bluuebunny/crossref_metadata_2025 huggingface dataset:
Greater neighborhood deprivation is related to shorter survival in behavioral‐variant frontotemporal degeneration
Authors: Boyle Rory , Dehghani Nadia , Stites Shana D. , Nelson Brian , Irwin David J , McMillan Corey T , Massimo Lauren
Published: January 2025

Background

Emerging evidence relates neighborhood deprivation to cognitive decline and neurodegeneration but this is understudied in frontotemporal degeneration (FTD). We assessed the association of neighborhood deprivation with survival in 147 individuals with behavioral‐variant FTD (bvFTD).

Method

Neighborhood deprivation was measured using the Area Deprivation Index (ADI), a national percentile ranking of deprivation based on income, education, employment, and housing quality. ADI was split into tertiles: lowest deprivation (ADI:1‐19), intermediate deprivation (ADI:20‐40), and highest deprivation (ADI:41‐93). In a Cox regression, we examined the association between ADI (reference group = lowest deprivation) and survival time (time from symptom onset to death), adjusting for age at symptom onset, sex (reference group = women), and education years. Individuals alive at study close were censored at their last clinic visit.

Result

Older age at symptom onset was associated with shorter survival (hazard ratio [HR] = 1.03[95%CI = 1.01–1.06], p = 0.005). Male sex was associated with longer survival (HR = 0.63[95%CI = 0.42–0.96], p = 0.03). Highest deprivation (HR = 1.84[95%CI = 1.09‐3.1], median survival years = 7[women]‐9[men], p = 0.017), but not intermediate deprivation (HR = 1.58[95%CI = 0.95‐2.63], median survival years = 7[women]‐10[men], p = 0.081), was associated with shorter survival time compared to the lowest deprivation group (median survival years = 10[women]‐12[men]). Similar results were observed in a sex‐stratified model.

Conclusion

Our results suggest that increased neighborhood deprivation contributes to shorter survival in bvFTD. Further research is needed to replicate this finding and uncover the underlying mechanisms.
Primary results from SPRINT MIND 2020
Authors: Williamson Jeff D.
Published: January 2025

Background

The Systolic Blood Pressure Intervention (SPRINT) randomized clinical trial evaluated the effect of intensive blood pressure (BP) control, defined by targeting systolic BP < 120 mm Hg, versus the standard target of < 140 mm Hg. Participants were recruited from 102 sites in the United States and Puerto Rico, aged 50 years or older with hypertension but without diabetes or history of stroke. SPRINT stopped early, after a median treatment of only 3.34 years of intervention, due to benefit on its primary outcome (a composite of cardiovascular events) and all‐cause mortality. SPRINT‐MIND, a sub‐study of SPRINT that evaluated cognitive outcomes, found intensive BP control reduced risk of mild cognitive impairment (MCI) by 19% and reduced the risk of developing either MCI or probable dementia (PD) by 15%. There was also a statistically non‐significant reduction of 17% in PD alone. We investigated the long‐term impact of intensive BP control on MCI and PD by conducting extended cognitive assessment for SPRINT‐MIND, adding follow‐up for cognitive outcomes through December 31, 2023.

Methods

The extended follow‐up was designed to administer a cognitive assessment battery by phone to 7221 participants in the main trial that were not withdrawn or had been adjudicated as having probable dementia and consented to future research. Participants were contacted by phone were asked to provide verbal informed consent. Phone calls began on December 2nd 2019.

Results

There were 9361 participants originally randomized (mean age, 67.9 years; 3332 women [35.6%]) and of these, 7221 (77%) were free of dementia, and consented to long‐term follow‐up cognitive assessment. During this extended total median follow‐up of 6.9 years, adjudicated PD occurred in a total of 541 participants and MCI occurred in a total of 810 participants.

Conclusion

The results from SPRINT MIND 2020 will demonstrate the long‐term benefit of intensive systolic blood pressure control on cognitive function.
A randomized trial of over‐the‐counter hearing aids for adults with cognitive decline due to Alzheimer’s Disease and related dementias
Authors: Mueller Kimberly D , Chin Nathaniel A. , Williams Victoria J. , McAlister Courtney B. , Souza Pamela E.
Published: January 2025

Background

Hearing loss occurs commonly with age and is more prevalent among adults with Mild Cognitive Impairment (MCI) or Alzheimer’s Disease and related dementias (ADRD) than among older adults with typical cognitive abilities. Over‐the‐counter (OTC) hearing aids are a recently approved, lower‐cost method of hearing treatment which can be accessed directly by patients. However, there are almost no data which can guide whether to recommend this treatment for adults with MCI or ADRD. OTC aids also have technology constraints that may limit their benefit for wearers with ADRD, who have specific communication and rehabilitation needs.

Method

Participants in this randomized clinical trial will be recruited at the time of diagnosis of either MCI or early ADRD. The trial design embeds a brief hearing assessment within the structure of a memory assessment at Geriatrics and Neurology clinics, in both urban (Madison, WI) and rural (La Crosse, WI) settings. Trial participants will be randomized to receive either OTC aids or communication strategies tailored for adults with cognitive decline. To maximize access for patients (including patients from rural or underserved areas), treatment will be delivered via telehealth. Outcomes will be measured at baseline and after one month of use of the OTC hearing aids or communication strategies. The primary outcome is subjective assessment of dyadic communication by the listener’s primary communication partner. Additional outcomes include hearing‐related quality of life and a novel assessment of communication ability using structured conversation analysis.

Result

This presentation will describe the trial design, expertise and roles of the multidisciplinary study team, mechanism of treatment delivery via telehealth, and planned outcome measurements.

Conclusion

Results of this trial will provide important evidence to guide treatment recommendations in community‐dwelling older adults with MCI or early ADRD. This project will also establish feasibility of conducting hearing assessment as part of a memory assessment.
Lecanemab Slows Amyloid‐Induced Tau Pathology as Supported by CSF MTBR‐tau243 in Clarity AD
Authors: Wildsmith Kristin R , Sachdev Pallavi , Horie Kanta , Reyderman Larisa , Charil Arnaud , Kanekiyo Michio , Yin Han , Li David , Koyama Akihiko , Dhadda Shobha , Irizarry Michael C. , Kramer Lynn D
Published: January 2025

Background

Lecanemab is a humanized immunoglobulin G1 monoclonal antibody targeting neurotoxic Aβ protofibrils and Aβ plaques, which reduces markers of amyloid and significantly slows clinical decline on multiple cognition and function measures. Cerebrospinal fluid (CSF) microtubule‐binding region (MTBR) of tau containing the residue 243 (MTBR‐tau243) is an emerging tau pathology biomarker that tracks with tangle formation in Alzheimer’s disease (AD) [Horie et al. Nat Med. 2023;29:1954‐1963]. In order to evaluate effects of lecanemab on MTBR‐tau243, CSF was analyzed in a subset of early AD participants from the phase 3 (Clarity AD) trial.

Method

CSF from n = 167 early AD participants from Clarity AD was analyzed using an IP‐MS based method [Horie et al. Nat Med. 2023;29:1954‐1963.]. Pearson correlation analysis was performed to assess relationships between CSF MTBR‐tau243, AD fluid biomarkers, amyloid PET and tau PET SUVR in multiple regions of interest. Mixed model for repeated measures was used to analyze change from baseline and assess treatment effect over 18 months.

Result

Baseline correlation analysis show that CSF MTBR‐tau243 has the highest correlation with Tau PET SUVR across regions of interest (ROI) (Braak 1‐6, whole cortical grey (WCG) vs. all other fluid biomarkers assessed (CSF markers: ptau181, total tau, neurogranin, NfL, Aβ40 and Aβ42; plasma markers: pTau217, pTau181, Aβ42/40, NfL and GFAP). CSF MTBR‐tau243 has a higher correlation with Tau PET SUVR (r = 0.74, WCGROI) vs. amyloid PET Centiloids (r = 0.39, WCG ROI). Levels of CSF MTBR‐tau243 increased over time in early AD (placebo). Treatment with lecanemab slowed the rate of increase of MTBR‐tau243 vs. placebo, with a greater separation from placebo observed at 18 month (77 weeks) vs. 12 months (53 weeks). While the results have limitations due to sample size and do not reach statistical significance, at 18 months lecanemab slowed the rate of increase in CSF MTBR‐tau243 by 44% vs. placebo.

Conclusion

These results support that CSF MTBR‐tau243 is a specific biomarker of tau tangle pathology and are consistent with the effects of lecanemab on Tau PET, which similarly showed a slowing of tau accumulation vs. placebo. These results demonstrate that lecanemab‐associated amyloid removal slows the formation of tau pathology in the brain.
Association among Cognitive Stress Appraisal, Chronic Stress, and Cognition in Cognitively Normal Older Adults: Preliminary Findings
Authors: Aduen Paula , Badillo‐Cabrera Alex L , Vila‐Castelar Clara , Noriega‐Makarskyy Daisy , Munera Diana , Lucas John A. , Kirschbaum Clemens , Slavich George M , Quiroz Yakeel T.
Published: January 2025

Background

Characterizing stress can inform our understanding of direct and indirect pathways impacting mental and physical health outcomes, including age‐related cognitive decline. Chronic stress has been strongly associated with increased risk for cognitive decline, and hair cortisol concentration (HCC) has emerged as a viable neuroendocrine biomarker for its quantification. Cognitive appraisal of stress (CAS) provides key insight into the cognitive framework for responding to a given stressor. We implemented a multi‐pronged approach to evaluate chronic stress and examined its relation to cognition in older adults.

Method

Participants were 22 cognitively normal individuals (x̄ MMSE = 29.33, 0.92; x̄ age: 67.3 ± 8.8 years old, 17.0 ± 2.9 years of education, 54.5% female, 92.6% Non‐Hispanic White). Participants completed the Stress and Adversity Inventory (STRAIN) assessing lifetime stressor exposure and the Primary and Secondary Cognitive Appraisal Scale (PSCAS). HCC was used as a neuroendocrine biomarker of chronic stress. A brief cognitive battery assessing episodic memory and executive functions (Digit Span, HVLT‐R, Trail Making Test, Letter Fluency) and mood/anxiety measures were completed. To correct for skewness, log‐transformed HCC values were used for Pearson and partial correlation analyses controlling for age and education.

Result

Lifetime stressor exposure and CAS were not significantly related to cognitive performance (all ps > 0.05). There was a marginally significant association between HCC and executive functions (r = ‐0.41, p = 0.08). Total lifetime stressor count, chronicity, and severity were unrelated to symptoms of depression and anxiety (all ps > 0.05). Although lifetime stressor exposure and mood were not significantly related to HCC, higher HCC was associated with higher perceived control of stress (r = 0.45, p = 0.03).

Conclusion

HCC may be more sensitive to CAS rather than to objective stressor exposure. This highlights the potential of interventions targeted at improving coping in those with chronic stress. Results are preliminary, and the present study will explore impact of social and structural determinants of health on chronic stressor exposure, appraisal, and cognition.
Chronic Pain in Latin America: Prevalence, Risk Factors, and Their Association with Dementia
Authors: Hernandez Hernan , Caviedes Ariel , Oyanedel Lorena , Franco Teresita Ramos , Olavarria Loreto , Ibañez Agustin , Santamaria‐Garcia Hernando , Custodio Nilton , Montesinos Rosa , Bruno Martin Alejandro , Slachevsky Andrea , Ochoa‐Rosales Carolina , Duran‐Aniotz Claudia , Gonzalez‐Silva Carolina
Published: January 2025

Background

Chronic pain (CP) is defined as the persistence of pain beyond the expected recovery period of an injury, or alternatively, with a duration exceeding three months. It has been recognized as a risk factor for dementia in European and North American cohorts. However, in Latin America (LA), there remains a significant gap in understanding CP prevalence, its risk factors, and its association with Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Our study aims to shed light on the impact of CP on the LA population, along with its implications for AD and FTD.

Method

We analyzed data from the National Health Survey (NHS) conducted in Chile in 2009‐2010 and 2016‐2017. This study comprised 2179 subjects from the 2009‐2010 survey and 1447 subjects from the 2016‐2017 survey. Additionally, we assessed CP in LA patients with dementia (AD and FTD) using a concise 6‐question survey, which evaluated the presence, duration, frequency, location, and intensity of pain. Our patients are from Chile, Peru, Argentina, and Colombia, all of whom actively participate in the Multicenter Consortium to Expand Dementia Research in Latin America (ReDLat).

Result

Our analysis revealed from the Chilean NHS that the prevalence of CP increased by approximately 30% across both surveys among individuals aged 20 to 70. Key factors associated with CP in the Chilean population include reduced mobility, anxiety, depression, malnutrition, socioeconomic disadvantage, and lower educational attainment. The results also suggest an association between CP and the presence of dementia in the Chilean population that warrants further detailed investigation. In the analysis of the ReDLat cohort, we observed that patients with AD report experiencing CP at a higher proportion (53.6%) than patients with FTD (31.3%) and control subjects (34.8%).

Conclusion

This study highlights the substantial impact of CP on the LA population, particularly in AD patients. To our knowledge, this is the first study in LA to investigate the prevalence and risk factors associated with CP. Additionally, our findings suggest that CP is associated with the pathology of dementia, emphasizing the critical need for further research in this area.
An Innovation to Address Brain Health and Dementia in Individuals with Intellectual and Developmental Disabilities
Authors: Pettis Jennifer , Tracy Karen K
Published: January 2025

Adults with intellectual and developmental disabilities (I/DD) and their caregivers may face many barriers to obtaining an accurate assessment of cognitive decline. For example, primary care providers may mistake manifestations of new cognitive impairments or dementia for symptoms of the underlying disability. Pre‐existing cognitive impairments, communication challenges, unfavorable reactions by members of the care team to adults with pre‐existing cognitive deficits, and lack of understanding regarding common behaviors and needs of adults with I/DD can further complicate assessments. Furthermore, mainstream cognitive screening and assessment tools are not appropriate for many of the more than 7 million people living with I/DD in the United States. To address this unmet need and better equip primary care teams to appropriately address brain health in adults with I/DD, the Gerontological Society of America (GSA) developed a new companion resource to supplement The GSA KAER Toolkit for Brain Health.

The four steps in the KAER framework—Kickstart, Assess, Evaluate, and Refer—are intended to improve health‐related outcomes and well‐being for people living with dementia and their families. The Toolkit includes practical approaches, educational resources, and validated clinical tools that help primary care teams implement initiatives related to brain health and timely detection of cognitive impairment. GSA developed the companion publication addressing the unique needs of adults with I/DD. The publication, Addressing Brain Health in Adults with Intellectual Disabilities and Developmental Disabilities: A Companion to the KAER Toolkit for Primary Care Providers, aims to:

• Raise awareness of unique needs of adults living with I/DD.

• Equip and encourage caregivers and health care teams to engage in appropriate brain health conversations with adults with I/DD.

• Promote brain health conversations and early detection of changes in cognitive and adaptive function for adults with I/DD.

• Assist with the identification of community supports and resource networks aimed at enhancing function and quality of life for adults with dementia and I/DD.

This presentation will provide insights into the KAER framework and how, when combined with The GSA KAER Toolkit for Brain Health, the new companion can support person‐centered brain health promotion, early detection of dementia, and dementia care planning for individuals with I/DD.
Age associated changes in behavioral and memory functions in genetically heterogeneous mice UM‐HET3
Authors: Kaur Harpreet , Badenoch Bretton , Reifsnyder Peter C. , O'Connell Kristen MS , Miller Richard A. , Harrison David E. , Kaczorowski Catherine C.
Published: January 2025

Background

Previous studies have documented age‐related changes in behavior and cognitive functions and investigated the molecular changes in aging brain using inbred mouse strains such as C57BL/6, BALB/c etc. In this study using a genetically heterogenous mouse population (UM‐HET3) we investigated age‐related changes in motor and memory functions and their association with blood cell measures.

Method

Both male and female UM‐HET3 mice at age of 11 months (middle‐aged) and 25 months (old) were used in this study. Complete blood count, grip‐strength, Rotarod, visual acuity, startle response, voluntary wheel running activity and contextual fear conditioning assays were performed on these mice. Further, a correlation analysis was performed on blood cells and contextual fear memory (CFM) to identify signatures associated with age related cognitive decline.

Result

Our results showed significantly lower body temperature, decrease in hemoglobin, changes in blood related parameters (including RBC, hematocrit, platelets, MPV, WBC), reduced visual acuity, reduced grip strength (not normalized by BW) and impaired memory functions in older mice when compared to middle‐aged mice. We found no correlation between blood cells and CFM in middle‐aged mice, but the percentage of neutrophils (R = 0.794, p = 0.009) and lymphocytes (R = ‐0.734, p = 0.022) were found to be associated with CFM in older male mice. A reduced startle reactivity was also observed in older male and female mice which is likely to be the result of impaired hearing, although these mice were not tested for hearing loss. No statistical significance was observed in Rotarod performance and in wheel running activity when middle aged mice compared to old UM‐HET3 mice.

Conclusion

Our study showed that UM‐HET3 mice exhibit age related impairment in sensory and memory functions as compared to middle aged mice. In older mice, reduced memory correlates with increased percentage of neutrophils and decreased lymphocytes in blood, suggesting a possible role of white blood cells in age‐related memory decline in UM‐HET3 mice. However, further studies are needed to understand the mechanisms driving age‐related decline in cognition with focus on changes in immune cells for developing therapies to slow down the rate of cognitive decline in normal aging as well as neurological disorders such as Alzheimer’s disease.
AD04 – modifying Alzheimer’s Disease by modulation of neuroinflammation
Authors: Abraham Carmela R , Schneeberger Achim , III Agustin F Santana , Hoffmann Thomas , Fischer Anita , Trembleau Sylvie
Published: January 2025

Background

We aim to repurpose the widely used adjuvant and immunomodulator AlhydrogelTM at a specific dose and schedule (AD04) as a disease‐modifying treatment for mild Alzheimer’s disease (AD). AD04 is a potent adjuvant commonly used in vaccines and allergy immunotherapies to augment the magnitude and durability of the immune response. Our preliminary data come from a clinical Phase 2 study in which AD04 served as a control arm. In this study, AD04 showed promising results in delaying hippocampal atrophy and cognitive decline, as well as improving the quality of life in patients with mild AD. A global statistical test (GST) was used to compare the treatment effect of AD04 to other drugs/drug candidates. GST used is a combination of ADAS‐cog, ADCS‐ADL and the CDR‐sb. As such, it combines three important perspectives of three different aspects of AD progression. The effect size seen with AD04 is comparable or better than that of most other available treatments. However, the precise mode of action of subcutaneous (s.c.) administration of AD04 on the brain has not been deciphered.

Method

Aged (24 mo) C57BL/6 mice were injected s.c. with AD04 or with PBS, three times, and 3‐5 days after the last injection they were tested for fear conditioning. One day later, the mice were sacrificed, and hippocampi and peripheral organs were subjected to proteomics. Young (10wks) mice were used as controls.

Result

In the fear conditioning test, AD04‐treated old mice, exhibited an improved freezing behavior compared with the PBS‐injected mice. Proteomics analysis of the hippocampi revealed that peripheral AD04 administration modulated the production of proteins involved in lipid metabolism regulation and affected microglial phenotype into a phagocytic type.

Conclusion

Based on these preclinical results we conclude that AD04 administration induces microglia to phagocytose brain debris, such as apoptotic neurons, synapses and degraded myelin in the aged brain, and in the AD brain also Abeta, extracellular tau tangles and oxidized lipids. By changing the microglial phenotype, AD04, indirectly reduces the neuroinflammation induced by Abeta, tau and neuronal debris, leading to an anti‐inflammatory milieu in the brain which protects and rescues the hippocampus from neurodegeneration.
A Brief Digital Neuropsychological Protocol – IV: Relations Compared to Comprehensive Paper and Pencil Neuropsychological Assessment
Authors: De Anda‐Duran Ileana , Bazzano Lydia , Harville Emily , Fernandez‐Alonso Camilo , Banks Russell , Tobyne Sean , Jannati Ali , Showalter John , Bates David , Pascual‐Leone Alvaro , Swenson Rodney , Libon David J.
Published: January 2025

Background

A typical paper/pencil neuropsychological evaluation to assess for mild cognitive impairment (MCI) and dementia is lengthy. There is a need for a brief, digitally administered/scored neuropsychological protocol that can differentiate patients who are cognitively normal versus MCI and dementia. This need is particularly acute with the advent of disease‐modifying medications to treat MCI and early Alzheimer’s disease (AD).

Method

The Digital Assessment of Cognition (DAC) assesses memory with a 6‐word Philadelphia (repeatable) Verbal Learning Test [P(r)VLT]; executive abilities with three trials of 5 digits backward (BDST); and language/lexical access abilities with the ‘animal’ fluency test. 105 ambulatory care/memory clinic patients were assessed. DAC outcome measures include words recalled, recognition discriminability, BDST serial recall, and ‘animal fluency output; and separate episodic and executive summary indices. A portion of this sample (n = 70) underwent traditional, paper and pencil assessment.

Result

Cluster analysis (Table 1) classified participants into groups suggesting normal (NL = 25), dysexecutive MCI (n = 25), amnestic MCI (n = 11), mixed MCI (n = 24), and dementia (n = 25) cognitive abilities. Concordance between cluster classification and clinical diagnosis using a lengthy paper/pencil protocol was 90%. The ANOVA for the episodic memory summary index found no difference between NL/dMCI groups; all other groups differed. The ANOVA for the executive index found no differences between NL/aMCI, and dMCI/mixed MCI groups; all other groups were differentiated from each other. Within‐group, dMCI patients scored lower on the executive versus the memory index (p<0.001); aMCI patients scored lower on the memory versus executive index (p<0.001); NL patients scored higher on the executive versus the memory indices (p< 0.021); and mixed MCI patients did not differ on either index. The DAC memory index was correlated with CVLT‐short form delayed free recall (r = 0.648; p< 0.001) and recognition discriminability (r = 0.625, p<0.001) scores. The DAC executive index significantly correlated with WMS‐IV Symbol Span (r = 0.620, p<0.001; Trails B (r = 0.477, p< 0.001), and letter fluency (r = 0.538, p<0.001).

Conclusion

The DAC is able to identify clinically meaningful groups, showed diagnostic concordance with lengthy paper/pencil assessment, and is positively correlated with traditional paper and pencil tests. The DAC provides a reasonable means to screen for patients with putative MCI and dementia.
Phase 3 Trial of Oral Anti‐Amyloid Agent ALZ‐801/Valiltramiprosate in APOE4/4 Homozygotes with Early Alzheimer’s Disease: Baseline Characteristics and Prevalence of Comorbid Cerebral Amyloid Angiopathy
Authors: Power Aidan , Watson David , Abushakra Susan , MacSweeney Emer , Porsteinsson Anton P. , Sabbagh Marwan N. , Liang Earvin , McLaine Rosalind , Boada Mercè , Snædal Jón , Flint Susan , Pak Winnie , Hey John A. , Tolar Martin
Published: January 2025

Background

ALZ‐801/valiltramiprosate, an oral small molecule inhibitor of amyloid oligomer formation, is being evaluated in a Phase 3 trial in APOE4/4 Early AD subjects (APOLLOE4). Topline results are expected in 3Q 2024. APOE4 is a major risk factor for Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA) with a gene‐dose effect. APOE4/4 subjects with CAA are at higher risk of amyloid related imaging abnormalities (ARIA) with anti‐amyloid antibodies, including ARIA‐E (effusion/edema) and ARIA‐H [lobar microhemorrhages (MH), macrohemorrhages, and superficial siderosis (SS)]. APOE4 carriers are also at higher risk of hyperlipidemia and cardiovascular disease (CVD). Baseline prevalence of CAA and CVD risk factors were analyzed.

Method

This Phase 3 trial (NCT04770220) enrolled 325 APOE4/4 Early AD subjects (MMSE ≥22, 50‐80 years); 313 had baseline MRIs with central readings. Subjects with MH and SS were enrolled; ARIA‐E was exclusionary. Subjects with CAA (>4 MH, any siderosis, any macrohemorrhage) were compared to rest of population.

Result

Study population was 51% female, age 69 years, MMSE 26, 65%/MCI, 82% Caucasians. CAA group included 47/313 subjects (15%) of study, was mostly male (70% vs 45%), older (71 vs. 68 years, p = 0.004), more advanced (MMSE 25 vs 26, p = 0.018; ADAS‐cog 27 vs. 23, p = 0.002) with more severe deep WMD (p = 0.015). Both groups had similar prevalence of hypertension, diabetes, obesity, hyperlipidemia, and statin use but with higher coronary artery disease prevalence (17% vs. 8%, p = 0.049) and anti‐platelets use (38% vs 22%, p = 0.026) in the CAA group. No anticoagulants were allowed.

Conclusion

ALZ‐801 showed no ARIA‐E in prior AD studies allowing its evaluation in the high‐risk APOE4/4 homozygotes. This pivotal APOLLOE4 Phase 3 trial of ALZ‐801 enrolled homozygous APOE4/4 subjects with higher CAA burden than anti‐amyloid antibody trials. The APOE4/4 CAA subjects were older with more advanced AD and higher rates of CAD and antiplatelets use than non‐CAA subjects, which may increase brain edema and microhemorrhage risk, requiring heightened vigilance with anti‐amyloid antibodies. If this Phase 3 trial is positive, ALZ‐801 could become a potentially safer alternative to anti‐amyloid antibodies for this population. The Phase 3 results are expected in 3Q 2024.
Multi‐Marker Approach to Reducing the Intermediate Range of a High Accuracy 2‐Cutoff Plasma p‐Tau 217 Test for Amyloid Detection
Authors: Wilson David H , Khare Meenakshi , Wolfe Michele , Sheehy Patrick , Copeland Karen , Hesterberg Lyndal , Vasko Ann‐Jeanette , van der Flier Wiesje M. , van Harten Argonde C. , Verberk Inge M.W. , Teunissen Charlotte , Miller Mike
Published: January 2025

Background

p‐Tau 217 is considered the most accurate single plasma biomarker for detecting amyloid pathology. Recent draft Alzheimer’s Association criteria for diagnosing Alzheimer’s recommends that p‐Tau 217 tests be designed with two cut‐offs in recognition of signal overlap between diseased and non‐diseased subjects. Two cutoffs maximizes the accuracy of the test, but leaves a diagnostic intermediate zone with uncertainty of amyloid status. It is desirable to minimize the indeterminant zone to reduce the number of patients receiving uncertain results. We investigated whether the inclusion of plasma amyloid b42/40 ratio, NfL, and GFAP into a multi‐marker logistic regression model including p‐Tau 217 would enable amyloid classification of uncertain results from p‐Tau 217 alone.

Method

We optimized diagnostic thresholds for the Simoa LucentAD p‐Tau 217 plasma test to achieve ≥90% accuracy for MCI and AD patients across 2 independent cohorts (Bio‐Hermes, n = 242, Amsterdam Dementia Cohort, n = 737) representing divergent clinical settings, comparator methods, and geographic/ethnic/racial/mean age samplings. Across these diverse cohorts, the intermediate zone was 32.9%. Next we tested all samples for amyloid ratio, NfL, and GFAP using the Simoa N4PE kit. Multivariate logistic regression modeling was performed on all biomarker results to arrive at a probability scale. Samples with uncertain p‐Tau 217 results were re‐classified based on their probabilities being outside 90% lower and upper boundaries of the multi‐marker intermediate zone.

Result

Tables 1 and 2 exhibit preliminary amyloid classification results for p‐Tau 217 alone and the multi‐marker model respectively. “Amyloid Status” was determined by amyloid PET (Bio‐Hermes) or CSF biomarkers (Amsterdam). The multi‐marker model enabled amyloid classifications for 189 previously uncertain results. 137 uncertain results were re‐classified as positive (accuracy 88%), and 52 uncertain results were re‐classified as negative (accuracy 87%), reducing the intermediate zone 2.4‐fold from 32.9% to 13.7%.

Conclusion

Previous studies have found no benefit to combining additional AD‐relevant biomarkers with p‐Tau 217 to enhance accuracy. We show for the first time that additional biomarkers reduces the intermediate zone of a 2‐cutoff p‐Tau 217 test while preserving high accuracy. This finding can help provide amyloid status certainty for a greater number of symptomatic patients undergoing evaluation for Alzheimer’s.
Understanding Biomarker Discordance: MRI and PET Phenotypes Shed Light on Alzheimer’s Pathology
Authors: Gunasekaran Tamil Iniyan , Lee Annie J. , Lao Patrick J. , Gutierrez Jose , Manly Jennifer J. , Gu Yian , Brickman Adam M. , Honig Lawrence S. , Vardarajan Badri N. , Mayeux Richard
Published: January 2025

Background

Plasma biomarkers for Alzheimer’s disease (AD) are indicators of neuropathological changes. Biomarker cutoffs may not consistently indicate the presence or absence of a pathology. Discrepant biomarker levels are observed in some cognitively normal subjects and patients with clinically diagnosed AD, with some asymptomatic individuals having biomarker evidence of AD pathophysiology and some symptomatic individuals without evidence of AD pathophysiology. The purpose of this study is to understand the discordant biomarker levels among CN and AD using phenotypes from MRI and PET images.

Method

We measured phosphorylated tau 181 (P‐tau181) in plasma from 685 individuals in the Washington Heights Inwood Columbia Aging Project (WHICAP; Mean age = 76.52; women = 64.59%; non‐Hispanic Whites = 29.61%, African Americans = 30.62%; Caribbean Hispanics = 37.30%) and characterized them as biomarker positive based on a ptau181 cutoff of 2.648 pg/mL: 556 cognitively normal (CN, 241 biomarker+), 59 mild cognitively impaired (MCI, 26 biomarker+), and 70 had clinical AD (40 biomarker+). We used MRI (n = 685) and [18F] Florbetaben (FBB) Aβ PET in 167 (24.2%) individuals, and [18F]‐MK‐6420 tau PET 23 (3.36%) individuals) to compare white matter hyperintensity volume (WMH), hippocampus volume, number of silent brain infarcts (SBI), Aβ standard uptake value ratios (SUVR), and tau SUVR among the six biomarker groups (CN‐, CN+, MCI‐, MCI+, AD‐, AD+) with ANCOVA model adjusting for age, sex, and ethnicity.

Result

The AD+ group had larger WMH volume (P = 2.81×10−26), smaller hippocampus volume (P = 5.34×10−04), higher Aβ SUVR (P = 2.26×10−03) and tau SUVR (P = 8.11×10−04) compared to the CN‐. The AD‐ group had larger WMH volumes (P = 1.96×10−04) and smaller hippocampal volume (P = 0.039) to CN‐. When compared to the AD‐ group, the AD+ group had larger WMH volume (P = 4.34×10−03). The CN+ group had a larger WMH volume (P = 4.17×10−03) and smaller hippocampal volume (P = 4.13×10−05) than CN‐ group. Both MCI+ (P = 0.048) and MCI‐ (P = 0.022) groups showed smaller hippocampal volume compared with the CN‐ group. Except for hippocampal volume, no other phenotypes demonstrated statistical significance in the MCI+ and MCI‐ groups.

Conclusion

MRI and PET phenotypes exhibited a strong association with pathophysiological changes in the AD+ group. Specifically, MRI phenotypes such as WMH volume and hippocampal volume could be instrumental in characterizing AD pathophysiology, even with discrepancies in biomarker profiles.
Restoring activity‐dependent synaptic and microglial transcriptomic alterations in late‐stage Alzheimer’s Disease
Authors: Latif‐Hernandez Amira , III Robert R. Butler , Moran‐Losada Patricia , Yang Tao , Tran Kevin C , Liu Harry , Wyss‐Coray Tony , Longo Frank M.
Published: January 2025

Background

Activity‐dependent transcription is crucial in establishing the late phase of long‐term potentiation (L‐LTP), which is altered in Alzheimer’s disease (AD). TrkB and TrkC signaling‐activator (BD10‐2) reduces AD‐related synaptic dysfunction. We determined whether the synapse‐sparing effects of BD10‐2 are reflected in transcriptional changes following L‐LTP induction.

Method

We orally administered BD10‐2 or vehicle to 13‐month old APPL/S and WT mice, daily for 3 months. We measured L‐LTP‐dependent gene expression through RNA‐sequencing in hippocampal slices with or without induction of Theta‐Burst‐Stimulation (TBS)‐induced LTP.

Result

L‐LTP induction failed in APPL/S‐Veh but was restored in APPL/S‐BD2‐10 mice similarly to WT‐veh. Analysis of overlap enrichment between mouse TBS‐dependent gene expression and human AD‐relevant modules, revealed: (1) greater downregulation of neuronal genes by TBS in WT‐Veh and APPL/S‐BD10‐2 than in APPL/S‐Veh; and (2) upregulation of microglial associated AD‐enriched genes by TBS in all groups.

Conclusion

BD10‐2 prevented AD‐related LTP deficits and restored activity‐dependent AD‐related gene transcription.
Stable Isotope Labelling Kinetics (SILK) tracing of neurofilament light in human cerebrospinal fluid and brain tissue
Authors: Giovannucci Tatiana A. , Leckey Claire A. , Coulton John , Zetterberg Henrik , Elbert Donald L. , Bateman Randall J. , Mills Kevin , Wray Selina , Ghoshal Nupur , Sato Chihiro , Paterson Ross W.
Published: January 2025

Background

Neurofilament light protein (NfL) is a promising biomarker of neuronal injury and neurodegeneration. NfL levels in cerebrospinal fluid (CSF) and blood provide information about disease progression and are increasingly relied on as outcome measure in clinical trials. Understanding NfL kinetics in vivo is critical for interpreting NfL in response to new events where a steady state cannot be assumed, such as acute injury, disease onset or progression, or response to disease‐modifying therapies.

Method

We infused human participants with diagnosed primary tauopathies (progressive supranuclear palsy, n = 5; corticobasal syndrome, n = 3; behavioural variant frontotemporal dementia, n = 2) with a stable isotope tracer (13C6‐leucine) and collected CSF by lumbar puncture at 4, 14, 20, 60 and 120 days post‐labelling. In addition, post‐mortem brain tissue from three participants who were infused with the tracer 18, 44 and 50 months earlier were homogenised and biochemically fractionated to separate the soluble and insoluble fraction. NfL was enriched in all samples via immunoprecipitation. The ratio of labelled to unlabelled NfL was measured monitoring proteotypic peptides using established targeted mass spectrometry workflows to quantitate the tracer‐to‐tracee ratio (TTR).

Result

Analysis of CSF detected low labelling of NfL (0.04 – 0.36% TTR) by 120 days that was comparable to the TTR levels detected in the soluble brain fraction. There was NfL present in the insoluble fraction (2.87% of the total NfL at 18‐, 8.87% at 44‐ and 14.03% at 50‐months post‐mortem, averaged across several NfL peptides), with different relative abundances of NfL domains between these fractions. Interestingly, the 13C6‐labelled NfL signal detected in the insoluble fraction was more abundant, despite a higher recovery of total NfL in the soluble fraction.

Conclusion

NfL turnover in vivo is remarkably slow as it is scarcely captured by 120 days post‐labelling. The labelling results from brain tissue suggest that in these cases of primary tauopathies newly‐synthesized NfL might be delocalized to a pool of protein of low solubility that does not contribute to NfL levels in CSF. Current experiments are addressing whether newly‐synthesized NfL might be sequestered into pathological inclusions.
Body mass index moderates the relationship between the apnea‐hypopnea index and CSF biomarker of activated microglia
Authors: Bink Julia , Ma Yue , Mander Bryce A , Plante David T , Carboni Margherita , Wild Norbert , Chin Nathaniel A. , Okonkwo Ozioma C , Carlsson Cynthia M. , Gleason Carey E. , Asthana Sanjay , Johnson Sterling C. , Blennow Kaj , Zetterberg Henrik , Benca Ruth M , Bendlin Barbara B.
Published: January 2025

Background

Prior studies suggest that obstructive sleep apnea (OSA) may be associated with Alzheimer’s disease (AD) pathology, including Aβ42/Aβ40 and p‐Tau181. However, less is known about relationships between OSA and non‐AD pathology, including neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), S100, chitinase 3‐like 1 (YKL40), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), as well as the effect of potential moderating factors. The present study investigated the relationship between the apnea‐hypopnea index (AHI) and cerebrospinal fluid (CSF) biomarkers of AD and related pathology.

Method

In this cross‐sectional study, 73 cognitively unimpaired adults with no prior OSA diagnosis underwent an overnight PSG and/or testing with an at home ApneaLink. Participants completed a lumbar puncture to determine Aβ42/Aβ40, pTau181, NfL, GFAP, s100, YKL‐40, and sTREM2 as part of the Roche NeuroToolKit research platform (Roche International). Relationships between AHI and CSF biomarkers were tested using multiple linear regression adjusting for age, sex, APOE genotype, and BMI. Given prior studies suggesting potential interaction effects, we also examined interactions between AHI and APOE and interactions between AHI and BMI.

Result

AHI determined using PSG and at home Apnealink were highly correlated (r = 0.78, p < 0.01). There were no significant main effects of AHI on any of the CSF biomarkers, controlling for covariates (p > 0.05). Further, there was no significant interaction between APOE and AHI (p > 0.05). We found a significant interaction between BMI and AHI, such that participants with lower BMI showed higher sTREM2 with greater AHI, (p = 0.02; Figure 1). However, this positive relationship diminished with higher BMI.

Conclusion

OSA and obesity are intrinsically linked processes, however prior studies in sleep have also shown that these factors have interactive effects on several outcomes, including measures of inflammation and cognitive function. Here, we found that individuals who had lower BMI showed a potentially deleterious effect of AHI on measures of microglial activation. Additional studies are needed to determine whether these results are due to possible protective effects of higher BMI, or differences in sleep quality among individuals with high and low BMI.
TOP‐LINE CSF Biomarker Outcomes from the Phase 2 Clinical Trial SHINE in Alzheimer’s Patients
Authors: Caro Valentina Di , Cho Eunah , Knezovich Nicole , Blennow Kaj , Zetterberg Henrik , Teunissen Charlotte , Grundman Michael , Caggiano Anthony O , Hamby Mary E.
Published: January 2025

Background

A Phase 2 randomized, double‐blind, placebo‐controlled 6‐month trial, SHINE (NCT03507790), was designed to include up to 144 participants with mild to moderate Alzheimer’s disease (AD) to study the effects of the sigma‐2 receptor (S2R) modulator CT1812 on cognition, safety, and biomarkers. CSF canonical and exploratory biomarkers were assessed to determine treatment effects with CT1812.

Method

Participants (n = 153) received a daily oral dose of either CT1812 (100 mg or 300 mg) or placebo during the treatment period of 6‐months. The levels of CSF biomarkers Aβ40, Aβ42, pTau181, tTau, Nfl were measured by Lumipulse, neurogranin, GFAP and α‐synuclein by ELISA, SNAP‐25 and synaptotagmin by IP‐LC‐MS assay, and Aβ42/40 ratio calculated. An ANCOVA model was used to assess treatment effects comparing change from baseline values of CT1812 vs placebo. Significance was assessed at p<0.05 using 2‐tailed tests, and p‐values determined. A p‐value of <0.10 but >0.05 was considered evidence of a trend.

Result

At the end of the 6‐month treatment period, change from baseline levels and assessment of treatment effects (p<0.05) for CSF Aβ40, Aβ42, pTau181, tTau, Nfl, neurogranin, GFAP, SNAP‐25, synaptotagmin, and αSynuclein will be presented for the full trial. In an interim analysis of the first 24 participants, a significant (p<0.05) change from placebo for Aβ40, Aβ42 was observed with 300 mg of CT1812, along with trends of changes in other biomarkers. Treatment effects for all biomarkers assessed in the entire study will be presented. We hypothesize that the effect seen in lowering Aβ40 and Aβ42 will persist in the full analysis.

Conclusion

Understanding the effect of CT1812 on CSF biomarkers should lend support towards the clinical development of CT1812 for AD. The significant decrease in Aβ42and Ab40 levels may reflect pathway engagement given the mechanism of action of action of CT1812, and replication of this finding in the fully completed trial is prudent.
Cardiovascular health predicts working memory decline among cognitively healthy older African Americans
Authors: Amoateng Brad , Sheikh Mustafa , Fausto Bernadette A. , Gluck Mark A.
Published: January 2025

Background

African Americans are at increased risk for cardiovascular‐related health problems (e.g., hypertension, cardiovascular disease, stroke, obesity) and cognitive dysfunction, including Alzheimer’s disease (AD)1,2. However, few studies have looked at the longitudinal influence of cardiovascular health and cognitive function in older African Americans. This study investigated the relationship between cardiovascular health markers and cognition in older African Americans.

Method

836 participants were drawn from Pathways to Healthy Aging in African Americans, a longitudinal cohort study at Rutgers University–Newark. Participants completed a battery of self‐reported health and demographic questionnaires, neuropsychological tests, and a short physical battery of both anthropometric and physical assessments. Linear mixed models were used to examine the relationship between baseline cardiovascular health markers and cognitive function up to 6 years of follow up.

Result

Higher diastolic blood pressure was significantly associated with worse Trail Making Test Part A (B = 0.035, p < .001), and Montreal Cognitive Assessment (B = 0.085, p = .0029) performance across time. Higher systolic blood pressure was significantly associated with poorer Trail Making Test Part A (B = 0.017, p < .001) and MoCA (B = 0.055, p < .001). Higher resting heart rate was significantly associated with worse Trail Making Test Part A (B = 0.018, p = .0031) and Part B (B = 0.085, p = .013), Controlled Oral Word Association Test (B = 0.036, p = .025), and Montreal Cognitive Assessment performance across time (B = 0.047, p = .046).

Conclusion

In cognitively unimpaired older African Americans, cardiovascular health markers are predictive biomarkers for early working memory decline in preclinical AD. Our findings may inform holistic clinical decision‐making in AD prevention and personalized AD monitoring in patients with cardiovascular disease.
Porphyrin–based Vinylene–linked 3D Covalent Organic Framework with Unprecedented cya Topology for Photocatalytic H2O2 Production
Authors: Gong Zihan , Gao Ying , Li Jing , Cai Zichen , Liu Naifang , Jiang Jianzhuang
Published: January 2025

Designing and realizing new topologies represent one of the most important ways toward developing new structures and functionalities for molecule–based frameworks including SOFs, MOFs, and COFs. Herein, Aldol condensation between 5,10,15,20–tetrayl(tetrakis(([1,1':3',1''–terphenyl]–4,4''–dicarbaldehyde)))–porphyrin (TTEP) and 2,4,6–trimethyl–1,3,5–triazine (TMT) affords the vinylene–linked 3D covalent organic framework Por–COF–cya. Powder X–ray diffraction (PXRD) in combination with structural simulation reveals its high crystalline structure with an unprecedented cya topology in the molecule–based frameworks reported thus far. Por–COF–cya displayed polycrystallinity and possessed high permanent porosity. Especially, the incorporation of light–harvesting porphyrin unit and vinylene linkages in Por–COF–cya enables a conjugation effect within the framework, endowing it with a photocatalytic H2O2 production rate of 2209 μmol g−1h−1 in pure aqueous solution under visible–light irradiation (λ > 400 nm). Inclusion of the guest molecules TTF into the pores of Por–COF–cya results in a donor–acceptor system TTF@Por–COF–cya, enhancing the photocatalytic activity with H2O2 production rate of 6994 μmol g−1h−1.  This work paves a new way for the development of new topological functional molecule–based frameworks toward diverse application potentials.
Synthesis and Characterization of Silver Nanoparticles‐Filled and Polyvinyl Alcohol‐Grafted Copolymer Composites for Column Adsorption and Photochemical Degradation of p‐Nitrophenol
Authors: Debnath Pampa , Ray Samit Kumar
Published: January 2025

Polyvinyl alcohol (PVA), sodium polyacrylate, and polyacrylonitrile are very effective for stabilizing and controlling the size of nanoparticles. Thus, PVA was grafted to the copolymer of acrylonitrile (AN) and acrylic acid/sodium acrylate (AA/NaAA) using N,N′‐methylenebisacrylamide comonomer–crosslinker (MBA). Silver nanoparticles (AgNPs) were synthesized in situ in the polymerization mixtures by reduction of AgNO3 with ascorbic acid. These nanocomposites were characterized and used for the removal and photocatalytic degradation of p‐nitrophenol (PNP) from water. Based on the Box–Behnken design of the response surface methodology, the nanocomposite prepared with the AN:NaAA/AA molar ratio/MBA wt.%/PVA wt.% of 5:1/0.5/2 and impregnated with AgNPs of 18–30 nm average size (noted as PVACP5Ag) showed the optimized results. PVACP5Ag showed the equilibrium batch adsorption (qe, mg/g) of 240.93 from 50 mg/L PNP in water and a qe of 36.2 in fixed bed adsorption at a feed inlet concentration (mgL−1)/inflow rate (mLmin−1)/bed height (mm) of 50/30/30. The same composite showed a degradation of 96% after 7 min of exposure to sunlight in the presence of NaBH4 with a first‐order rate constant of 0.3 min−1 and 90.3% degradation after 110 min of exposure with a first‐order rate constant of 0.01 min−1 without any reducing agent.