Potentially inappropriate medication use in older adults with mild-moderate Alzheimer's disease:Prevalence and associations with adverse events

Aim: Potentially inappropriate medication (PIM) use is prevalent in older adults and is associated with adverse events, hospitalisation and mortality. We assessed the patterns and associations of PIM use in older adults with mild-to-moderate Alzheimer's Disease (AD), who may represent a particularly vulnerable group. Design: Analysis of data from NILVad, an 18-month Randomised Control Trial of Nilvadapine in mild-to-moderate AD. The v2 STOPP criteria were applied in duplicate to identify PIM use. Associations between PIM use and adverse events/unscheduled healthcare visits in addition to the associations between PIM use and AD progression were evaluated. Setting and Participants: 448 older adults with mild-to-moderate AD from 23 centres in nine European countries. Results: Of 448 participants (mean age: 72.56 ± 8.19 years), over half (55.8%) were prescribed a PIM with 30.1% being prescribed 2+ PIMs. The most frequent PIMs were (i) long-term benzodiazepines (11.6% N = 52/448), (ii) selective serotonin reuptake inhibitors without appropriate indication (11.1% N = 50/448), and (iii) Proton-Pump Inhibitors (PPIs) without appropriate indication (10.7% N = 48/448). Increasing number of PIMs was associated with a greater risk of adverse events (IRR 1.17, 1.13-1.19, P < 0.001), serious adverse events (IRR 1.27; 1.17-1.37, P < 0.001), unscheduled hospitalisations (IRR 1.16, 1.03-1.30, P = 0.016) and GP visits (IRR 1.22, 1.15-1.28, P < 0.001). PIM use was not associated with dementia progression. Conclusions and Implications: PIM use is highly prevalent in mild-to-moderate AD and is associated with adverse events and unscheduled healthcare utilisation. Further attention to de-prescribing in this vulnerable group is warranted

Dementia and other mental disorders among 95-year olds

The aims of this study were to estimate the prevalence of mental disorders and age related differences in the very elderly. In addition, five-year mortality after age 95 in relation to dementia and cognitive function in non-demented, was examined. A population sample of 338 95-year olds (response rate 65%) living in Gothenburg, Sweden, was compared with 85- (N=494) and 75-year olds (N=303) from the same birth cohort. All participants were examined by psychiatrists. The assessments included the Comprehensive Psychopathological Rating Scale, cognitive tests, the Mini Mental State Examination (MMSE), medical history, physical examination and a telephone interview with a key informant. Dementia, depression, anxiety and psychosis were classified according to DSM-III-R criteria, Alzheimer’s disease according to NINCDS-ADRDA criteria and vascular dementia (VaD) according to NINDS-AIREN criteria. Two-thirds (66%) of the 95-year olds fulfilled criteria for a mental disorder. Dementia was more common (52% vs. 30%; p<0.001) and more severe in 95-year olds than in 85-year olds. Among 95-year olds, dementia was more common in women than in men (56% vs. 37%; p=0.006). The proportion of VaD was lower among 95-year olds than among 85-year olds (30% vs. 40%; p<0.001). Almost one-third (29%) of the non-demented 95-year olds had a psychiatric disorder (depression 17%, anxiety disorders 9%, psychotic disorder 7%). Psychotic symptoms among non-demented 95-year olds were not associated with other psychiatric symptoms, sensory impairments or cognitive function. The prevalence of psychiatric disorders among non-demented was higher for 85- and 95-year olds than for 75-year olds. Five-year survival after age 95 was similar in men and women, but when controlling for dementia, male sex predicted mortality. Dementia was the leading predictor for death after age 95 and attributed to 40% of deaths. For each point increase in the MMSE score among the non-demented 95-year olds, mortality decreased by 13% (RR 0.87; p<0.0002). The high prevalence of psychiatric disorders emphasizes the importance of detecting and treating psychiatric problems among the oldest old, and also the need for further research on mental health in this age group. There is a concern that psychiatric symptoms among the very old are considered “normal for age” and therefore neglected by the patients themselves, their relatives and health care professionals

Tau-targeting antisense oligonucleotide MAPTRx in mild Alzheimer’s disease: a phase 1b, randomized, placebo-controlled trial

Tau plays a key role in Alzheimer’s disease (AD) pathophysiology, and accumulating evidence suggests that lowering tau may reduce this pathology. We sought to inhibit MAPT expression with a tau-targeting antisense oligonucleotide (MAPTRx) and reduce tau levels in patients with mild AD. A randomized, double-blind, placebo-controlled, multiple-ascending dose phase 1b trial evaluated the safety, pharmacokinetics and target engagement of MAPTRx. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal bolus administrations of MAPTRx or placebo every 4 or 12 weeks during the 13-week treatment period, followed by a 23 week post-treatment period. The primary endpoint was safety. The secondary endpoint was MAPTRx pharmacokinetics in cerebrospinal fluid (CSF). The prespecified key exploratory outcome was CSF total-tau protein concentration. Forty-six patients enrolled in the trial, of whom 34 were randomized to MAPTRx and 12 to placebo. Adverse events were reported in 94% of MAPTRx-treated patients and 75% of placebo-treated patients; all were mild or moderate. No serious adverse events were reported in MAPTRx-treated patients. Dose-dependent reduction in the CSF total-tau concentration was observed with greater than 50% mean reduction from baseline at 24 weeks post-last dose in the 60 mg (four doses) and 115 mg (two doses) MAPTRx groups. Clinicaltrials.gov registration number: NCT03186989