Barry Reisberg

Background: Rates of hospitalization are 3 times higher for community‐dwelling Alzheimer’s disease (AD) persons than non‐affected, age‐matched persons (Rudolph et al., J Am Geriatr Soc. 2010). These investigators reported that hospital outcomes were significantly worse for AD patients regarding delirium, prolonged length of stay, institutionalization and death. They concluded, “Given the frequency of hospitalization in …[AD]… patients, an intervention to prevent or shorten hospitalization would potentially save Medicare billions of dollars per year.” We conducted 28‐week, controlled, clinician‐blind, parallel group and 24‐week extension studies in which advanced AD persons were randomized to receive a comprehensive, individualized, person‐centered management program (CI‐PCM) developed by Sunnie Kenowsky and memantine or usual community care (UCC) and memantine (Reisberg…Kenowsky, Dement Geriatr Cogn Disord., 2017). Herein, we investigate the occurrence of hospitalization and emergency department visits (EDV) in the two groups at 52‐weeks.Methods: Each occurrence of death, hospitalization and EDV was documented. Investigators blind to group assignment analyzed occurrences. Any fraction of a hospital stay or EDV occurring on or between the baseline and week 52 visit days was recorded as one incident. Relative Risk Reduction (RRR) was calculated for the incidence of hospitalization and EDV.Results: 40% of UCC subjects experienced EDV, 40% were hospitalized and 10% died. Comparatively, only 10% of CI‐PCM subjects experienced EDV and 10% were hospitalized. UCC subjects were hospitalized for C. difficile infection, a fall and subsequent pelvic fracture, syncope and gastrointestinal disease. One CI‐PCM subject was hospitalized for a fall and hip fracture secondary to osteoporosis. UCC subject falls were attributed to neuropsychiatric symptoms of dementia. A CI‐PCM subject had C. difficile successfully treated by their physician. The RRR for utilization of the CI‐PCM program was 0.75 for EDV and 0.75 for hospitalizations (Tables 1&2).Conclusions: CI‐PCM subjects had a 75% decreased risk of EDV and a 75% decreased risk of hospitalization. Given the 5.8 million USA AD persons and the current high cost of hospitalization, the CI‐PCM program could potentially, significantly decrease the costs of care for AD persons, Medicare, and Medicaid while greatly increasing the AD person’s quality of life and alleviating their caregiver’s burden.

Background: We have described the clinical stages of the brain aging and Alzheimer’s disease (AD) continuum. In terms of the pre-dementia stages of AD, we introduced the terminology “mild cognitive impairment” (MCI) for the first pre-dementia stage and “subjective cognitive decline” (SCD) for the pre-MCI stage. We now report the characteristics of a pre-SCD condition eventuating in likely AD. Objective: The aim of this study was to characterize a pre-SCD condition eventuating in AD. Method: Sixty healthy persons with “no cognitive decline” (NCD) were recruited and 47 were followed (mean baseline age, 64.1 ± 8.9 years; mean follow-up time, 6.7 ± 3.1 years). Outcome was determined at the final assessment prior to 2002 as “decliner,” if SCD or worse, or “nondecliner” if NCD. Results: After controlling for age, gender, years of education, and follow-up time, there was a between-group difference in the decline rate (p < 0.001). Also, after controlling for demographic variables and follow-up time, the combinatorial psychometric score was lower at baseline in the future decliners (p = 0.035). Of the 9 psychometric variables, after controlling for demographic variables and follow-up time, 3 were significantly lower at baseline in future decliners. Since AD is known to be age related and all subjects in this study were otherwise healthy, we also did an analysis without controlling for age. The combinatorial psychometric score was highly significantly better at baseline in the future nondecliners than in the future decliners (p = 0.008). Conclusion: This is ostensibly the first study to link psychometric cognitive decline to the subsequent SCD stage of eventual AD.

Risk for late-onset Alzheimer’s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer’s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10⁻⁷), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

Background: Little is known with respect to behavioral markers of subjective cognitive decline (SCD), a condition initially described in association with Global Deterioration Scale (GDS) stage 2. Objective: Two-year interval behavioral markers were investigated herein. Methods: Subjects from a published 7-year outcome study of GDS stage 2 subjects were selected. This study had demonstrated a hazard ratio of 4.5 for progression of GDS stage 2, in comparison with GDS stage 1 (no subjective or objective cognitive decline) subjects, after controlling for demographic and temporal variables. Because GDS 2 subjects have previously demonstrated impairment in comparison with healthy persons free of complaints, we herein suggest the terminology “SCD(I)” for these persons. 98 SCD(I) persons, 63 women and 35 men, mean baseline age, 67.12±8.75 years, with a mean educational background of 15.55±2.60 years, and mean baseline MMSE scores of 28.9±1.24 were followed for 2.13±0.30 years. Results: Observed annual decline on the GDS was 6.701% per annum, very close to a 1986 published estimate. At follow up, the MMSE, and 7 of 8 psychometric tests did not decline significantly. Of 21 Hamilton Depression Scale items, 2 improved and the remainder were unchanged. Anxieties declined from multiple perspectives. The Brief Cognitive Rating Scale (BCRS) declined significantly ( p < 0.001), with component declines in Remote memory ( p < 0.01), and Functioning/self-care ( p = 0.01). Conclusion: SCD(I) persons decline at an annual rate of approximately 6.7% /year from several recent studies. The BCRS assessments and the Digit Symbol Substitution Test can be sensitive measures for future studies of progression mitigation.

Introduction: In this multicenter study on subjective cognitive decline (SCD) in community‐based and memory clinic settings, we assessed the (1) incidence of Alzheimer's disease (AD) and non‐AD dementia and (2) determinants of progression to dementia.Methods: Eleven cohorts provided 2978 participants with SCD and 1391 controls. We estimated dementia incidence and identified risk factors using Cox proportional hazards models.Results: In SCD, incidence of dementia was 17.7 (95% Poisson confidence interval 15.2‐20.3)/1000 person‐years (AD: 11.5 [9.6‐13.7], non‐AD: 6.1 [4.7‐7.7]), compared with 14.2 (11.3‐17.6) in controls (AD: 10.1 [7.7‐13.0], non‐AD: 4.1 [2.6‐6.0]). The risk of dementia was strongly increased in SCD in a memory clinic setting but less so in a community‐based setting. In addition, higher age (hazard ratio 1.1 [95% confidence interval 1.1‐1.1]), lower Mini–Mental State Examination (0.7 [0.66‐0.8]), and apolipoprotein E ε4 (1.8 [1.3‐2.5]) increased the risk of dementia.Discussion: SCD can precede both AD and non‐AD dementia. Despite their younger age, individuals with SCD in a memory clinic setting have a higher risk of dementia than those in community‐based cohorts.

Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2, ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease. We identified rare coding variants associated with Alzheimer's disease in a three-stage case–control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10−4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10−8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10−10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10−10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10−14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein–protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

Background/Aims: The aim was to examine added benefits of a Comprehensive, Individualized, Person-Centered Management (CI-PCM) program to memantine treatment. Methods: This was a 28-week, clinician-blinded, randomized, controlled, parallel-group study, with a similar study population, similar eligibility criteria, and a similar design to the memantine pivotal trial of Reisberg et al. [N Engl J Med 2003;348:1333-1341]. Twenty eligible community-residing Alzheimer disease (AD) subject-caregiver dyads were randomized to the CI-PCM program (n = 10) or to usual community care (n = 10). Primary outcomes were the New York University Clinician's Interview-Based Impression of Change Plus Caregiver Input (NYU-CIBIC-Plus), assessed by one clinician set, and an activities of daily living inventory, assessed by a separate clinician set at baseline and at weeks 4, 12, and 28. Results: Primary outcomes showed significant benefits of the CI-PCM program at all post-baseline evaluations. Improvement on the NYU-CIBIC-Plus in the management group at 28 weeks was 2.9 points over the comparator group. The memantine 2003 trial showed an improvement of 0.3 points on this global measure in memantine-treated versus placebo-randomized subjects at 28 weeks. Hence, globally, the management program intervention benefits were 967% greater than memantine treatment alone. Conclusion: These results are approximately 10 times those usually observed with both nonpharmacological and pharmacological treatments and indicate substantial benefits with the management program for advanced AD persons.

Dementia is a major medical and social scourge. Neither pharmacological nor nonpharmacological interventions and treatments have received sufficient funding to be meaningful in combatting this tsunami. Because the term—“nonpharmacological”—refers to what these interventions are not, rather than what they are, nonpharmacological treatments face a special set of challenges to be recognized, accepted, funded, and implemented. In some ways, the current situation is analogous to using the term “nonhate” to mean “love.” This article presents a carefully reasoned argument for using the terminology “ecopsychosocial” to describe the full range of approaches and interventions that fall into this category. These include interventions such as educational efforts with care partners, social support programs for individuals with various levels of dementia, efforts to improve community awareness of dementia, an intergenerational school where persons with dementia teach young children, and the design of residential and community settings that improve functioning and can reduce behavioral symptoms of dementia. The proposed terminology relates to the nature of the interventions themselves, rather than their outcomes, and reflects the broadest range of interventions possible under the present rubric—nonpharmacological. The goal of this new label is to be better able to compare interventions and their outcomes and to be able to see the connections between data sets presently not seen as fitting together, thereby encouraging greater focus on developing new ecopsychosocial interventions and approaches that can improve the lives of those with dementia, their care partners, and the broader society.