Insulin-like growth factor-1 and cognition in normoglycemia, prediabetes, and type 2 diabetes mellitus.

BACKGROUND: The relationship between insulin-like growth factor-1 (IGF-1) and cognition has been studied in healthy individuals, but not extensively with regards to insulin resistance and type 2 diabetes mellitus (T2DM). In this retrospective observational study, we investigated relationships of IGF-1 with memory and executive function across people with normoglycemia, prediabetes, and T2DM. METHODS: Data from the Midlife in the United States (MIDUS) study were used. Episodic memory and executive function were assessed using the Brief Test of Adult Cognition by Telephone approximately 21.42 ± 12.10 months prior to measuring IGF-1 levels from a fasting blood sample. Normoglycemia was identified as individuals without a physician diagnosis of diabetes and glycated hemoglobin (HbA1c) ≤5.6%. Prediabetes was identified as those without a physician diagnosis of diabetes and HbA1c between 5.7%-6.4%. T2DM was identified as anyone with a physician diagnosis of diabetes, or HbA1c ≥6.5%, or anyone using an oral hypoglycemic medication. The associations were assessed using linear regressions controlling for age, sex, education, body mass index, C-reactive protein, HbA1c or homeostatic model of insulin resistance, MIDUS wave, exercise, smoking status, sleep quality, alcohol intake, oral hypoglycemic use, and insulin use. RESULTS: The study included 1400 participants, which consisted of 583 normoglycemic (48.4% female, mean age 51.0 ± 12.2 years), 512 prediabetes (58.4% female, mean age 57.3 ± 11.8 years), and 305 T2DM participants (53.8% female, mean age 57.6 ± 11.5 years). Peripheral IGF-1 concentrations were lower (F2,1397 = 28.29, p < 0.001) in people with prediabetes or T2DM, vs. normoglycemia. Participants with prediabetes or T2DM had lower episodic memory (F2,1397 = 9.21, p < 0.001) and executive function (F2,1397 = 20.29, p < 0.001) composite z-scores than people with normoglycemia. Higher IGF-1 concentrations were associated with better executive performance in individuals with prediabetes (ß = 0.115 [0.028, 0.202], p = 0.010), but not in individuals with normoglycemia or T2DM. An interaction between IGF-1 and sex in predicting executive function was observed in the prediabetes group (ß = -0.344, p = 0.042), where the relationship was weaker in females (ß = 0.106 [-0.012, 0.224], p = 0.077) than males (ß = 0.251 [0.123, 0.380], p < 0.001). No associations were seen between IGF-1 and memory. CONCLUSION: The results suggest that peripheral IGF-1 concentrations may be related to executive function, and that the relationship may be sex-specific and dependent on diabetes status.

Perivascular spaces mediate a relationship between diabetes and other cerebral small vessel disease markers in cerebrovascular and neurodegenerative diseases.

Type 2 diabetes mellitus (T2DM) and hypertension are risk factors for cerebral small vessel disease (SVD); however, few studies have characterised their relationships with MRI-visible perivascular spaces (PVS). MRI was used to quantify deep (d) and periventricular (p) white matter hyperintensities (WMH), lacunes, PVS in the white matter (wmPVS) or basal ganglia (bgPVS), and diffusion metrics in white matter. Patients with T2DM had greater wmPVS volume and there were greater wmPVS volumes in patients with T2DM and hypertension together. Counterfactual moderated mediation models found indirect effects of T2DM on volumes of other SVD and diffusion markers that were mediated by wmPVS: pWMH, dWMH, periventricular lacunes, and deep lacunes, and progression of deep lacunes over 1 year, in patients with hypertension, but not in patients without hypertension. Studying the regulation of cortical perivascular fluid dynamics may reveal mechanisms that mediate the impact of T2DM on cerebral small vessels.

Association of sulfonylureas with the risk of dementia: A population-based cohort study.

BACKGROUND: Sulfonylureas are oral glucose-lowering medications positioned as a second-line therapy for type 2 diabetes. Evidence relating them to cognitive decline has been mixed. The objective was to determine whether sulfonylurea use was associated with a differential risk of dementia compared with dipeptidyl peptidase-4 (DPP4) inhibitor use. METHODS: Using administrative data from residents in Ontario, Canada, adults aged ≥66 years who were new users of a sulfonylurea or a DPP4 inhibitor from June 14, 2011, to March 31, 2021 entered this population-based retrospective cohort study. Dementia was ascertained using a validated algorithm for Alzheimer's disease and related dementias. Propensity-score weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and confidence intervals (CI) for time to incident dementia. The observation window started at 1 year after cohort entry to mitigate protopathic bias due to delayed diagnosis. The primary analysis used an intention-to-treat exposure definition. A separate propensity-score weighted analysis was conducted to explore within-class differences in dementia risk among sulfonylurea new users selected from the primary cohort. RESULTS: Among 107,806 DPP4 inhibitor new users and 37,030 sulfonylurea new users, sulfonylureas compared with DPP4 inhibitors were associated with a higher risk of dementia (18.4/1000 person-years; aHR [95% CI] = 1.09 [1.04-1.15]) over a mean follow-up of 4.82 years from cohort entry. Glyburide compared to gliclazide exhibited a higher dementia risk (aHR [95% CI] = 1.17 [1.03-1.32]). CONCLUSION: New use of a sulfonylurea especially glyburide was associated with a higher dementia risk compared with new use of a DPP4 inhibitor in older adults with diabetes.

Sex differences in associations between APOE ε2 and longitudinal cognitive decline.

INTRODUCTION: We examined whether sex modifies the association between APOE ε2 and cognitive decline in two independent samples. METHODS: We used observational data from cognitively unimpaired non-Hispanic White (NHW) and non-Hispanic Black (NHB) adults. Linear mixed models examined interactive associations of APOE genotype (ε2 or ε4 carrier vs. ε3/ε3) and sex on cognitive decline in NHW and NHB participants separately. RESULTS: In both Sample 1 (N = 9766) and Sample 2 (N = 915), sex modified the association between APOE ε2 and cognitive decline in NHW participants. Specifically, relative to APOE ε3/ε3, APOE ε2 protected against cognitive decline in men but not women. Among APOE ε2 carriers, men had slower decline than women. Among APOE ε3/ε3 carriers, cognitive trajectories did not differ between sexes. There were no sex-specific associations of APOE ε2 with cognition in NHB participants (N = 2010). DISCUSSION: In NHW adults, APOE ε2 may protect men but not women against cognitive decline. HIGHLIGHTS: We studied sex-specific apolipoprotein E (APOE) ε2 effects on cognitive decline. In non-Hispanic White (NHW) adults, APOE ε2 selectively protects men against decline. Among men, APOE ε2 was more protective than APOE ε3/ε3. In women, APOE ε2 was no more protective than APOE ε3/ε3. Among APOE ε2 carriers, men had slower decline than women. There were no sex-specific APOE ε2 effects in non-Hispanic Black (NHB) adults.

Association of Sodium-Glucose Cotransporter 2 Inhibitors With Time to Dementia: A Population-Based Cohort Study.

OBJECTIVE: Type 2 diabetes (T2D) increases dementia risk, but clear evidence to recommend interventions that can mitigate that risk remains lacking. This population-based retrospective cohort study aimed to determine whether new use of sodium-glucose cotransporter 2 (SGLT2) inhibitors compared with dipeptidyl peptidase 4 (DPP-4) inhibitors was associated with lower dementia risk. RESEARCH DESIGN AND METHODS: Ontario residents aged ≥66 years who were new users of an SGLT2 inhibitor or a DPP-4 inhibitor from 1 July 2016 to 31 March 2021 entered the cohort. Incident dementia was identified using a validated algorithm for Alzheimer's disease and related dementias. Propensity score-weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and CIs for time to incident dementia. To address reverse causality and disease latency, the observation window started at 1-year lag time from cohort entry. The primary analysis followed intention-to-treat exposure definition, and a secondary as-treated analysis was performed. RESULTS: Among 106,903 individuals, SGLT2 inhibitors compared with DPP-4 inhibitors were associated with lower risk of dementia (14.2/1,000 person-years; aHR 0.80 [95% CI 0.71-0.89]) over a mean follow-up of 2.80 years from cohort entry. When stratified by different SGLT2 inhibitors, dapagliflozin exhibited the lowest risk (aHR 0.67 [95% CI 0.53-0.84]), followed by empagliflozin (aHR 0.78 [95% CI 0.69-0.89]), whereas canagliflozin showed no association (aHR 0.96 [95% CI 0.80-1.16]). The as-treated analysis observed a larger association (aHR 0.66 [95% CI 0.57-0.76]) than the intention-to-treat analysis. CONCLUSIONS: SGLT2 inhibitors showed an association with lower dementia risk in older people with T2D. Randomized controlled trials are warranted.

Endosomal-Lysosomal and Autophagy Pathway in Alzheimer's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: The endosomal-lysosomal and autophagy (ELA) pathway may be implicated in the progression of Alzheimer's disease (AD); however, findings thus far have been inconsistent. OBJECTIVE: To systematically summarize differences in endosomal-lysosomal and autophagy proteins in the cerebrospinal fluid (CSF) of people with AD and healthy controls (HC). METHODS: Studies measuring CSF concentrations of relevant proteins in the ELA pathway in AD and healthy controls were included. Standardized mean differences (SMD) with 95% confidence intervals (CI) between AD and healthy controls in CSF concentrations of relevant proteins were meta-analyzed using random-effects models. RESULTS: Of 2,471 unique studies, 43 studies were included in the systematic review and meta-analysis. Differences in ELA protein levels in the CSF between AD and healthy controls were observed, particularly in lysosomal membrane (LAMP-1: NAD/NHC = 348/381, SMD [95% CI] = 0.599 [0.268, 0.930], I2 = 72.8%; LAMP-2: NAD/NHC = 401/510, SMD [95% CI] = 0.480 [0.134, 0.826], I2 = 78.7%) and intra-lysosomal proteins (GM2A: NAD/NHC = 390/420, SMD [95% CI] = 0.496 [0.039, 0.954], I2 = 87.7%; CTSB: NAD/NHC = 485/443, SMD [95% CI] = 0.201 [0.029, 0.374], I2 = 28.5%; CTSZ: NAD/NHC = 535/820, SMD [95% CI] = -0.160 [-0.305, -0.015], I2 = 24.0%) and in proteins involved in endocytosis (AP2B1:NAD/NHC = 171/205, SMD [95% CI] = 0.513 [0.259, 0.768], I2 = 27.4%; FLOT1: NAD/NHC = 41/45, SMD [95% CI] = -0.489 [-0.919, -0.058], I2 <0.01). LC3B, an autophagy marker, also showed a difference (NAD/NHC = 70/59, SMD [95% CI] = 0.648 [0.180, 1.116], I2 = 38.3%)), but overall there was limited evidence suggesting differences in proteins involved in endosomal function and autophagy. CONCLUSION: Dysregulation of proteins in the ELA pathway may play an important role in AD pathogenesis. Some proteins within this pathway may be potential biomarkers for AD.

Gastric acid suppressants and cognitive decline in people with or without cognitive impairment.

INTRODUCTION: Studies suggest associations between proton pump inhibitors (PPIs) and dementia risk; however, many neither considered histamine-2 receptor antagonists (H2RAs) nor baseline cognitive status. METHODS: Participants (National Alzheimer's Coordinating Center Database; 2005-2021) using a PPI or H2RA were compared. Covariate-adjusted Cox regression was used to estimate hazard ratios (HR) for progression from normal cognition to mild cognitive impairment (MCI), and from MCI to dementia over 5 years. In a propensity-score-matched subsample of mild-moderate Alzheimer's disease (AD), mixed-effects negative binomial regression was used to estimate decline in delayed recall memory. RESULTS: Compared to PPI, H2RA use was associated with earlier progression from MCI to dementia (HR = 1.40 [1.09-1.81]; n = 1701), and with faster memory decline in AD over time (rate ratio = 0.76 [0.64-0.92]; n = 628), but not with progression from normal cognition to MCI (HR = 0.94 [0.71-1.24]; n = 2784). DISCUSSION: Compared to PPIs, H2RAs were associated with cognitive decline, specifically among people with pre-existing cognitive impairment.

Associations Between Time After Stroke and Exercise Training Outcomes: A Meta-Regression Analysis.

Background Knowledge gaps exist regarding the effect of time elapsed after stroke on the effectiveness of exercise training interventions, offering incomplete guidance to clinicians. Methods and Results To determine the associations between time after stroke and 6-minute walk distance, 10-meter walk time, cardiorespiratory fitness and balance (Berg Balance Scale score [BBS]) in exercise training interventions, relevant studies in post-stroke populations were identified by systematic review. Time after stroke as continuous or dichotomized (≤3 months versus >3 months, and ≤6 months versus >6 months) variables and weighted mean differences in postintervention outcomes were examined in meta-regression analyses adjusted for study baseline mean values (pre-post comparisons) or baseline mean values and baseline control-intervention differences (controlled comparisons). Secondary models were adjusted additionally for mean age, sex, and aerobic exercise intensity, dose, and modality. We included 148 studies. Earlier exercise training initiation was associated with larger pre-post differences in mobility; studies initiated ≤3 months versus >3 months after stroke were associated with larger differences (weighted mean differences [95% confidence interval]) in 6-minute walk distance (36.3 meters; 95% CI, 14.2-58.5), comfortable 10-meter walk time (0.13 m/s; 95% CI, 0.06-0.19) and fast 10-meter walk time (0.16 m/s; 95% CI, 0.03-0.3), in fully adjusted models. Initiation ≤3 months versus >3 months was not associated with cardiorespiratory fitness but was associated with a higher but not clinically important Berg Balance Scale score difference (2.9 points; 95% CI, 0.41-5.5). In exercise training versus control studies, initiation ≤3 months was associated with a greater difference in only postintervention 6-minute walk distance (baseline-adjusted 27.3 meters; 95% CI, 6.1-48.5; fully adjusted, 24.9 meters; 95% CI, 0.82-49.1; a similar association was seen for ≤6 months versus >6 months after stroke (fully adjusted, 26.6 meters; 95% CI, 2.6-50.6). Conclusions There may be a clinically meaningful benefit to mobility outcomes when exercise is initiated within 3 months and up to 6 months after stroke.

Leukotriene receptor antagonist use and cognitive decline in normal cognition, mild cognitive impairment, and Alzheimer's dementia.

BACKGROUND: Leukotriene receptor antagonists (LTRAs) alleviate Alzheimer's disease (AD) pathology and improve cognition in animal models; however, clinical evidence is limited. This study aimed to explore the associations between the use of LTRAs (montelukast or zafirlukast) and cognitive performance in people with normal cognition, mild cognitive impairment (MCI), or AD dementia. We hypothesized that LTRA use would be associated with better cognitive performance over time. METHODS: This longitudinal observational study used data from the National Alzheimer's Coordinating Center. Within groups of participants with normal cognition, MCI, or AD dementia, LTRA users were matched 1:3 to non-users using propensity score matching. Cognitive domains including immediate and delayed memory (Wechsler Memory Scale Revised-Logical Memory IA and IIA), psychomotor processing speed (Digit Symbol Substitution Test), and language (animal naming, vegetable naming, and Boston Naming Test) were compared between users and non-users in mixed-effects linear or Poisson regression models. RESULTS: In AD dementia, LTRA use was associated with a slower decline in psychomotor processing speed, as measured by the Digit Symbol Substitution Test (Β = 1.466 [0.253, 2.678] symbols/year, n = 442), and language, as measured by animal naming (Β = 0.541 [0.215, 0.866] animals/year, n = 566), vegetable naming (B = 0.309 [0.056, 0.561] vegetables/year, n = 565), and the Boston Naming Test (B = 0.529 [0.005, 1.053] items/year, n = 561). Effect sizes were small but persisted after controlling for a 10% false discovery rate. LTRA use was not associated with changes in memory performance in AD, nor was it associated with changes in cognitive performance in people with normal cognition or MCI. In a post hoc analysis, LTRA use was associated with a slower decline in clinical progression in MCI (B = -0.200 [-0.380, -0.019] points/year, n = 800) and AD dementia (B = -0.321 [-0.597, -0.046] points/year, n = 604) as measured by CDR Sum of Boxes. CONCLUSIONS: The use of LTRAs was associated with preserved function in non-amnestic cognitive domains in AD dementia. The role of leukotrienes and their receptors in cognitive decline warrants further investigation and the leukotriene pathway may represent a target for AD treatment.