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Findings from Kronos Early Estrogen Prevention Study (KEEPS)-Cog trial suggested no cognitive benefit or harm after 48 months of menopausal hormone therapy (mHT) initiated within 3 years of final menstrual period. To clarify the long-term effects of mHT initiated in early postmenopause, the observational KEEPS Continuation Study reevaluated cognition, mood, and neuroimaging effects in participants enrolled in the KEEPS-Cog and its parent study the KEEPS approximately 10 years after trial completion. We hypothesized that women randomized to transdermal estradiol (tE2) during early postmenopause would show cognitive benefits, while oral conjugated equine estrogens (oCEE) would show no effect, compared to placebo over the 10 years following randomization in the KEEPS trial. The KEEPS-Cog (2005-2008) was an ancillary study to the KEEPS (NCT00154180), in which participants were randomized into 3 groups: oCEE (Premarin, 0.45 mg/d), tE2 (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d for 12 d/mo) or placebo pills and patch for 48 months. KEEPS Continuation (2017-2022), an observational, longitudinal cohort study of KEEPS clinical trial, involved recontacting KEEPS participants approximately 10 years after the completion of the 4-year clinical trial to attend in-person research visits. Seven of the original 9 sites participated in the KEEPS Continuation, resulting in 622 women of original 727 being invited to return for a visit, with 299 enrolling across the 7 sites. KEEPS Continuation participants repeated the original KEEPS-Cog test battery which was analyzed using 4 cognitive factor scores and a global cognitive score. Cognitive data from both KEEPS and KEEPS Continuation were available for 275 participants. Latent growth models (LGMs) assessed whether baseline cognition and cognitive changes during KEEPS predicted cognitive performance at follow-up, and whether mHT randomization modified these relationships, adjusting for covariates. Similar health characteristics were observed at KEEPS randomization for KEEPS Continuation participants and nonparticipants (i.e., women not returning for the KEEPS Continuation). The LGM revealed significant associations between intercepts and slopes for cognitive performance across almost all domains, indicating that cognitive factor scores changed over time. Tests assessing the effects of mHT allocation on cognitive slopes during the KEEPS and across all years of follow-up including the KEEPS Continuation visit were all statistically nonsignificant. The KEEPS Continuation study found no long-term cognitive effects of mHT, with baseline cognition and changes during KEEPS being the strongest predictors of later performance. Cross-sectional comparisons confirmed that participants assigned to mHT in KEEPS (oCEE and tE2 groups) performed similarly on cognitive measures to those randomized to placebo, approximately 10 years after completion of the randomized treatments. These findings suggest that mHT poses no long-term cognitive harm; conversely, it provides no cognitive benefit or protective effects against cognitive decline. In these KEEPS Continuation analyses, there were no long-term cognitive effects of short-term exposure to mHT started in early menopause versus placebo. These data provide reassurance about the long-term neurocognitive safety of mHT for symptom management in healthy, recently postmenopausal women, while also suggesting that mHT does not improve or preserve cognitive function in this population.

Background Early-onset dementia (EOD, onset age < 65) and late-onset dementia (LOD, onset age ≥ 65) exhibit distinct features. Understanding the risk factors for dementia development and mortality in EOD and LOD respectively is crucial for personalized care. While risk factors are known for LOD development and mortality, their impact on EOD remains unclear. We aimed to investigate how hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, and osteoporosis influence the development and mortality of EOD and LOD, respectively. Methods Using the Korean National Health Insurance Service (NHIS) database, we collected 546,709 dementia-free individuals and followed up for 11 years. In the two study groups, the Younger group (< 65 years old) and the Older group (≥ 65 years old), we applied Cox proportional hazard models to assess risk factors for development of EOD and LOD, respectively. Then, we assessed risk factors for mortality among EOD and LOD. Results Diabetes mellitus and osteoporosis increased the risk of EOD and LOD development. Hypertension increased the risk of EOD, while atrial fibrillation increased the risk of LOD. Conversely, hyperlipidemia exhibited a protective effect against LOD development. Additionally, diabetes mellitus increased mortality in EOD and LOD. Hypertension and atrial fibrillation increased mortality in LOD, while hyperlipidemia decreased mortality in EOD and LOD. Conclusions Risk factors influencing dementia development and mortality differed in EOD and LOD. Targeted public health interventions addressing age-related risk factors may reduce dementia incidence and mortality.

Primary care offers an important pathway for timely diagnosis and treatment of mild cognitive impairment and dementia. Transformative changes require a structured approach to implementation of early diagnosis workflows. Planning, designing, implementing, and sustaining are important aspects of these improvements. A practical approach for health system leaders is provided.

Background Patients and providers experience barriers to early detection of mild cognitive impairment (MCI) and dementia. We developed a new primary care-based role, the Brain Health Navigator (BHN), who is trained to assess patients for cognitive impairment, identify addressable causes, suggest appropriate diagnostic testing, connect patients to resources, and assist patients in accessing disease-modifying treatments and dementia care management. This study describes the BHN role, the feasibility of implementing the BHN in Primary Care (PC) clinics, and the initial patients’ outcomes for those who saw the BHN. Methods Patients ≥65 years were screened with a Digital Cognitive Assessment (DCA) in seven PC clinics from June 1, 2022, to May 31, 2023. Patients who scored likely cognitively impaired or borderline for impairment were eligible for referral to the BHN. Clinics and providers could determine if referrals were automatic or on a patient-by-patient basis. The BHN encounter included a comprehensive assessment of standardized tools and suggested laboratory and imaging studies to facilitate the diagnostic process and connect patients to resources, care and treatment, and research opportunities. Results 466 of 861 patients with likely impaired or borderline impaired DCA results were referred to the BHN.More patients with likely impaired scores (62.7%) were referred to the BHN compared to those with borderline scores (47.6%). Of the 466 referred patients, 28.9% with likely impaired scores and 23.5% with borderline scores completed a BHN visit. Patients who were seen by the BHN had a significantly higher likelihood of receiving a new diagnosis of MCI than patients who did not see the BHN and were more likely to have orders for diagnostic tests, such as vitamin B12 thyroid function and Magnetic Resonance Imaging of the head and neck. Referrals to both neurology and neuropsychology were significantly more common among patients who completed the BHN visit. Conclusions A BHN enhances follow-up care and monitoring for patients with abnormal cognitive screening tests. A BHN visit increases the rate of evidence-based diagnostic evaluation for MCI and dementia in PC. Trial Registration This study was designated as exempt by the Indiana University Institutional Review Board (#15281).

INTRODUCTION Blood biomarker (BBM) tests could improve early detection of Alzheimer's disease (AD), but their acceptability and feasibility in primary care (PC) are unclear. METHODS A BBM for AD pathology was offered to patients who screened positive for cognitive impairment in PC. Feasibility and acceptability were measured through rates of patient and provider consent and outcomes were assessed at 1 and 12 months post‐disclosure. RESULTS Two hundred thirty‐six patients were approached, 26 (22%) consented to BBM; 24 completed disclosures. BBM results showed 58% low, 7.7% intermediate, and 34.6% high likelihood of amyloid pathology. There were no changes in anxiety, depression, or distress at 1 month post disclosure. At 12 months, 5 (19.2%) were diagnosed with mild cognitive impairment, 3 (11.5%) with AD. Among 31 eligible PC providers, 53% consented to disclosure training and 26% completed disclosure. DISCUSSION BBM testing in PC is feasible but had limited uptake. Strategies to improve engagement are needed for implementation. Highlights This pilot study evaluated the use of a blood test for diagnosing Alzheimer's disease in primary care. Engagement with testing was limited in this real‐world setting. Testing was feasible and psychologically safe for patients. Future work should focus on strategies to improve patient and provider engagement

Background Subjective cognitive decline (SCD), defined as cognitive complaints in the absence of objective cognitive impairments, may reflect the earliest manifestation of preclinical Alzheimer's disease (AD). However, individuals with SCD are a heterogenous group with unclear cognitive and clinical trajectories. Building on our prior work examining short‐term practice effects (STPE) in Mild Cognitive Impairment (MCI) and AD, we examined if STPE were diminished in SCD and if they predicted cognitive trajectories. Method 76 participants classified as cognitively unimpaired according to the Jak/Bondi criteria were divided by whether they presented with cognitive complaints (i.e., SCD, n = 11) or not (i.e., CN, n = 65). They completed a brief cognitive battery twice across one week (Time 1 to Time 2) to quantify STPE and again after approximately 1.3 years (Time 1 to Time 3) to assess long term cognitive change. Result Across one week, those with SCD showed smaller STPE on 7 of the 8 neuropsychological test scores and a composite measure compared to those without cognitive complaints (see Figure 1 for the composite; negative Z‐scores reflect smaller STPE). STPE on visual scanning, set shifting, and processing speed showed the largest effect sizes in separating SCD from CN. In the entire sample, the composite measure of STPE was significantly related to change over 1.3 years (r = .31, p = .01), with smaller STPE predicting less improvement at long term follow‐up. When considering the two groups, composite STPE and change over 1.3 years showed similar relationships (CN r = .23 and SCD r = .21). However, when examining processing speed measures specifically, the association between STPE and long‐term changes were stronger in the SCD group (r = .91) than the CN group (r = .38). Conclusion Similar to our work over the past decade in MCI and AD, STPE were reduced in SCD relative to CN, and they predicted cognitive trajectories. As such, these preliminary findings require validation in a larger trial to see if STPE could be used to enrich clinical trials enrolling those with SCD.

Subjective cognitive decline (SCD), defined as cognitive complaints in the absence of objective cognitive impairments, may reflect the earliest manifestation of preclinical Alzheimer's disease (AD). However, individuals with SCD are a heterogenous group with unclear cognitive and clinical trajectories. Building on our prior work examining short-term practice effects (STPE) in Mild Cognitive Impairment (MCI) and AD, we examined if STPE were diminished in SCD and if they predicted cognitive trajectories. 76 participants classified as cognitively unimpaired according to the Jak/Bondi criteria were divided by whether they presented with cognitive complaints (i.e., SCD, n = 11) or not (i.e., CN, n = 65). They completed a brief cognitive battery twice across one week (Time 1 to Time 2) to quantify STPE and again after approximately 1.3 years (Time 1 to Time 3) to assess long term cognitive change. Across one week, those with SCD showed smaller STPE on 7 of the 8 neuropsychological test scores and a composite measure compared to those without cognitive complaints (see Figure 1 for the composite; negative Z-scores reflect smaller STPE). STPE on visual scanning, set shifting, and processing speed showed the largest effect sizes in separating SCD from CN. In the entire sample, the composite measure of STPE was significantly related to change over 1.3 years (r = .31, p = .01), with smaller STPE predicting less improvement at long term follow-up. When considering the two groups, composite STPE and change over 1.3 years showed similar relationships (CN r = .23 and SCD r = .21). However, when examining processing speed measures specifically, the association between STPE and long-term changes were stronger in the SCD group (r = .91) than the CN group (r = .38). Similar to our work over the past decade in MCI and AD, STPE were reduced in SCD relative to CN, and they predicted cognitive trajectories. As such, these preliminary findings require validation in a larger trial to see if STPE could be used to enrich clinical trials enrolling those with SCD.

Subjective cognitive decline (SCD), defined as cognitive complaints in the absence of objective cognitive impairments, may reflect the earliest manifestation of preclinical Alzheimer's disease (AD). However, individuals with SCD are a heterogenous group with various etiologies. Building on our prior work examining short-term practice effects (STPE) in Mild Cognitive Impairment (MCI) and AD, we examined if STPE in SCD were associated with biomarker positivity. 75 participants classified as cognitively unimpaired according to the Jak/Bondi criteria were divided by whether they presented with cognitive complaints (i.e., SCD, n = 11) or not (i.e., CN, n = 64). They completed a brief cognitive battery twice across one week to quantify STPE. They also completed a blood draw for APOE genotyping, an MRI for hippocampal volumes, and a PET for amyloid deposition. For APOE, there was no relationship between STPE and ε4 status in those without cognitive complaints (r = .06), but the greater number of ε4 alleles was associated with smaller STPE in those with SCD (r = -.42). For MRI, larger hippocampal volumes were associated with larger STPE (r = .25). For amyloid PET, 19% of those without cognitive complaints were amyloid positive, whereas 73% of those with SCD were amyloid positive, which is statistically significantly different (p < 0.001, see Figure). Similar to our prior work in MCI and AD, STPE were associated with three biomarkers of AD in the expected direction (i.e., smaller STPE associated with worse biomarker outcomes), especially in those with SCD. Although these findings need to be replicated in a rigorous, prospective study with a larger and more diverse sample, STPE seems to indicate biomarker positivity in SCD participants, which could be used as a safer and more cost-effective variable for enriching clinical trials in AD.

Background Subjective cognitive decline (SCD), defined as cognitive complaints in the absence of objective cognitive impairments, may reflect the earliest manifestation of preclinical Alzheimer's disease (AD). However, individuals with SCD are a heterogenous group with various etiologies. Building on our prior work examining short‐term practice effects (STPE) in Mild Cognitive Impairment (MCI) and AD, we examined if STPE in SCD were associated with biomarker positivity. Method 75 participants classified as cognitively unimpaired according to the Jak/Bondi criteria were divided by whether they presented with cognitive complaints (i.e., SCD, n = 11) or not (i.e., CN, n = 64). They completed a brief cognitive battery twice across one week to quantify STPE. They also completed a blood draw for APOE genotyping, an MRI for hippocampal volumes, and a PET for amyloid deposition. Result For APOE, there was no relationship between STPE and ε4 status in those without cognitive complaints (r = .06), but the greater number of ε4 alleles was associated with smaller STPE in those with SCD (r = ‐.42). For MRI, larger hippocampal volumes were associated with larger STPE (r = .25). For amyloid PET, 19% of those without cognitive complaints were amyloid positive, whereas 73% of those with SCD were amyloid positive, which is statistically significantly different (p < 0.001, see Figure). Conclusion Similar to our prior work in MCI and AD, STPE were associated with three biomarkers of AD in the expected direction (i.e., smaller STPE associated with worse biomarker outcomes), especially in those with SCD. Although these findings need to be replicated in a rigorous, prospective study with a larger and more diverse sample, STPE seems to indicate biomarker positivity in SCD participants, which could be used as a safer and more cost‐effective variable for enriching clinical trials in AD.

Background Practice effects on cognitive testing in Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD) remain understudied, especially with how they compare to biomarkers of AD. The current study sought to add to this growing literature. Method Cognitively intact older adults (n = 68), those with amnestic MCI (n = 52), and those with mild AD (n = 45) repeated a brief battery of cognitive tests twice across one week, and they also completed a baseline amyloid PET scan, a baseline MRI, and a baseline blood draw to obtain APOE e4 status. Result The intact participants showed significantly larger practice effects than the other two groups on an overall composite measure, and those with MCI showed significantly larger practice effects than those with AD. For amyloid deposition, the intact participants had significantly less tracer uptake, whereas MCI and AD participants were comparable. For total hippocampal volumes, all three groups were significantly different in the expected direction (intact>MCI>AD). For APOE e4, the intact had significantly fewer copies of e4 than MCI and AD. Overall, the effect sizes of practice effects were significantly larger than effect sizes of biomarkers in 7 of the 9 comparisons (see Table). Conclusion Short‐term practice effects on cognitive tests appear to be a sensitive marker in late life cognitive disorders, as they separated groups better than commonly‐used biomarkers in AD. Further refinement of short‐term practice effects as a tool for clinical diagnosis, prognostic indication, and enrichment of clinical trials seems warranted.