FindMyApps compared with usual tablet use to promote social health of community-dwelling people with mild dementia and their informal caregivers:a randomised controlled trial

Background: FindMyApps is a tablet-based eHealth intervention designed to help people learn to use a tablet and find easy-to-use apps. This study evaluated the effectiveness of FindMyApps for supporting social health of people living with dementia, and sense of competence of their informal caregivers. Methods: A single-centre, two-arm, non-blinded randomised controlled trial was conducted (Netherlands Trial Register NL8157). From 1st January 2020 to 31st July 2022, community-dwelling people in the Netherlands with a pre-established diagnosis of mild cognitive impairment (MCI) or dementia (Brief Cognitive Rating Scale 17–32), an informal caregiver and internet connection were allocated by block randomisation to receive FindMyApps or digital care-as-usual. Primary outcomes (measured at baseline and after three months) for people with dementia/MCI were self-management (Adult Social Care Outcomes Toolkit total score) and social participation (Maastricht Social Participation Profile frequency and diversity scores), and for caregivers, sense of competence (Short Sense of Competence Questionnaire total score). Between-group differences were tested by MANCOVA or ANCOVA (alpha = 0.05). Findings: 150 dyads were randomised (FindMyApps n = 76, care-as-usual n = 74). Follow-up data were available for 128 dyads (FindMyApps n = 64, care-as-usual n = 64), who were included in the analysis in the trial arm to which they were assigned. No harms of the intervention were identified. There were no statistically significant differences in outcomes for people with dementia/MCI at group level. Diagnosis and experiencing apathy appeared to be relevant effect modifiers of secondary outcomes (neuropsychiatric symptoms, positive affect, sense of belonging, and pleasurable activities). Caregivers who received FindMyApps had higher sense of competence at three months (F [1,123] = 7.01, p = 0.0092, η2 = 0.054). Interpretation: Overall we found no evidence that the FindMyApps intervention better supported social participation or self-management of people with MCI/dementia than digital care-as-usual. FindMyApps does seem to better support informal caregivers’ sense of competence. For people with a diagnosis of mild dementia and older people, better tailored interventions, implementation and outcome measures may be needed. Funding: Marie Skłodowska Curie Actions Innovative Training Network H2020 MSCA ITN, grant agreement number 813196.</p

Prescreening for European Prevention of Alzheimer Dementia (EPAD) trial-ready cohort: impact of AD risk factors and recruitment settings

Abstract: Background: Recruitment is often a bottleneck in secondary prevention trials in Alzheimer disease (AD). Furthermore, screen-failure rates in these trials are typically high due to relatively low prevalence of AD pathology in individuals without dementia, especially among cognitively unimpaired. Prescreening on AD risk factors may facilitate recruitment, but the efficiency will depend on how these factors link to participation rates and AD pathology. We investigated whether common AD-related factors predict trial-ready cohort participation and amyloid status across different prescreen settings. Methods: We monitored the prescreening in four cohorts linked to the European Prevention of Alzheimer Dementia (EPAD) Registry (n = 16,877; mean ± SD age = 64 ± 8 years). These included a clinical cohort, a research in-person cohort, a research online cohort, and a population-based cohort. Individuals were asked to participate in the EPAD longitudinal cohort study (EPAD-LCS), which serves as a trial-ready cohort for secondary prevention trials. Amyloid positivity was measured in cerebrospinal fluid as part of the EPAD-LCS assessment. We calculated participation rates and numbers needed to prescreen (NNPS) per participant that was amyloid-positive. We tested if age, sex, education level, APOE status, family history for dementia, memory complaints or memory scores, previously collected in these cohorts, could predict participation and amyloid status. Results: A total of 2595 participants were contacted for participation in the EPAD-LCS. Participation rates varied by setting between 3 and 59%. The NNPS were 6.9 (clinical cohort), 7.5 (research in-person cohort), 8.4 (research online cohort), and 88.5 (population-based cohort). Participation in the EPAD-LCS (n = 413 (16%)) was associated with lower age (odds ratio (OR) age = 0.97 [0.95–0.99]), high education (OR = 1.64 [1.23–2.17]), male sex (OR = 1.56 [1.19–2.04]), and positive family history of dementia (OR = 1.66 [1.19–2.31]). Among participants in the EPAD-LCS, amyloid positivity (33%) was associated with higher age (OR = 1.06 [1.02–1.10]) and APOE ɛ4 allele carriership (OR = 2.99 [1.81–4.94]). These results were similar across prescreen settings. Conclusions: Numbers needed to prescreen varied greatly between settings. Understanding how common AD risk factors link to study participation and amyloid positivity is informative for recruitment strategy of studies on secondary prevention of AD

Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis

IMPORTANCE: Amyloid-β positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaques, a core neuropathological feature of Alzheimer disease (AD). Its diagnostic utility is still unclear because amyloid plaques also occur in patients with non-AD dementia. OBJECTIVE: To use individual participant data meta-analysis to estimate the prevalence of amyloid positivity on PET in a wide variety of dementia syndromes. DATA SOURCES: The MEDLINE and Web of Science databases were searched from January 2004 to April 2015 for amyloid PET studies. STUDY SELECTION: Case reports and studies on neurological or psychiatric diseases other than dementia were excluded. Corresponding authors of eligible cohorts were invited to provide individual participant data. DATA EXTRACTION AND SYNTHESIS: Data were provided for 1359 participants with clinically diagnosed AD and 538 participants with non-AD dementia. The reference groups were 1849 healthy control participants (based on amyloid PET) and an independent sample of 1369 AD participants (based on autopsy). MAIN OUTCOMES AND MEASURES: Estimated prevalence of positive amyloid PET scans according to diagnosis, age, and apolipoprotein E (APOE) ε4 status, using the generalized estimating equations method. RESULTS: The likelihood of amyloid positivity was associated with age and APOE ε4 status. In AD dementia, the prevalence of amyloid positivity decreased from age 50 to 90 years in APOE ε4 noncarriers (86% [95% CI, 73%-94%] at 50 years to 68% [95% CI, 57%-77%] at 90 years; n = 377) and to a lesser degree in APOE ε4 carriers (97% [95% CI, 92%-99%] at 50 years to 90% [95% CI, 83%-94%] at 90 years; n = 593; P < .01). Similar associations of age and APOE ε4 with amyloid positivity were observed in participants with AD dementia at autopsy. In most non-AD dementias, amyloid positivity increased with both age (from 60 to 80 years) and APOE ε4 carriership (dementia with Lewy bodies: carriers [n = 16], 63% [95% CI, 48%-80%] at 60 years to 83% [95% CI, 67%-92%] at 80 years; noncarriers [n = 18], 29% [95% CI, 15%-50%] at 60 years to 54% [95% CI, 30%-77%] at 80 years; frontotemporal dementia: carriers [n = 48], 19% [95% CI, 12%-28%] at 60 years to 43% [95% CI, 35%-50%] at 80 years; noncarriers [n = 160], 5% [95% CI, 3%-8%] at 60 years to 14% [95% CI, 11%-18%] at 80 years; vascular dementia: carriers [n = 30], 25% [95% CI, 9%-52%] at 60 years to 64% [95% CI, 49%-77%] at 80 years; noncarriers [n = 77], 7% [95% CI, 3%-18%] at 60 years to 29% [95% CI, 17%-43%] at 80 years. CONCLUSIONS AND RELEVANCE: Among participants with dementia, the prevalence of amyloid positivity was associated with clinical diagnosis, age, and APOE genotype. These findings indicate the potential clinical utility of amyloid imaging for differential diagnosis in early-onset dementia and to support the clinical diagnosis of participants with AD dementia and noncarrier APOE ε4 status who are older than 70 years

ABIDE Delphi study: Topics to discuss in diagnostic consultations in memory clinics

Background: Information given to patients and caregivers during the clinician-patient encounter varies considerably between memory clinic professionals. Patients and caregivers express a clear desire for more information. It is unclear what information patients and caregivers value most during the diagnostic process and whether this is concordant with professionals' opinion. We aimed to identify a topic list on which health care professionals, patients, and caregivers agree that these should be discussed during diagnostic consultations in memory clinics. Further, we aimed to establish the optimal moment for each topic to be discussed during the diagnostic process. Methods: We performed a three-round Delphi consensus study. Professionals (N = 80), patients (N = 66), and caregivers (N = 76) rated the importance of 44 informative topics through an online questionnaire. Consensus was defined as a topic rating of 6 or 7 on a 7-point Likert scale by ≥ 75% of each panel. In round 2 and 3, a survey was added to identify the optimal moment during the diagnostic process to discuss each topic. Results: By round 3, consensus was achieved on 17 topics divided into four categories, information about (1) diagnostic testing, (2) test results, (3) diagnosis, and (4) practical implications. Eight additional topics showed significant differences between panels. Most notable panel differences regard the risk for developing dementia and the distinction between Alzheimer's disease and dementia, which patients and caregivers evaluated as more important compared to professionals. The optimal moment to discuss topics during the diagnostic process was identified for the 17 core topics, and the eight topics with significant differences. Conclusions: We present a core list of informative topics, which professionals, patients, and caregivers agree they should be discussed during the diagnostic process in a memory clinic. The topic list can support professionals and empower patients and caregivers during diagnostic physician-patient consultations

Testing the link between isoaspartate and Alzheimer's disease etiology

Isoaspartate (isoAsp) is a damaging amino acid residue formed in proteins as a result of spontaneous deamidation. IsoAsp disrupts protein structures, making them prone to aggregation. Here we strengthened the link between isoAsp and Alzheimer's disease (AD) by novel approaches to isoAsp analysis in human serum albumin (HSA), the most abundant blood protein and a major carrier of amyloid beta (A beta) and phosphorylated tau (p-tau) in blood. We discovered a reduced amount of anti-isoAsp antibodies (P &lt; 0.0001), an elevated isoAsp level in HSA (P &lt; 0.001), more HSA aggregates (P &lt; 0.0001), and increased levels of free A beta (P &lt; 0.01) in AD blood compared to controls. We also found that deamidation significantly reduces HSA capacity to bind with A beta and p-tau (P &lt; 0.05). These suggest the presence in AD of a bottleneck in clearance of A beta and p-tau, leading to their increased concentrations in the brain and facilitating their aggregations there

Steeper memory decline after COVID-19 lockdown measures

BACKGROUND: During COVID-19 lockdown measures, memory clinic patients reported worries for faster cognitive decline, due to loss of structure and feelings of loneliness and depression. We aimed to investigate the impact of the COVID-19 lockdown on rate of cognitive decline in a mixed memory clinic population, compared to matched historical controls. METHODS: We included patients who visited Alzheimer Center Amsterdam 6 months to 1 week before the first Dutch COVID-19 lockdown, and had a second visit 1 year later, after this lockdown period (n = 113; 66 ± 7 years old; 30% female; n = 55 dementia, n = 31 mild cognitive impairment (MCI), n = 18 subjective cognitive decline (SCD), n = 9 postponed diagnosis). Historical controls (visit in 2016/2017 and second visit 1 year later (n = 640)) were matched 1:1 to lockdown patients by optimal Mahalanobis distance matching (both groups n = 113). Groups were well matched. Differences between lockdown patients and historical controls over time in Mini-Mental State Examination, Trail Making Test part A and B, Rey-Auditory Verbal Learning Test (RAVLT) immediate and delayed recall, and category fluency scores were analyzed using linear mixed effect models with random intercepts. We examined differences in rate of cognitive decline between whole groups, and after stratification in SCD, MCI, and dementia separately. RESULTS: Lockdown patients had a faster rate of memory decline compared to controls on both RAVLT immediate [B(SE) =  - 2.62 (1.07), p = 0.015] and delayed recall [B(SE) =  - 1.07 (0.34), p = 0.002]. Stratification by syndrome diagnosis showed that this effect was largely attributable to non-demented participants, as we observed faster memory decline during lockdown in SCD and MCI (RAVLT immediate [SCD: B(SE) =  - 6.85 (2.97), p = 0.027; MCI: B(SE) =  - 6.14 (1.78), p = 0.001] and delayed recall [SCD: B(SE) =  - 2.45 (1.11), p = 0.035; MCI: B(SE) =  - 1.50 (0.51), p = 0.005]), but not in dementia. CONCLUSION: Memory clinic patients, specifically in pre-dementia stages, showed faster memory decline during COVID-19 lockdown, providing evidence that lockdown regulations had a deleterious effect on brain health. In individuals that may have been able to deal with accumulating, subclinical neuropathology under normal and structured circumstances, the additional stress of lockdown regulations may have acted as a "second hit," resulting in less beneficial disease trajectory

Pre-amyloid stage of Alzheimer's disease in cognitively normal individuals

Objective: To study risk factors for decreasing aβ1–42 concentrations in cerebrospinal fluid (CSF) in cognitively unimpaired individuals with initially normal amyloid and tau markers, and to investigate whether such aβ1–42 decreases are associated with subsequent decline in cognition and other biomarkers of Alzheimer's disease. Methods: Cognitively normal subjects (n = 83, 75 ± 5 years, 35(42%) female) with normal CSF aβ1–42 and tau and repeated CSF sampling were selected from ADNI. Subject level slopes of aβ1–42 decreases were estimated with mixed models. We tested associations of baseline APP processing markers (BACE1 activity, aβ1–40, aβ1–38 and sAPPβ) and decreasing aβ1–42 levels by including an interaction term between time and APP marker. Associations between decreasing aβ1–42 levels and clinical decline (i.e., progression to mild cognitive impairment or dementia, MMSE, memory functioning) and biological decline (tau, hippocampal volume, glucose processing and amyloid PET) over a time period of 8–10 years were assessed. Results: Aβ1–42 levels decreased annually with −4.6 ± 1 pg/mL. Higher baseline BACE1 activity (β(se) = −0.06(0.03), P < 0.05), aβ1–40 (β(se)= −0.11(.03), P < 0.001), and aβ1–38 levels (β(se) = −0.11(0.03), P < 0.001) predicted faster decreasing aβ1–42. The fastest tertile of decreasing aβ1–42 rates was associated with subsequent pathophysiological processes: 11(14%) subjects developed abnormal amyloid levels after 3 ± 1.7 years, showed increased risk for clinical progression (Hazard Ratio[95CI] = 4.8[1.1–21.0]), decreases in MMSE, glucose metabolism and hippocampal volume, and increased CSF tau and amyloid aggregation on PET (all P < 0.05). Interpretation: Higher APP processing and fast decreasing aβ1–42 could be among the earliest, pre-amyloid, pathological changes in Alzheimer's disease

The Impact of Amyloid PET Disclosure on Quality of Life in Patients With Young Onset Dementia

Introduction: The impact of amyloid positron emission tomography (PET) imaging on patient health outcomes for individuals with dementia is unknown. In the present study, we explored the association between diagnostic outcome and clinician's level of certainty with quality of life (QoL) after [18F]flutemetamol PET results were disclosed in young onset dementia patients in a memory clinic cohort. Methods: In 154 patients suspected of dementia, QoL was measured before and after [18F]flutemetamol PET results were disclosed. Multiple regression analyses were conducted with (changed) general and disease-specific QoL measures as dependent factors [QoL-Alzheimer disease (AD) and EQ-5D Dutch tariff] and etiological diagnosis and clinician's certainty as independent factors. Results: (Change in) diagnosis of AD was associated to QOL in 2 of the 4 analyses (utility-based QoL β=0.15, P=0.010; disease-specific QoL β=2.0, P=0.037). Diagnostic certainty was associated to QOL in 1 of the 4 analyses (generic QoL β=0.002, P=0.028). Discussion: The diverse results in this explorative analysis do not reflect a univocal association between diagnosis, certainty, and QoL. Nevertheless, this result could be interpreted as a possible potential for advanced diagnostic technologies for AD, which requires confirmation in future research