Journals
2025 EN
Andreozzi Erica · Hersch Steven · Gee Michelle
+2 more
Abstract Background Lecanemab is a novel, humanized immunoglobulin G (IgG) 1 monoclonal antibody, which has demonstrated the ability to substantially reduce markers of amyloid and slow clinical decline in early Alzheimer’s disease (AD). Subcutaneous administration using an autoinjector improves convenience and eliminates burden on patients, providers and healthcare systems necessitated by intravenous infusion, thereby broadening access. Herein, we share results from the human factors (HF) program implemented to support the lecanemab autoinjector clinical program. Methods The HF validation study evaluated whether the lecanemab autoinjector could be used safely and effectively – with and without training – under expected use environments. It characterized the type, frequency, and severity of potential use errors (including incomplete dosing) as well as labelling comprehension. The study participants (n=110; patients with self‐ or caregiver‐reported diagnosis of mild cognitive impairment or mild AD [n=63], caregivers [n=32], and healthcare providers [HCPs; n=15]) represented lecanemab autoinjector end users and included a mix of injection‐experienced and injection‐naïve. The patients were administered the Mini Mental State Examination (MMSE) and subsequently divided into low MMSE (22‐26) and high MMSE (27‐30) groups. Patients and caregivers were evaluated under trained and untrained conditions, while HCPs were always untrained. Results Overall, 94.5% (n=104/110) of participants were successful at delivering the first of 2 injections: untrained, low MMSE patients (93.3%, n=14/15); trained, low MMSE patients (100%, n=15/15); untrained, high MMSE patients (100%, n=16/16); trained, high MMSE patients (94.1%, n=16/17); untrained caregivers (100%, n=15/15); trained caregivers (100%, n=17/17); HCPs (100%, n=15/15). Furthermore, 82.7% (n=91/110) of participants were successful at delivering 2 consecutive injections: untrained, low MMSE patients (53.3%, n=8/15); trained, low MMSE patients (93.3%, n=14/15); untrained, high MMSE patients (93.8%, n=15/16); trained, high MMSE patients (88.2%, n=15/17); untrained caregivers (73.3%, n=11/15); trained caregivers (94.1%, n=16/17); HCPs (80%, n=12/15). Training increased injection success in caregivers and low MMSE patients. Critical information in the labelling was understood by 91.8% (n=101/110) of overall participants. No device malfunctions or harmful events occurred. Conclusions The HF validation study confirms that the lecanemab autoinjector is safe and effective for the intended users, uses, and use environments.
Journals
2025 EN
Xu Hanzhang · Grory Brian C. Mac · Ikeaba Uchechukwu
+9 more
Abstract Background About one in three COVID‐19 patients experience neurological problems; and acute ischemic stroke (AIS) is one of the common comorbidities of COVID‐19. As stroke doubles the risk of dementia, AIS patients with COVID‐19 infection may experience even higher risk of developing poststroke dementia. Still, little is known about the incidence of poststroke dementia in AIS patient with COVID‐19 infection. Method Using data from the Get With The Guidelines–Stroke linked Medicare claims, we conducted a retrospective cohort study to estimate the incidence of poststroke dementia in AIS patients (1) with COVID‐19 with or without bacterial infection, (2) with bacterial infection only, and (3) with no infection. AIS Patients aged 66+ without pre‐stroke dementia from January 1, 2020, to June 30, 2021 were included and followed up for 12 months post discharge. Primary outcome—incident poststroke dementia—was obtained based on the International Classification of Diseases, Tenth Revision, from Medicare claims. Secondary outcomes include incident vascular dementia, poststroke mild cognitive impairment, and composite of poststroke mild cognitive impairment and dementia. Poisson regression was used to model the incidence of poststroke dementia accounting for age and stroke severity. Result Of 103,378 patients (median [interquartile range] age, 79 [73‐86], 56,769 [54.9%] female; 84.074 [81.3.9%] white), 1,438 (1.4%) had COVID‐19 infection during stroke onset, and 6,084 (5.9%) had bacterial infection only. A total of 12,925 incident dementia cases developed during 1,310,658 person‐days after stroke onset. Poststroke dementia incidence rate was 0.011 in patients with COVID‐19 infection, 0.011 in patients with bacterial infection only, and 0.010 in patients with no infection. Compared to patients with no infection, the rates of poststroke dementia were significantly higher in patients with only bacterial infection (adjusted rate ratio[aRR]: 1.13 [95% CI, 1.06‐1.22]). Similar trends were observed in patients with COVID‐19 infection, although not statistically significant (aRR: 1.14 [95% CI, 0.96‐1.36]). Similar results were seen in the incidence of vascular dementia and composite cognitive outcome. Conclusion We observed a higher incidence of poststroke dementia in AIS patients with bacterial infection only and those with COVID‐19 infection. COVID‐19 infection may be associated with higher risk of dementia post stroke.
Journals
2025 EN
Perweiler Elyse · Overbeck Kevin · Libon David J.
+5 more
Abstract Background Virtua Health, the largest health system in southern New Jersey, serves >140,000 Medicare patients, including 70,000 primary care patients aged ≥65 years, across 38 primary care practices. Fewer than 25% of these patients are screened annually for cognitive impairment, with only 2.5% having a confirmed diagnosis of Alzheimer's or related dementias, far below the national average of 10.9%. To address this gap, Virtua Health, through the Davos Alzheimer's Collaborative Healthcare System Preparedness (DAC‐SP) U.S. Early Detection Fellowship program, is implementing an early detection program for cognitive impairment in primary care, building on the foundational elements of its participation in the DHHS‐HRSA funded Geriatric Workforce Enhancement Program (GWEP), the CMS GUIDE model, and creating a geriatric service line. Method The DAC‐SP Early Detection Blueprint will accelerate early detection of cognitive impairment in primary care by developing workflows and standing order sets in 5 pilot practices with plans for future expansion. Rapid Cycle Quality Improvement will address barriers, incorporate stakeholder feedback, and guide structure and process adjustments for early detection of cognitive impairment. Digitized iPad‐based cognitive screening will be integrated into Annual Wellness Visits. Positive cognitive screens will trigger clinical pathways and standing orders to assist providers in diagnosing and managing cognitive impairment. Scheduling accommodations will support providers in the early detection and diagnostic process. Result Virtua Health hopes to increase screening of eligible patients for cognitive impairment by 30‐50% across 5 pilot practices and exceed the 10.9% national average dementia diagnosis rate. Project participation will create new care pathways and improve patient access to team‐based comprehensive dementia evaluation, advanced diagnostic modalities, care navigators, brain health programs, and disease‐modifying therapies. Conclusion The DAC‐SP U.S. Early Detection Fellowship is a catalyst for system‐wide change, creating a sustainable model to enhance dementia care, reduce disease burden, and improve quality of life for older individuals, their families, and caregivers. Standardized care pathways, AI tools, clinician training, and stakeholder collaboration enable Virtua Health and its primary care providers to play a pivotal role in early detection of dementia, leading to improved access to disease‐modifying therapies, promotion of brain health, and better management of cognitive impairment.
Journals
2025 EN
Cooper Gregory · Patton Steven · Lockridge Deborah
+1 more
Abstract Background The Norton Healthcare (NHC) not‐for‐profit system includes five adult hospitals and one children's hospital in Louisville, KY and three hospitals in southern Indiana. We are the largest healthcare system in the region with around than 22,000 employees and over 2,100 employed medical providers. Norton provides care at more than 400 locations including primary, pediatric, and specialty care practices. Though we have a strong memory disorder clinic and one of the busiest anti‐amyloid programs in the country, our clinic sees a relatively small fraction of the total number of NHC patients who are likely to have mild cognitive impairment (MCI) or dementia. Participating in the US BHN Program will enable us to develop better protocols for detecting patients at risk and those with mild memory impairment as early as possible and to efficiently and effectively navigate them from primary to specialty care for evaluation and, ultimately, treatment. Method The proposed pilot site of care is the Norton Community Medical Associates—Preston primary care practice, one of 40 primary care clinics in our system. NCMAPreston is located on the borders of Metro City Council Districts 13 and 24. District 13 has a higher proportion of people living in poverty and low‐income households than the city as a whole. It is critically important to test the DAC‐SP BHN Model in a diverse setting with lower social determinants of health. NHC community medical directors offer direct community outreach and also participate in neighborhood educational health programs that address health and racial inequalities in underserved communities. Result We anticipate that group development of the brain health navigator role and processes will yield a more thoroughly considered protocol that is adaptable to the diverse practices across our system. Better navigation will also enable improved coordination of care and utilization of our NNI Resource Center to connect families with needed resources. Conclusion The Brain Health Navigator Model and other resources of DAC‐SP support the implementation of boundary spanning roles across primary and specialty care, designed for a sustainable and scalable timely and accurate diagnostic journey across Norton Healthcare and similar health systems.
Journals
2025 EN
Parks Anna L · Lykken Jacquelyn M · RieuWerden Meghan L
+7 more
Abstract Background Anti‐amyloid monoclonal antibody treatments may interact with anticoagulants and thrombolytics to increase the risk of intracranial hemorrhage (ICH). Expert guidance advises against co‐prescribing antithrombotic drugs due to increased ICH risk. However, because new cardiovascular diagnoses are common in older adults, some people may develop an indication for anticoagulant or thrombolytic therapy during an anti‐amyloid treatment course. Our goal was to estimate how many people with mild cognitive impairment (MCI) or dementia develop a new condition for which antithrombotic therapy is indicated. Method We conducted a longitudinal cohort study using the nationally representative Health and Retirement Study (HRS) data (2010‐2020). We included adults aged ≥65 years who consented to Medicare claims linkage and had no indication for anticoagulants in the 12 months prior to a baseline interview. Participants’ cognition was categorized as normal, MCI (defined in HRS as mild or moderate cognitive impairment without dementia), or dementia. We fit Fine‐Gray survival models accounting for competing risk of death to estimate the 1‐year incidence of atrial fibrillation (AF), deep vein thrombosis (DVT) or pulmonary embolism (PE), acute myocardial infarction (MI), stroke, and new anticoagulant prescriptions. Separate models were fit for each outcome, and models used a robust sandwich estimator to account for repeated observations. Result The study included 22,373 participants (Table; median age 71 years, 59% female). Among participants with MCI, the 1‐year incidence was 1.7% for AF, 1.2% for DVT, 0.4% for PE, 1.2% for AMI, 2.0% for stroke, and 2.2% for new anticoagulant prescription (Figure). Overall, the 1‐year likelihood of developing a new indication for anticoagulants or thrombolytics for any reason was 6.9%. Among participants with dementia, 1‐year rates were 1.7% for AF, 1.8% for DVT, 0.3% for PE, 1.0% for AMI, 2.4% for stroke, 1.9% for new anticoagulant prescription, and 7.6% for any indication. Conclusion In this national sample of people with MCI or dementia, over 1 year, 7‐8% of people were newly diagnosed with a cardiovascular disease requiring antithrombotic therapy. The risk of developing a condition for which anticoagulants or thrombolytics are indicated should be incorporated into discussions about anti‐amyloid treatment to enhance shared decision‐making.
Journals
2025 EN
WilliePermor Daniel · Lopez Oscar L · Reis Steven E.
+8 more
Abstract Background Some individuals escape the development of Alzheimer's disease (AD) amyloid and tau pathology suggesting resistance, and not all individuals with these pathologies develop cognitive impairment (CI), suggesting resilience. Social, physical, and cognitive activities may impact resistance and resilience, and this study explores their roles. Method This is a secondary analysis of existing data from the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study. Multiple activities were collected via the CHAMPS Activities Questionnaire. We grouped them into five domains: social, cognitive, physical, leisure, and household/gardening Total weekly hours were calculated for each domain. We also created combined cognitive‐social activities and combined physical activities. Tau burden was measured using [18F]Flortaucipir (FTP) PET imaging, and amyloid using [11C] Pittsburgh Compound‐B (PiB) PET imaging (Table 1). Cognition was categorized clinically as either unimpaired cognition (CU) or impaired cognition (MCI/dementia). Resilience and resistance profiles were defined as follows: tau‐resilient: tau‐positive, CI‐negative; tau‐resistant: tau‐negative, CI‐negative and amyloid resistant). We used logistic regression to identify activity predictors of tau and amyloid resistance and resilience. Result The study included 152 participants, with demographic characteristics stratified by tau and amyloid status at baseline (Table 2). Throughout the period of follow‐up, greater cognitive activity was significantly associated with tau resilience, while leisure activity was inversely associated with tau resilience (Table 3) Among demographic and health factors, throughout the follow‐up, being White and having a history of cardiovascular disease significantly predicted tau resilience. Hypercholesterolemia was significantly and inversely associated with tau resistance. Increased leisure activity hours were significantly associated with amyloid resistance, while social activity showed an inverse association. Among demographic and health predictors, none were significant, though diabetes was associated with reduced amyloid resistance while education was positively associated (Table 3). Amyloid resilience could not be included due to model non‐convergence secondary to low power. Conclusion Cognitive activities and leisure activities may contribute to tau resilience and amyloid resistance respectively. Promoting a multifaceted approach to activity engagement and cardiovascular risk‐factor control may be key in mitigating the impact of tau and amyloid pathology on cognitive health.
Journals
2025 EN
Sahoo Saswat · Antoine Darlene · Mustapic Maja
+11 more
Abstract Background Dysregulated insulin signaling in the IRS‐1/Akt/mTOR pathway underlies insulin resistance in prediabetes (PreD) and type 2 diabetes (T2D) and may contribute to the pathogenesis of Alzheimer’s disease and related dementias (AD/ADRD). However, the relationship between neuronal and systemic insulin signaling abnormalities and their association with AD/ADRD biomarkers in PreD/T2D remains unclear. Plasma‐derived extracellular vesicles (EVs) carry signaling and pathogenic proteins, providing a platform to examine molecular relationships between PreD/T2D and AD/ADRD pathophysiology. Method In 456 participants with PreD/T2D from the Diabetes Prevention Program Outcomes Study, we isolated neuronal and total circulating EVs (NEVs and TEVs) from fasting plasma collected at Year 22 follow‐up visits using size‐exclusion chromatography followed by immunocapture (NEVs: anti‐L1CAM/NLGN3/GAP43; TEVs: anti‐CD9/CD63/CD81). NEV‐associated p ‐tau217, t‐tau, Aβ 42 , and Aβ 40 were quantified by SIMOA. Phosphorylated and total levels of IR, IGF1R, IRS‐1, PTEN, Akt, mTOR, p70S6K, GSK3α/β, TSC2, and RPS6 were measured in NEVs and TEVs (reflecting neuronal and systemic insulin signaling, respectively) using Luminex immunoassays. Cross‐sectional biomarker associations were examined using Pearson's correlations with Bonferroni adjustment for multiple testing. Result pS636‐IRS‐1, a marker associated with impaired insulin signaling, was moderately correlated between NEVs and TEVs (r=0.49; Figure 1). NEV‐associated AD/ADRD biomarkers were intercorrelated (Figure 2), with strong associations observed between p ‐tau217 and Aβ 42 (r=0.78), p ‐tau217 and Aβ 42 /Aβ 40 (r=0.62), and t‐tau and Aβ 40 (r=0.72). Accordingly, p ‐tau217, Aβ 42 , and Aβ 42 /Aβ 40 showed moderate‐to‐strong correlations with NEV‐associated phosphoproteins linked to insulin resistance in histopathologic studies (Figure 3A). Among NEV‐associated AD/ADRD biomarkers, p ‐tau217 demonstrated the strongest correlations with key NEV‐associated insulin signaling phosphoproteins (pS636‐IRS1: r=0.78; pS473‐Akt: r=0.77; p ‐p70S6K: r=0.62; Figures 3E‐G). In contrast, correlations between p ‐tau217 and the same phosphoproteins in TEVs were weaker (pS636‐IRS1: r=0.31; pS473‐Akt: r=0.29; p ‐p70S6K: r=0.15). Correlations for t‐tau and Aβ 40 with insulin signaling mediators were weak overall. Conclusion In individuals with PreD/T2D, NEV‐associated AD/ADRD biomarkers were more strongly associated with dysregulated insulin signaling mediators in NEVs than those in TEVs. Strong correlations were observed for NEV‐associated pS636‐IRS‐1 and pS473‐Akt with p ‐tau217 and Aβ 42 , suggesting a link between dysregulated neuronal insulin signaling and AD/ADRD pathophysiology. Future studies will determine how these relationships relate to metabolic and cognitive measures.
Journals
2025 EN
Ankeny Sarrah E. · Ong Mei Ling · Beach Steven R. H.
+3 more
Abstract Background Inflammatory processes are associated with aging, neurodegeneration, and cognitive decline and are proposed to have a potential role in the preclinical stage of dementia. However, studies examining the relationship between systemic inflammation and Alzheimer’s disease and related dementias (ADRD) blood‐based biomarkers (BBMs) are mixed. Few studies have examined associations between inflammation and ADRD BBMs in mid‐life, when changes in inflammation related to preclinical dementia pathology would most likely occur. This study examined the cross‐sectional associations between midlife peripheral measures of inflammation and ADRD BBMs in an underserved cohort. Method This study included 305 middle‐aged (mean [SD] age, 47.5 [8.6] years) African American participants from the Family and Community Health Study (FACHS). Cross‐sectional associations between serum‐levels of Tumor Necrosis Alpha (TNFα), Interleukin (IL)‐1β, IL‐6, Macrophage Inflammatory Protein (MIP)‐1β, and an epigenetic measure of C‐Reactive Protein (CRP) with serum‐levels of phosphorylated tau 181 (pTau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were analyzed using linear regression. Prior to analyses, peripheral inflammatory markers and ADRD BBMs were log (log(x+1)) transformed to correct for right‐skewed distributions. Models were adjusted for age, gender, and education. Result Serum levels of peripheral inflammation were significantly associated with serum levels of GFAP. A one‐unit increase in TNFα ( β = ‐0.026, p = 0.008), IL1β ( β = ‐0.031, p = 0.009), IL6 ( β = ‐0.026, p = 0.027), MIP1β ( β = ‐0.041, p = 0.027), and CRP methylation ( β = ‐0.076, p = 0.027) were associated with lower GFAP. Serum levels of peripheral inflammation were not significantly associated with serum levels of pTau181 or NfL. Conclusion We found negative association between peripheral markers of inflammation and GFAP in this mid‐life underserved cohort. Future analyses will investigate associations between peripheral markers of inflammation and 10‐year change in ADRD BBMs in this cohort.
Journals
2025 EN
Singh Ramkrishna Kumar · Bekena Semere · Zhu Yiqi
+4 more
Abstract Background Plasma neurofilament light chain (NfL), a biomarker of neuroaxonal damage, is associated with cognitive decline and neurodegeneration. High‐density lipoprotein (HDL) cholesterol, known for its anti‐inflammatory and antioxidative properties, has been linked to cognitive performance in aging populations. However, the relationship between HDL and neurodegeneration remains unclear. This study examines how HDL influences the relationship between plasma NfL and cognitive performance across mid to late adulthood, using data from individuals aged 36 years and older. Method This cross‐sectional study analyzed baseline data from 418 participants of the Aging Adult Brain Connectome (AABC) study (mean age=66.5 years, 55.4% female). Plasma NfL was measured using the Simoa platform, and HDL cholesterol via enzymatic colorimetric assays. Cognitive performance was assessed with the Montreal Cognitive Assessment (MoCA) and Preclinical Alzheimer’s Cognitive Composite (PACC). Generalized linear models assessed the interaction between NfL and HDL on cognitive outcomes, adjusting for age, sex, race, and education. Sensitivity analyses included APOE ε4 genotype, body mass index, total cholesterol, LDL, and triglycerides. Result The interaction between NfL and HDL was statistically significant across both cognitive outcomes (Table 1). Higher HDL levels consistently moderate the negative association between NfL and cognitive performance. For individuals with elevated HDL (≥60 mg/dL), increasing NfL concentrations were associated with lower scores on MoCA (β = ‐0.00019, p =0.006) and PACC (β = ‐0.00004, p =0.004). These associations were visualized in interaction plots (Figure A & B), which illustrate stronger inverse relationships between NfL and cognitive scores at higher HDL levels. The interaction effects remained robust after adjusting for additional covariates, including APOE ε4 genotype, BMI, total cholesterol, LDL, and triglycerides. Conclusion HDL cholesterol moderates the association between plasma NfL and cognitive performance in older adults. Elevated HDL levels enhance the negative impact of NfL on cognition, challenging the assumption that HDL is uniformly protective in aging. As a modifiable factor, HDL offers a clinically actionable target in efforts to delay cognitive decline. These findings align with the United States Department of Health and Human Services (HHS) priorities on biomarker‐based strategies and underscore the value of integrating metabolic and neurodegenerative biomarkers for improved cognitive risk profiling and targeted interventions.
Journals
2025 EN
Puleio Alexa · Hoti Ina · Barr William B.
+18 more
Abstract Background Exposure to repetitive head impacts (RHI) is associated with developing chronic traumatic encephalopathy (CTE) neuropathology. Cognitive and behavioral symptoms have been associated with CTE neuropathology, but efforts to define the specific clinical syndrome are ongoing. This study characterizes the current use of centrally acting medications (CAMs), chronic pain, and number of orthopedic surgeries in former American football players and evaluates for associations with cognitive and behavioral symptoms. Methods This study analyzed data from the DIAGNOSE CTE Research Project, which includes 120 former professional football players, 60 collegiate football players, and 56 asymptomatic men without history of RHI. Medical history was obtained by self‐report, and participants completed the Montreal Cognitive Assessment (MoCA), Brief Pain Inventory, Barratt Impulsiveness Scale‐11 (BIS‐11), BRIEF‐A Behavioral Regulation Index (BRI), Beck Depression Inventory‐II (BDI‐II), Beck Anxiety Index (BAI), and Brown‐Goodwin Lifetime History of Aggression adulthood score (BGLHA). Logistic regression assessed the association of CAMs, average pain score, and orthopedic surgeries on the cognitive impairment and neurobehavioral dysregulation components of the NINDS traumatic encephalopathy syndrome (TES) research criteria, in former American football players. Linear regression assessed the associations with MoCA and behavioral scales. Models were adjusted for age, education, race, and years of football played. Results Tables 1 and 2 describe the sample and CAM burden. More orthopedic surgeries, CAMs, and higher average pain were observed in former American football players. Number of CAMs was associated with neurobehavioral dysregulation (OR = 2.18), lower MoCA (β = ‐0.47), and higher BIS‐11 (β = 2.23), BDI‐II (β = 2.01), BRI (β = 3.71), BAI (β = 2.04), and BGLHA (β = 0.68) scores. Higher average pain was associated with neurobehavioral dysregulation (OR = 1.57) and higher BIS‐11 (β = 2.20), BDI‐II (β = 1.98), BRI (β = 2.20), BAI (β = 1.84), and BGLHA (β = 0.52) scores. No associations were observed with orthopedic surgeries. Conclusions In former American football players, the number of CAMs and higher average pain were associated with neurobehavioral dysregulation. No associations were observed with diagnosis of cognitive impairment by TES criteria, though the number of CAMs was associated with decreased MoCA.