BackgroundThe course of Alzheimer’s disease (AD) includes a 10–20-year preclinical period with progressive accumulation of amyloid β (Aβ) plaques and neurofibrillary tangles in the absence of symptomatic cognitive or functional decline. The duration of this preclinical stage in part depends on the rate of pathologic progression, which is offset by compensatory mechanisms, referred to as cognitive reserve (CR). Comorbid medical conditions, psychosocial stressors, and inappropriate medication use may lower CR, hastening the onset of symptomatic AD. Here, we describe a randomized controlled trial (RCT) designed to test the efficacy of a medication therapy management (MTM) intervention to reduce inappropriate medication use, bolster cognitive reserve, and ultimately delay symptomatic AD.Methods/designOur study aims to enroll 90 non-demented community-dwelling adults ≥ 65 years of age. Participants will undergo positron emission tomography (PET) scans, measuring Aβ levels using standardized uptake value ratios (SUVr). Participants will be randomly assigned to MTM intervention or control, stratified by Aβ levels, and followed for 12 months via in-person and telephone visits. Outcomes of interest include: (1) medication appropriateness (measured with the Medication Appropriateness Index (MAI)); (2) scores from Trail Making Test B (TMTB), Montreal Cognitive Assessment (MoCA), and California Verbal Learning Test (CVLT); (3) perceived health status (measured with the SF-36). We will also evaluate pre- to post-intervention change in: (1) use of inappropriate medications as measured by MAI; 2) CR Change Score (CRCS), defined as the difference in scopolamine-challenged vs unchallenged cognitive scores at baseline and follow-up. Baseline Aβ SUVr will be used to examine the relative impact of preclinical AD (pAD) pathology on CRCS, as well as the interplay of amyloid burden with inappropriate medication use.DiscussionThis manuscript describes the protocol of INCREASE (“INtervention for Cognitive Reserve Enhancement in delaying the onset of Alzheimer’s Symptomatic Expression”): a randomized controlled trial that investigates the impact of deprescribing inappropriate medications and optimizing medication regimens on potentially delaying the onset of symptomatic AD and AD-related dementias.Trial registrationClinicalTrials.gov, NCT02849639. Registered on 29 July 2016.

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Objective: Older adults often spontaneously engage in compensatory strategies (CS) to support completion of everyday tasks. However, factors that influence the success of chosen strategies remain unclear. The present study aimed to examine if evaluation of the overall quality of compensatory strategies, as compared to a count of strategies, better predicts completion of real-world prospective memory (PM) tasks. Method: Seventy community-dwelling older adults (M = 70.80, SD = 7.87) completed two testing sessions remotely from their own homes through video conferencing. Participants were presented four novel real-world PM tasks designed to be carried out independently in the future. Upon task presentation, participants were given time to plan and encouraged to use their typical CS. The examiner captured detailed information about CS planned at task presentation and strategies utilized at follow-up testing, as well as PM task accuracy. In addition to a count of CS, participants’ CS were assigned a quality score upon video review. Results: Hierarchical regression revealed that Compensatory Strategy Quality (CSQ) score provides incremental validity in predicting PM task accuracy over and above CS count, global cognition, and age (ΔR2 = 0.24, ΔF = 29.36, p < 0.001). CSQ uniquely accounted for 24.01% of the variance in PM task accuracy (sr = 0.49, p < 0.001). Conclusions: Evaluating quality of cognitive CS provides enhanced precision in predicting PM. Findings of this study may provide researchers with tools to study compensation in a more nuanced manner. Furthermore, findings have the potential to be translated into clinical interventions, such as targeted compensatory strategy trainings.

Background Falls, a leading cause of disability and mortality in older adults,1 are associated cognitive impairment and inappropriate medication use.2 We propose a novel construct, “mobility reserve” (MR), which describes an individual’s resilience against mobility decline. We hypothesize that augmenting MR may delay fall‐associated morbidity. Here, we investigate the association between MR and inappropriate medication use among participants with and without preclinical Alzheimer’s disease (pAD) enrolled in a randomized medication therapy management trial.3 Methods Non‐demented older adults who used ≥1 potentially inappropriate medication4 were recruited for the RCT. The Medication Appropriateness Index was calculated for all medications (MAI) and for potentially inappropriate medications (MAI‐PIM). Participants’ gait speed (cm/s) was measured under normal conditions and while challenged with 1.5mg of scopolamine to unmask vulnerability. The difference in gait speeds was calculated as mobility reserve change score (MRCS). PET amyloid total brain relative standardized uptake values > 1.4 was used to define pAD.5Spearman correlation coefficients (rs) assessed the relationship between medication appropriateness and MRCS. Results 36 participants were included in this analysis (mean age 75.0 years [SD 6.0]; 78% female); 10 (27.8%) were classified as pAD. The mean (SD) MAI and MAI‐PIM were 10.3 (5.1) and 5.4 (4.0) respectively, not differing by pAD status (p=0.92 and 0.11 for MAI and MAI‐PIM). The mean (SD) MRCS was ‐0.39 cm/s (9.4) (no difference by pAD status; p=0.84). Among those with pAD, MAI and MAI‐PIM were negatively correlated with MRCS (r = ‐0.53 and ‐0.46 respectively), which was not the case among those without pAD (r = 0.37 and 0.34), though a larger sample size is needed to add confidence to these estimates. Conclusion Among community‐dwelling non‐demented older adults, more inappropriate medication use was associated with lower mobility reserve among those with pAD. These results support the hypothesized relationship between MR and medication appropriateness. Future studies should further operationalize measures of MR to open a novel intervention pathway for reducing fall‐related morbidity in cognitively at‐risk populations. References: 1. Katz R, Shah P. JAMA. 2010;303(3):273‐274. 2. Enderlin C et al. Geriatr Nurs. 2015;36(5):397‐406. 3. Moga DC et al. Trials. 2019;20(1):806. 4. American Geriatrics Society. J Am Geriatr Soc. 2015;63(11):2227‐2246. 5.Jack CR et al. Brain. 2015;138(12):3747‐3759.

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