Current pharmacological therapy for Alzheimer's disease (AD) includes the cholinesterase inhibitors (ChEIs) donepezil, rivastigmine, and galantamine and the N-methyl D-aspartate receptor antagonist memantine. Based on the results of randomized controlled trials and several meta-analyses, ChEIs appear to show modest but statistically significant improvements on several measures, including cognition and global functioning. Given their modest effects, there is a lack of consensus among clinicians regarding issues related to initiation, optimal duration, and discontinuation of ChEI therapy across the spectrum of AD. There is evidence from long-term observational controlled studies that early initiation and persistent exposure to AD therapy lead to delays in nursing home admission and significantly slower rates of cognitive and functional impairment. In the moderate to severe stages of AD, therapeutic trials of higher dose ChEIs and the addition of memantine are recommended for patients who are no longer responding to lower doses. While side effects are generally mild and gastrointestinal in nature, these events can lead to significant morbidity in more susceptible patients with advanced disease. Patients should thus be regularly monitored for any potential serious side effects of ChEI therapy, which also may include syncope and bradycardia. At the terminal stages of AD, such as when patients become hospice eligible, attempts to cautiously discontinue all medications not necessary for quality of life, including AD drugs, should be made.

Alzheimer's disease (AD) is a prevalent and currently incurable brain disease whose impact will continue to rise as the population ages. With limited treatment options, a variety of experimental therapies are currently in clinical trials. EVP-6124 (encenicline) is an α7 nicotinic acetylcholine receptor partial agonist under investigation for the symptomatic treatment of AD. EVP-6124 activates the α7 nicotinic acetylcholine receptor at low nanomolar brain concentrations and improves memory performance in rats. Treatment with EVP-6124 in Phase I and II trials involving patients with mild-to-moderate AD was well tolerated and showed statistically significant improvements compared with placebo on cognitive and functional measures. Two Phase III trials under the title COGNITIV AD will assess the efficacy and tolerability of EVP-6124 in patients with mild-to-moderate AD. Based on the completed clinical trials and proposed mechanism of action, EVP-6124 would appear to be a good candidate for therapy in combination with cholinesterase inhibitors.

Currently available therapies for the treatment of Alzheimer’s disease (AD) consist of cholinesterase inhibitors (ChEIs), such as donepezil, and the N-methyl-D-aspartate receptor antagonist memantine. In December 2014, the US Food and Drug Administration approved Namzaric™, a once-daily, fixed-dose combination (FDC) of memantine extended-release (ER) and donepezil for patients with moderate-to-severe AD. The FDC capsule is bioequivalent to the coadministered individual drugs, and its bioavailability is similar when taken fasting, with food, or sprinkled onto applesauce. The combination of memantine and ChEIs in moderate-to-severe AD provides additional benefits to ChEI monotherapy across multiple domains and may delay the time to nursing home admission. A dedicated study of memantine ER compared to placebo in patients on a stable dose of a ChEI found statistically significant benefits on cognition and global status but not functioning. Treatment with memantine ER and donepezil is generally well tolerated, although higher doses of ChEIs are associated with more serious adverse events such as vomiting, syncope, and weight loss. Potential advantages of the FDC include a simpler treatment regimen, reduction in pill burden, and the ability to sprinkle the capsule onto soft foods. Patients who may benefit from the FDC include those with significant dysphagia, a history of poor compliance, or limited caregiver interaction. However, available evidence that these advantages would increase treatment adherence and persistence is conflicting, meaning that the added cost of switching patients from generic options to an FDC may not always be justified.

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OBJECTIVES To examine the association between self‐reported vision impairment (VI), hearing impairment (HI), and dual‐sensory impairment (DSI), stratified by dementia status, on hospital admissions, hospice use, and healthcare costs. DESIGN Retrospective analysis. SETTING Medicare Current Beneficiary Survey from 1999 to 2006. PARTICIPANTS Rotating panel of community‐dwelling Medicare beneficiaries, aged 65 years and older (N = 24 009). MEASUREMENTS VI and HI were ascertained by self‐report. Dementia status was determined by self‐report or diagnosis codes in claims data. Primary outcomes included any inpatient admission over a 2‐year period, hospice use over a 2‐year period, annual Medicare fee‐for‐service costs, and total healthcare costs (which included information from Medicare claims data and other self‐reported payments). RESULTS Self‐reported DSI was present in 30.2% (n = 263/871) of participants with dementia and 17.8% (n = 4112/23 138) of participants without dementia. In multivariable logistic regression models, HI, VI, or DSI was generally associated with increased odds of hospitalization and hospice use regardless of dementia status. In a generalized linear model adjusted for demographics, annual total healthcare costs were greater for those with DSI and dementia compared to those with DSI without dementia ($28 875 vs $3340, respectively). Presence of any sensory impairment was generally associated with higher healthcare costs. In a model adjusted for demographics, Medicaid status, and chronic medical conditions, DSI compared with no sensory impairment was associated with a small, but statistically significant, difference in total healthcare spending in those without dementia ($1151 vs $1056; P < .001) but not in those with dementia ($11 303 vs $10 466; P = .395). CONCLUSION Older adults with sensory and cognitive impairments constitute a particularly prevalent and vulnerable population who are at increased risk of hospitalization and contribute to higher healthcare spending. J Am Geriatr Soc 67:1617–1624, 2019

There is an increasing recognition of the immune system as an important mediator in the pathogenesis of Alzheimer's disease (AD). As immune system modulators, non-steroidal anti-inflammatory drugs (NSAIDs) garnered initial enthusiasm from pre-clinical and epidemiologic studies as agents to reduce the risk of AD. Areas covered: This article will examine the evidence for the use of NSAIDs in AD by discussing the proposed mechanism of action, results from epidemiologic studies, and data from randomized controlled trials. In addition, a survey of several novel approaches to targeting inflammatory pathways currently in pre-clinical and clinical phases of development is presented. These agents primarily act to modulate microglial functioning, enhance amyloid-β phagocytosis, suppress potentially harmful pro-inflammatory responses, or enhance systemic immunity. Expert commentary: While long-term use of NSAIDs is associated with a reduced incidence of AD in epidemiologic studies, randomized controlled trials have not replicated these findings. Thus, NSAID use cannot currently be recommended either for primary prevention or treatment of AD. However, the available evidence does suggest that cognitively normal patients taking long-term courses of NSAIDs for other indications likely have a decreased risk of AD, which represents an important finding given the high prevalence of NSAID use among older adults.

IMPORTANCEThe clinical decision to initiate bisphosphonate therapy for the treatment of osteoporosis requires balancing shorter-term harms and burdens (eg, gastroesophageal irritation or severe musculoskeletal pain) with longer-term benefits in reducing potential fractures.OBJECTIVE To assess the time to benefit (TTB) of bisphosphonate therapy for the prevention of nonvertebral and other fractures among postmenopausal women with osteoporosis.DATA SOURCES Randomized clinical trials (RCTs) were identified from systematic reviews commissioned by the US Preventive Services Task Force (1 review), the Agency for Healthcare Research and Quality (1 review), the Cochrane Library (2 reviews), and the Endocrine Society (1 review).STUDY SELECTION Studies selected were RCTs involving postmenopausal women with a diagnosis of osteoporosis based on existing vertebral fractures or bone mineral density T scores of −2.5 or lower. The selection process was focused on studies of alendronate, risedronate, and zoledronic acid because they are guideline-recommended first-line agents for reducing nonvertebral fractures. Studies were excluded if they did not focus on women with a primary diagnosis of osteoporosis, had no placebo arm, or had a lack of data on time to fracture.DATA EXTRACTION AND SYNTHESIS Random-effects Weibull survival curves were fitted and Markov chain Monte Carlo methods were used to estimate the absolute risk reduction (ARR) and TTB for each study. These estimates were pooled using a random-effects meta-analysis model. MAIN OUTCOMES AND MEASURESThe primary outcome was the time to 3 different ARR thresholds (0.002, 0.005, and 0.010) for the first nonvertebral fracture. Secondary outcomes included the time to 4 ARR thresholds (0.001, 0.002, 0.005, and 0.010) for hip fracture, any clinical fracture, and clinical vertebral fracture. RESULTSOf 67 full-text articles identified, 10 RCTs comprising 23 384 postmenopausal women with osteoporosis were included either as the original RCT or part of subsequently published pooled analyses. Among the studies, the number of participants ranged from 994 to 7765, with mean (SD) age ranging from 63 (7) years to 74 (3) years and follow-up duration ranging from 12 to 48 months. The pooled meta-analysis found that 12.4 months (95% CI, 6.3-18.4 months) were needed to avoid 1 nonvertebral fracture per 100 postmenopausal women receiving bisphosphonate therapy at an ARR of 0.010. To prevent 1 hip fracture, 200 postmenopausal women with osteoporosis would need to receive bisphosphonate therapy for 20.3 months (95% CI, 11.0-29.7 months) at an ARR of 0.005. In addition, 200 postmenopausal women with osteoporosis would need to receive bisphosphonate therapy for 12.1 months (95% CI, 6.4-17.8 months) to avoid 1 clinical vertebral fracture at an ARR of 0.005. CONCLUSIONS AND RELEVANCEThis meta-analysis found that the TTB of bisphosphonate therapy was 12.4 months to prevent 1 nonvertebral fracture per 100 postmenopausal women with osteoporosis. These results suggest that bisphosphonate therapy is most...

ImportanceEstimating mortality risk in older adults with dementia is important for guiding decisions such as cancer screening, treatment of new and chronic medical conditions, and advance care planning.ObjectiveTo develop and externally validate a mortality prediction model in community-dwelling older adults with dementia.Design, Setting, and ParticipantsThis cohort study included community-dwelling participants (aged ≥65 years) in the Health and Retirement Study (HRS) from 1998 to 2016 (derivation cohort) and National Health and Aging Trends Study (NHATS) from 2011 to 2019 (validation cohort).ExposuresCandidate predictors included demographics, behavioral/health factors, functional measures (eg, activities of daily living [ADL] and instrumental activities of daily living [IADL]), and chronic conditions.Main Outcomes and MeasuresThe primary outcome was time to all-cause death. We used Cox proportional hazards regression with backward selection and multiple imputation for model development. Model performance was assessed by discrimination (integrated area under the receiver operating characteristic curve [iAUC]) and calibration (plots of predicted and observed mortality).ResultsOf 4267 participants with probable dementia in HRS, the mean (SD) age was 82.2 (7.6) years, 2930 (survey-weighted 69.4%) were female, and 785 (survey-weighted 12.1%) identified as Black. Median (IQR) follow-up time was 3.9 (2.0-6.8) years, and 3466 (81.2%) participants died by end of follow-up. The final model included age, sex, body mass index, smoking status, ADL dependency count, IADL difficulty count, difficulty walking several blocks, participation in vigorous physical activity, and chronic conditions (cancer, heart disease, diabetes, lung disease). The optimism-corrected iAUC after bootstrap internal validation was 0.76 (95% CI, 0.75-0.76) with time-specific AUC of 0.73 (95% CI, 0.70-0.75) at 1 year, 0.75 (95% CI, 0.73-0.77) at 5 years, and 0.84 (95% CI, 0.82-0.85) at 10 years. On external validation in NHATS (n = 2404), AUC was 0.73 (95% CI, 0.70-0.76) at 1 year and 0.74 (95% CI, 0.71-0.76) at 5 years. Calibration plots suggested good calibration across the range of predicted risk from 1 to 10 years.Conclusions and RelevanceWe developed and externally validated a mortality prediction model in community-dwelling older adults with dementia that showed good discrimination and calibration. The mortality risk estimates may help guide discussions regarding treatment decisions and advance care planning.