6 years (sensitivity 80%, specificity 76%), ≥23 for 7‐12 years (sensitivity 86%, specificity 76%) and ≥24 for ≥12 years (sensitivity 70%, specificity 85%). For distinguishing MCI from mild dementia, the optimal overall cut‐off score was ≥15 (sensitivity 65%, specificity 85%). When stratified by years of education, cut‐off scores of ≥14 showed better accuracy for ≤6 years (sensitivity 70%, specificity 88%), ≥15 for 7‐12 years (sensitivity 79%, specificity 95%) and ≥17 for ≥12 years (sensitivity 67%, specificity 93%). Conclusions: A MoCA cut‐off score of ≥23 in Costa Rican population showed better diagnostic accuracy and may reduce the false positive rate. Our findings may be helpful for primary care clinical settings and further referral criteria. Keywords: MoCA, Montreal Cognitive Assessment [ABSTRACT FROM AUTHOR]