Journal of Alzheimer's Disease - Volume 96, issue 1

Authors: Qeadan, Fares | McCunn, Ashlie | Tingey, Benjamin | Price Jr , Ron | Bobay, Kathleen L | English, Kevin | Madden, Erin F.

Article Type: Research Article

Abstract: Background: Past research suggests associations between heavy alcohol use and later life dementia. However, little is known about whether opioid use disorder (OUD) and dementia share this association, especially among age groups younger than 65 years old. Objective: Examine the association between OUD and Alzheimer’s disease (AD) and dementia. Methods: Electronic health records between 2000 and 2021 for patients age 12 or older were identified in the Cerner Real-World database™. Patients with a prior diagnosis of dementia were excluded. Patients were followed for 1-10 years (grouped by one, three, five, and ten-year follow-up periods) in a …matched retrospective cohort study. Cox proportional hazards regressions were used to estimate adjusted hazard ratios (aHRs) of incident AD/dementia stratified by age and follow-up group. Results: A sample of 627,810 individuals with OUD were compared to 646,340 without OUD. Individuals with OUD exhibited 88% higher risk for developing AD/dementia compared to those without OUD (aHR = 1.88, 95% CI 1.74, 2.03) within 1 year follow-up and 211% (aHR = 3.11, 95% CI 2.63, 3.69) within 10 years follow-up. When stratifying by age, younger patients (age 12-44) had a greater disparity in odds of AD/dementia between OUD and non-OUD groups compared with patients older than 65 years. Conclusions: Additional research is needed to understand why an association exists between OUD and AD/dementia, especially among younger populations. The results suggest that cognitive functioning screening programs for younger people diagnosed with OUD may be useful for targeting early identification and intervention for AD/dementia in particularly high risk and marginalized populations. Show more

Keywords: Alzheimer’s disease, cerner real-world data, cox proportional hazards, dementia, opioid use disorder

DOI: 10.3233/JAD-230714

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 229-244, 2023

Authors: Boulares, Ayoub | Fabre, Claudine | Cherni, Ala | Jdidi, Hela | Gaied Chortane, Sabri | Trompetto, Carlo | Puce, Luca | Bragazzi, Nicola Luigi

Article Type: Research Article

Abstract: Background: Aging often leads to cognitive function decline, sensory structure deterioration, and musculoskeletal system weakening. This impacts postural control during static and dynamic activities like walking, increasing the fall risk among the elderly. Older adults with mild cognitive impairment (MCI) face an elevated fall risk and cognitive decline, magnifying the public health concern. Objective: This study aimed to explore solutions by investigating the effects of a multi-component physical activity program on cognitive and motor functions in MCI patients. Methods: Twenty-three participants were enrolled in the study and assigned into two groups: an intervention group (n  = 13; …age = 85.7±5.5 years) and a control group (n  = 9; age = 85±6.7 years). The study spanned two months, with participants engaging in three 60-minute weekly physical exercise sessions. The intervention focused on improving proprioception, muscle strength, and balance. Results: Results demonstrated significant enhancements in physical performance, fall risk reduction, and balance (p  < 0.05). Various tests, including the timed up and go test, Unipedal Stance test, Tinetti test, Short Physical Performance Battery, and 6-minute walking test, indicated these improvements. Cognitive function was evaluated with the Mini-Mental State Examination, revealing non-significant progress (p  > 0.05). Predictive models for outcomes were developed using linear regression analysis during the follow-up stage. Conclusions: This study underscores the effectiveness of a multi-component physical activity program encompassing balance, proprioception, and muscle-strengthening exercises as a non-pharmaceutical approach in improving balance skills and playing a key role in mitigating the risk of falls among old adults with MCI. Show more

Keywords: Alzheimer’s disease, balance, cognitive functions, fall risk, mild cognitive impairment, motor functions, multi-component physical exercise, older adults, proprioception

DOI: 10.3233/JAD-230305

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 245-260, 2023

Authors: Lanza, Giuseppe

Article Type: Article Commentary

Abstract: In the relevant study by Boulares and colleagues, the importance of a multicomponent physical activity program in improving balance skills and leading to falling risk and fear reduction in older adults with mild cognitive impairment (MCI) is highlighted, despite the lack of cognitive effects. Given this apparent discrepancy between “body” and “mind” in MCI rehabilitation, the present commentary faces and discusses these findings within the existing literature and poses the question whether there were actually no cognitive results or if the program design and evaluation tool used were not sensitive enough to detect them, at least at this stage.

Keywords: Alzheimer’s disease, cognitive functions, mild cognitive impairment, motor functions, multicomponent physical exercise

DOI: 10.3233/JAD-230951

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 261-264, 2023

Authors: Utz, Janine | Olm, Pauline | Jablonowski, Johannes | Siegmann, Eva-Maria | Spitzer, Philipp | Lewczuk, Piotr | Kornhuber, Johannes | Maler, Juan Manuel | Oberstein, Timo Jan

Article Type: Research Article

Abstract: Background: The established Erlangen Score (ES) for the interpretation of cerebrospinal fluid (CSF) biomarkers in the diagnostics of Alzheimer’s disease (AD) uses markers of amyloidopathy and tauopathy, equally weighted to form an easy-interpretable ordinal scale. However, these biomarkers are not equally predictive for AD. Objective: The higher weighting of the Aβ42 /Aβ40 ratio, as a reconceptualized ERlangen Score (ERS), was tested for advantages in diagnostic performance. Methods: Non-demented subjects (N  = 154) with a mean follow up of 5 years were assigned to a group ranging from 0 to 4 in ES or ERS. Psychometric trajectories …and dementia risk were assessed. Results: The distribution of subjects between ES and ERS among the groups differed considerably, as grouping allocated 32 subjects to ES group 2, but only 2 to ERS group 2. The discriminative accuracy between the ES (AUC 73.2%, 95% CI [64.2, 82.2]) and ERS (AUC 72.0%, 95% CI [63.1, 81.0]) for dementia risk showed no significant difference. Without consideration of the Aβ42 /Aβ40 ratio in ES grouping, the optimal cut-off of the ES shifted to ≥2. Conclusions: The ERS showed advantages over the ES in test interpretation with comparable overall test performance, as fewer cases were allocated to the intermediate risk group. The established cut-off of ≥2 can be maintained for the ERS, whereas it must be adjusted for the ES when determining the Aβ42 /Aβ40 ratio. Show more

Keywords: Alzheimer’s disease, dementia risk, Erlangen Score, longitudinal study, neuropsychological trajectories

DOI: 10.3233/JAD-230524

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 265-275, 2023

Authors: Ding, Huitong | Mandapati, Amiya | Hamel, Alexander P. | Karjadi, Cody | Ang, Ting F.A. | Xia, Weiming | Au, Rhoda | Lin, Honghuang

Article Type: Research Article

Abstract: Background: Early prediction of dementia risk is crucial for effective interventions. Given the known etiologic heterogeneity, machine learning methods leveraging multimodal data, such as clinical manifestations, neuroimaging biomarkers, and well-documented risk factors, could predict dementia more accurately than single modal data. Objective: This study aims to develop machine learning models that capitalize on neuropsychological (NP) tests, magnetic resonance imaging (MRI) measures, and clinical risk factors for 10-year dementia prediction. Methods: This study included participants from the Framingham Heart Study, and various data modalities such as NP tests, MRI measures, and demographic variables were collected. CatBoost was …used with Optuna hyperparameter optimization to create prediction models for 10-year dementia risk using different combinations of data modalities. The contribution of each modality and feature for the prediction task was also quantified using Shapley values. Results: This study included 1,031 participants with normal cognitive status at baseline (age 75±5 years, 55.3% women), of whom 205 were diagnosed with dementia during the 10-year follow-up. The model built on three modalities demonstrated the best dementia prediction performance (AUC 0.90±0.01) compared to single modality models (AUC range: 0.82–0.84). MRI measures contributed most to dementia prediction (mean absolute Shapley value: 3.19), suggesting the necessity of multimodal inputs. Conclusion: This study shows that a multimodal machine learning framework had a superior performance for 10-year dementia risk prediction. The model can be used to increase vigilance for cognitive deterioration and select high-risk individuals for early intervention and risk management. Show more

Keywords: Alzheimer’s disease, dementia risk prediction, machine learning, magnetic resonance imaging, multimodal data, neuropsychological test

DOI: 10.3233/JAD-230496

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 277-286, 2023

Authors: Sun, Yifei | Moghekar, Abhay | Soldan, Anja | Pettigrew, Corinne | Greenberg, Barry | Albert, Marilyn | Wang, Mei-Cheng

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) are altered many years before the onset of clinical symptoms of mild cognitive impairment (MCI). Incorporating clinical symptom onset time into biomarker modeling may enhance our understanding of changes preceding MCI. Objective: Using a new analytical approach, we examined patterns of biomarker change prior to MCI symptom onset among individuals who progressed from normal cognition to MCI, stratified based on the age of symptom onset. We also analyzed biomarker patterns of change among participants who remained cognitively normal, and examined potential modifiers of biomarker trajectories, including demographics and apolipoprotein …E (APOE ) status. Methods: Analyses included 93 participants who progressed from normal cognition to MCI and 186 participants who remained cognitively normal, over an average follow-up period of 16.2 years. CSF biomarkers, including Aβ42 , Aβ40 , total tau (t-tau), and phosphorylated tau181 (p-tau181 ), were measured using the fully automated Lumipulse assays. Results: Among participants who progressed to MCI, Aβ42 /Aβ40 decreased, and t-tau and p-tau181 increased. For participants who did not progress to MCI, CSF biomarkers showed relatively stable patterns. In both progressors and non-progressors, APOE4 carriers showed lower Aβ 42 /Aβ40 levels (compared to non-carriers) at each point of the mean curves. Among non-progressors, APOE4 carriers had higher levels of p-tau181 , p-tau181 /(Aβ 42 /Aβ40 ), and t-tau/(Aβ 42 /Aβ 40 ). Additionally, among those who did not progress, female sex was associated with higher levels of t-tau, p-tau181 , t-tau/(Aβ 42 /Aβ 40 ), and p-tau181 /(Aβ 42 /Aβ 40 ). Conclusions: These findings suggest that this analytic approach may provide additional insights into biomarker changes during early phases of AD. Show more

Keywords: Alzheimer’s disease, amyloid, APOE genotype, biomarkers, cerebrospinal fluid, preclinical AD, tau

DOI: 10.3233/JAD-230807

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 287-300, 2023

Authors: Kero, Katherine | Halter, Colt M. | Moll, Allison C. | Hanna, Sophie M. | Woodard, John L. | Giordani, Bruno | Daugherty, Ana M. | Kavcic, Voyko

Article Type: Research Article

Abstract: Background: Cognitive assessment of older adults typically includes symptom reports and objective evaluations. However, there is often poor agreement between these measures. Cultural norms, stress, and anxiety may also influence cognitive self-appraisal and performance. Little research describes how other factors affect the self-report/objective test discrepancies noted in the literature. Objective: This study investigated whether the disparity between subjective cognitive concerns and objective cognitive performance is related to measures of anxiety and stress in older Black and African American adults. Methods: Telephone screenings were administered to 206 older adults (ages 64–94) during the first year of the …pandemic. Demographic data, objective memory (Telephone Interview for Cognitive Status [TICS-m]), an adaptation of the subjective memory measure, the Cognitive Change Questionnaire, emphasizing executive functioning in everyday life [CCQ-e]), Generalized Anxiety Disorder-7 (GAD-7), and Perceived Stress Scale-4 (PSS4) were measured. Metacognition Discrepancy Index (MDI) was calculated from the standardized residual after regressing TICS-m on CCQ-e scores to quantify the discrepancy between cognitive self-appraisal and objective cognitive functioning. Results: Neither GAD-7 nor PSS-4 moderated the relationship between TICS-m and CCQ-e, and TICS-m scores weakly predicted subjective CCQ-e scores (F (1, 197)=4.37, p  = 0.038, R2  = 0.022). The MDI correlated with stress and anxiety (rs  = 0.294, 0.396, ps  < 0.001). Conclusion: Discrepancies exist between objectively measured and self-evaluated cognition. Elevations in stress and anxiety are associated with greater overestimation of cognitive difficulties relative to objective performance. Pandemic-related stressors may have worsened anxiety and diminished self-appraisal of cognitive abilities for some individuals, while others may remain reluctant to acknowledge impairments. Social and emotional factors are meaningful considerations in assessing cognitive difficulties. Show more

Keywords: affect, Alzheimer’s disease, anxiety, cognitive decline, metacognition, psychological stress

DOI: 10.3233/JAD-221140

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 301-311, 2023

Authors: Chow, Tiffany E. | Veziris, Christina R. | Mundada, Nidhi | Martinez-Arroyo, Alexis I. | Kramer, Joel H. | Miller, Bruce L. | Rosen, Howard J. | Gorno-Tempini, Maria Luisa | Rankin, Katherine P. | Seeley, William W. | Rabinovici, Gil D. | La Joie, Renaud | Sturm, Virginia E.

Article Type: Research Article

Abstract: Background: In Alzheimer’s disease (AD), the gradual accumulation of amyloid-β (Aβ) and tau proteins may underlie alterations in empathy. Objective: To assess whether tau aggregation in the medial temporal lobes related to differences in cognitive empathy (the ability to take others’ perspectives) and emotional empathy (the ability to experience others’ feelings) in AD. Methods: Older adults (n  = 105) completed molecular Aβ positron emission tomography (PET) scans. Sixty-eight of the participants (35 women) were Aβ positive and symptomatic with diagnoses of mild cognitive impairment, dementia of the Alzheimer’s type, logopenic variant primary progressive aphasia, …or posterior cortical atrophy. The remaining 37 (22 women) were asymptomatic Aβ negative healthy older controls. Using the Interpersonal Reactivity Index, we compared current levels of informant-rated cognitive empathy (Perspective-Taking subscale) and emotional empathy (Empathic Concern subscale) in the Aβ positive and negative participants. The Aβ positive participants also underwent molecular tau-PET scans, which were used to investigate whether regional tau burden in the bilateral medial temporal lobes related to empathy. Results: Aβ positive participants had lower perspective-taking and higher empathic concern than Aβ negative healthy controls. Medial temporal tau aggregation in the Aβ positive participants had divergent associations with cognitive and emotional empathy. Whereas greater tau burden in the amygdala predicted lower perspective-taking, greater tau burden in the entorhinal cortex predicted greater empathic concern. Tau burden in the parahippocampal cortex did not predict either form of empathy. Conclusions: Across AD clinical syndromes, medial temporal lobe tau aggregation is associated with lower perspective-taking yet higher empathic concern. Show more

Keywords: Alzheimer’s disease, affective resonance, empathy, mentalization, social cognition, tau proteins

DOI: 10.3233/JAD-230367

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 313-328, 2023

Authors: Bramen, Jennifer E. | Siddarth, Prabha | Popa, Emily S. | Kress, Gavin T. | Rapozo, Molly K. | Hodes, John F. | Ganapathi, Aarthi S. | Slyapich, Colby B. | Glatt, Ryan M. | Pierce, Kyron | Porter, Verna R. | Wong, Claudia | Kim, Mihae | Dye, Richelin V. | Panos, Stella | Bookheimer, Tess | Togashi, Tori | Loong, Spencer | Raji, Cyrus A. | Bookheimer, Susan Y. | Roach, Jared C. | Merrill, David A.

Article Type: Research Article

Abstract: Background: A carbohydrate-restricted diet aimed at lowering insulin levels has the potential to slow Alzheimer’s disease (AD). Restricting carbohydrate consumption reduces insulin resistance, which could improve glucose uptake and neural health. A hallmark feature of AD is widespread cortical thinning; however, no study has demonstrated that lower net carbohydrate (nCHO) intake is linked to attenuated cortical atrophy in patients with AD and confirmed amyloidosis. Objective: We tested the hypothesis that individuals with AD and confirmed amyloid burden eating a carbohydrate-restricted diet have thicker cortex than those eating a moderate-to-high carbohydrate diet. Methods: A …total of 31 patients (mean age 71.4±7.0 years) with AD and confirmed amyloid burden were divided into two groups based on a 130 g/day nCHO cutoff. Cortical thickness was estimated from T1-weighted MRI using FreeSurfer. Cortical surface analyses were corrected for multiple comparisons using cluster-wise probability. We assessed group differences using a two-tailed two-independent sample t -test. Linear regression analyses using nCHO as a continuous variable, accounting for confounders, were also conducted. Results: The lower nCHO group had significantly thicker cortex within somatomotor and visual networks. Linear regression analysis revealed that lower nCHO intake levels had a significant association with cortical thickness within the frontoparietal, cingulo-opercular, and visual networks. Conclusions: Restricting carbohydrates may be associated with reduced atrophy in patients with AD. Lowering nCHO to under 130 g/day would allow patients to follow the well-validated MIND diet while benefiting from lower insulin levels. Show more

Keywords: Alzheimer’s disease, amyloid, atrophy, carbohydrates, carbohydrate-restricted, cerebral cortical thinning, cognitive dysfunction, diet, magnetic resonance imaging

DOI: 10.3233/JAD-230458

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 329-342, 2023

Authors: Sung, Wonjae | Kwon, Hyuk Sung | Park, Yeonjae | Kim, Seung Hyun | Park, Sojeong | Kang, Dae Ryong | Choi, Hojin

Article Type: Research Article

Abstract: Background: Hyperuricemia in patients with gout is associated with a low risk of neurodegenerative diseases, including dementia. However, the prevalence of dementia in patients with gout has not yet been reported. Objective: To analyze the prevalence of dementia among patients diagnosed with gout by utilizing the Health Insurance and Review Assessment database, a nationwide registry of the South Korean population. Methods: Data from the Health Insurance and Review Assessment database of patients diagnosed with gout between 2011 and 2018 were extracted. The annual prevalence of dementia according to age and sex was analyzed. We investigated whether …there was an association between comorbidities and gout medication in patients with both gout and dementia and in patients with only gout. Results: Between 2011 and 2018, the age-adjusted prevalence of dementia per 100,000 persons ranged from 54.0 (95% confidence interval: 47.7–60.2) to 69.9 (95% confidence interval: 65.3–74.5). Compared to previous studies, the prevalence of dementia was lower in patients with gout than in the general population. Patients with both gout and dementia were more likely to be women, have a wide range of comorbidities, and be prescribed gout-related drugs, including allopurinol, febuxostat, nonsteroidal anti-inflammatory drugs, and steroids than patients with gout without dementia. Conclusions: This study demonstrated a relatively low prevalence of dementia in patients with gout. Gout, characterized by hyperuricemia, might be associated with a reduced risk of dementia. Show more

Keywords: Alzheimer’s disease, big data, dementia, gout, prevalence, uric acid

DOI: 10.3233/JAD-230468

Citation: Journal of Alzheimer's Disease, vol. 96, no. 1, pp. 343-349, 2023