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Background: Interventions to prevent cognitive decline and dementia in high‐risk populations such as those with remitted Major Depressive Disorder (rMDD) or Mild Cognitive Impairment (MCI) are urgently needed. Method: PACt‐MD was a double‐blind randomized trial conducted between 2015 and 2022 comparing cognitive remediation (CR) plus transcranial Direct Current Stimulation (tDCS) vs. sham‐CR+sham‐tDCS delivered 5 days/week for 8 weeks followed by 5‐day semi‐annual boosters and at‐home daily CR, in participants with rMDD or MCI. Participants were assessed at baseline, week‐8, and yearly. The hypotheses were that compared to sham+sham, CR+tDCS would: slow cognitive decline (H1); reduce progression to MCI or dementia (H2); and acutely improve cognition (H3). The primary outcome composite score was calculated when at least half of the tests for at least four of six cognitive domains were completed. Due to COVID‐19, some participants did not complete enough tests and a second composite score using all available data was generated. Result: 375 participants were randomized (Active: N = 188, Mean Age = 72.1 ± 6.3; Sham: N = 187, Mean Age = 72.3 ± 6.4) and received at least one intervention session. Over up to six years, there was no time‐by‐treatment interaction using the primary composite score but there was using the all‐data score. Change in composite score differed between the two intervention groups for the primary and all‐data scores for all years except for year‐6 primary score. The year‐5 adjusted z‐score difference was ‐0.15 (95%CI [‐0.29, ‐0.005]) for the primary and ‐0.21 (95%CI [‐0.34, ‐0.067]) for all‐data score (Fig.1). Comparing active vs. sham at 8‐week (H3), the adjusted z‐score difference was ‐0.06 (95%CI: [‐0.12, 0.005]; p = 0.072); and for progression (H2), HR was 0.66 (95%CI [0.40, 1.08] p = 0.101) in a stratified Cox model. In a preplanned secondary analysis of domain scores, there was a time‐by‐treatment interaction for verbal memory with a year‐5 adjusted z‐score difference of ‐0.30 (95%CI [‐0.53, ‐0.074]) (Fig.2) but not the other domains. In another preplanned secondary analysis, the model with a randomization diagnosis‐by‐time‐by‐treatment was different from the model without this three‐way interaction (p = 0.012; Fig.3). Conclusion: CR+tDCS may be effective in slowing cognitive decline (particularly verbal memory) in older patients with rMDD or MCI. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Methylphenidate has been shown to improve apathy in patients with Alzheimer's disease (AD). The authors evaluated the impact of methylphenidate on neuropsychiatric symptoms (NPS) of AD, excluding apathy, using data from the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) study. METHODS: A secondary analysis was conducted on data from the ADMET 2 study to determine the effect of methylphenidate on Neuropsychiatric Inventory (NPI) scores outside of apathy. Caregiver scores were compared from baseline to month 6 in 199 participants receiving methylphenidate (20 mg/day) or placebo regarding the presence or absence of individual neuropsychiatric symptoms, emergence of new symptoms, and individual domain scores. RESULTS: No clinically meaningful improvement was observed in any NPI domain, excluding apathy, in participants treated with methylphenidate compared to placebo after 6 months. A statistical difference between groups was appreciated in the domains of elation/euphoria (P = 0.044) and appetite/eating disorders (P = 0.014); however, these findings were not considered significant. DISCUSSION: Methylphenidate is a selective agent for symptoms of apathy in patients with AD with no meaningful impact on other NPS. Findings from this secondary analysis are considered exploratory and multiple limitations should be considered when interpreting these results, including small sample size and use of a single questionnaire. HIGHLIGHTS: Methylphenidate was not associated with significant improvement on the Neuropsychiatric Inventory in domains outside of apathy.Methylphenidate did not show a statistically significant emergence of new neuropsychiatric symptoms (NPS) throughout the 6‐month treatment period compared to placebo.Methylphenidate appears to be a highly selective agent for apathy in Alzheimer's disease, potentially supporting catecholaminergic dysfunction as the driving force behind this presentation of symptoms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS‐Cog) is used to assess decline in memory, language, and praxis in Alzheimer's disease (AD). Methods: A latent state–trait model with autoregressive effects was used to determine how much of the ADAS‐Cog item measurement was reliable, and of that, how much of the information was occasion specific (state) versus consistent (trait or accumulated from one visit to the next). Results: Participants with mild AD (n = 341) were assessed four times over 24 months. Praxis items were generally unreliable as were some memory items. Language items were generally the most reliable, and this increased over time. Only two ADAS‐Cog items showed reliability >0.70 at all four assessments, word recall (memory) and naming (language). Of the reliable information, language items exhibited greater consistency (63.4% to 88.2%) than occasion specificity, and of the consistent information, language items tended to reflect effects of AD progression that accumulated from one visit to the next (35.5% to 45.3%). In contrast, reliable information from praxis items tended to come from trait information. The reliable information in the memory items reflected more consistent than occasion‐specific information, but they varied between items in the relative amounts of trait versus accumulated effects. Conclusions: Although the ADAS‐Cog was designed to track cognitive decline, most items were unreliable, and each item captured different amounts of information related to occasion‐specific, trait, and accumulated effects of AD over time. These latent properties complicate the interpretation of trends seen in ordinary statistical analyses of trials and other clinical studies with repeated ADAS‐Cog item measures. Highlights: Studies have described unfavorable psychometric properties of the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS‐Cog), bringing into question its ability to track changes in cognition uniformly over time. There remains a need to estimate how much of the ADAS‐Cog measurement is reliable, of that how much is occasion specific versus consistent, and of the consistent information, how much represents enduring traits versus autoregressive effects (i.e., effects of Alzheimer's disease [AD] progression carried over from one assessment to the next).A latent state–trait model with autoregressive effects in mild AD found most items to be unreliable, and each item to capture different amounts of occasion‐specific, trait, and autoregressive information. Language items, specifically, naming and the memory item word recall, were the most reliable.Psychometric idiosyncrasies of individual items complicate the interpretation of their summed score, biasing ordinary statistical analyses of repeated measures in mild AD. Future studies should consider item trajectories individually. [ABSTRACT FROM AUTHOR]