Colin L. Masters

Background: Cognitive change is an important factor in understanding dementia. Estimating effects of exposures on cognitive change requires choosing an analytical timescale, typically time on study or current age. There is limited consensus regarding timescale choice in epidemiologic cognitive aging research. Methods: Using a coordinated analytic approach in 10 cohorts of older adults, we evaluated whether estimated effects of two exposures on memory change differed depending on timescale (time on study or current age). We modeled effects of apolipoprotein-E ( APOE ) ε4 genotype (a time-invariant exposure) and diabetes (a potentially time-varying/acquired exposure evaluated at baseline) using mixed-effects models with linear and nonlinear time specifications for both timescales. Results: Among APOE ε4 carriers, model-estimated memory scores at baseline (time on study timescale) or at each cohort's median baseline age (current age timescale) were lower, and the average rate of decline was faster than among APOE ε4 noncarriers. Model-estimated memory scores at baseline or at median baseline age were generally similar across baseline diabetes status, with variability across cohorts in the diabetes-memory change association. In some cohorts, trends in diabetes-memory change associations differed in direction across timescales. Conclusions: Timescale was largely inconsequential for estimated effects of APOE genotype, but yielded differences in estimated diabetes effects, raising questions about the appropriate scale. The current age scale may be problematic because diabetes was measured heterogeneously in age across individuals, a common issue in aging cohorts. Our work demonstrates approaches to evaluate alternative timescales, including in multicohort analyses, and highlights potential implications for estimated exposure effects on cognitive change.

Background: Cognitive change is an important factor in understanding dementia. Estimating effects of exposures on cognitive change requires choosing an analytical timescale, typically time on study or current age. There is limited consensus regarding timescale choice in epidemiologic cognitive aging research. Methods: Using a coordinated analytic approach in ten cohorts of older adults, we evaluated whether estimated effects of two exposures on memory change differed depending on timescale (time on study or current age). We modeled effects of APOE ε4 genotype (a time-invariant exposure) and diabetes (a potentially time-varying/acquired exposure evaluated at baseline) using mixed-effects models with linear and non-linear time specifications for both timescales. Results: Among APOE ε4 carriers, model-estimated memory scores at baseline (time on study timescale) or at each cohort's median baseline age (current age timescale) were lower and average rate of decline was faster than among APOE ε4 noncarriers. Model-estimated memory scores at baseline or at median baseline age were generally similar across baseline diabetes status, with variability across cohorts in the diabetes-memory change association. In some cohorts, trends in diabetes-memory change associations differed in direction across timescales. Conclusions: Timescale was largely inconsequential for estimated effects of APOE genotype, but yielded differences in estimated diabetes effects, raising questions about the appropriate scale. Current age scale may be problematic because diabetes was measured heterogeneously in age across individuals, a common issue in aging cohorts. Our work demonstrates approaches to evaluate alternative timescales, including in multi-cohort analyses, and highlights potential implications for estimated exposure effects on cognitive change.

Nationwide surveillance of Creutzfeldt-Jakob disease (CJD) and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable developments have occurred in pre-mortem diagnostics; in the delineation of new disease subtypes; and in heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2023. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2023, a total of 651 domestic CSF specimens were referred for diagnostic testing and 83 persons with suspected human prion disease were formally added to the national register. As of 31 December 2023, just under half of the 83 suspect case notifications (41) remain classified as 'incomplete'; 10 cases were classified as 'definite' and 28 as 'probable' prion disease; three cases were excluded through neuropathological examination and one was removed from the register as 'unlikely CJD' after clinical evaluation. For 2023, fifty-three percent of all suspected human-prion-disease-related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified.

Amyloid-plaque removal by monoclonal antibody therapies slows clinical progression in symptomatic Alzheimer's disease; however, the potential for delaying the onset of clinical symptoms in asymptomatic people is unknown. The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) is an ongoing platform trial assessing the safety and efficacy of multiple investigational products in participants with dominantly inherited Alzheimer's disease (DIAD) caused by mutations. On the basis of findings of amyloid removal and downstream biological effects from the gantenerumab arm of the platform trial, we continued a 3-year open-label extension (OLE) study to assess the safety and efficacy of long-term treatment with high doses of gantenerumab. The randomised, placebo-controlled, double-blind, phase 2/3 multi-arm trial (DIAN-TU-001) assessed solanezumab or gantenerumab versus placebo in participants who were between 15 years before to 10 years after their estimated years to symptom onset and had a Clinical Dementia Rating (CDR) global score of 0 (cognitively normal) to 1 (mild dementia). This study was followed by an OLE study of gantenerumab treatment, conducted at 18 study sites in Australia, Canada, France, Ireland, Puerto Rico, Spain, the UK, and USA. For inclusion in the OLE, participants at risk for DIAD had participated in the double-blind period of DIAN-TU-001 and were required to know their mutation status. We investigated increasing doses of gantenerumab up to 1500 mg subcutaneous every 2 weeks. Due to the lack of a regulatory path for gantenerumab, the study was stopped early after a pre-specified interim analysis (when most participants had completed 2 years of treatment) of the clinical measure CDR-SB. The primary outcome for the final analysis was the amyloid plaque measure PiB-PET SUVR at 3 years, assessed in the modified intention to treat population (defined as participants who received any gantenerumab treatment post-OLE baseline, had at least one PiB-PET SUVR assessment prior to gantenerumab treatment, and a post-baseline assessment). All participants who received at least one dose of study drug in the OLE were included in the safety analysis. DIAN-TU-001 (NCT01760005) and the OLE (NCT06424236) are registered with clinicaltrials.gov. Of 74 participants who were recruited into the OLE study between June 3, 2020 and April 22, 2021, 73 were enrolled and received gantenerumab treatment. 47 (64%) stopped dosing due to early termination of the study by the sponsor, and 13 (18%) prematurely discontinued the study for other reasons. The mITT population for the primary analysis comprised 55 participants. At the interim analysis, the hazard ratio for clinical decline of CDR-SB in asymptomatic mutation carriers was 0.79 (n=53, 95% CI 0.47 to 1.32) for participants who were treated with gantenerumab in either the double-blind or OLE period (Any Gant), and 0.53 (n=22, 0.27 to 1.03) for participants who were treated with gantenerumab the longest (Longest Gant). At the final analysis, the adjusted mean change from OLE baseline to year 3 in PiB-PET SUVR was -0.71 SUVR (95% CI -0.88 to -0.53, p<0.0001). Amyloid-related imaging abnormalities occurred in 53% (39/73) of participants: 47% (34/73) with microhaemorrhages, 30% (22/73) with oedema, and 6% (5/73) were associated with symptoms. No treatment-associated macrohaemorrhages or deaths occurred. Partial or short-term amyloid removal did not show significant clinical effects. However, long-term full amyloid removal potentially delayed symptom onset and dementia progression. Conclusions are limited due to the OLE design and use of external controls and need to be confirmed in long term trials. National Institutes on Aging, Alzheimer's Association, GHR, F. Hoffmann-La Roche, Ltd/Genentech.

The ability to predict the onset of mild cognitive impairment (MCI) and Alzheimer dementia (AD) could allow older adults and clinicians to make informed decisions about dementia care. To assess whether the age at onset of MCI and AD can be predicted using a statistical modeling approach. This prognostic study used data from 2 aging and dementia cohort studies-the Australian Imaging, Biomarker and Lifestyle (AIBL) study and the Alzheimer's Disease Neuroimaging Initiative (ADNI)-for model development and validation of the Florey Dementia Index (FDI), a tool used to predict the age at onset of MCI and AD in older adults. Data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer (A4) study were used for a simulated trial. Data were collected from 1665 AIBL participants, 2029 ADNI participants, and 93 A4 participants from October 1, 2004, to March 1, 2023. The data analysis was conducted between January and August 2024. Predicted age at onset compared with clinically observed age at onset. Among the 1665 AIBL participants (741 [44.5%] female) and 2029 ADNI participants (925 [45.6%] female), the mean (SD) age at first evaluation was 71.8 (7.1) years and 74.5 (6.7) years, respectively. The FDI achieved mean absolute errors of 2.78 (95% CI, 2.63-2.93) years for predicting MCI onset and 1.48 (95% CI, 1.32-1.65) years for predicting AD onset. In the simulated trial with 93 A4 participants (48 [51.6%] female; mean [SD] age at baseline, 73.4 [5.1] years), the FDI achieved mean absolute errors of 1.57 (95% CI, 1.41-1.71) years for predicting MCI onset and 0.70 (95% CI, 0.53-0.88) years for predicting AD onset. In this prognostic study, the FDI was developed and validated to predict the onset age of MCI and AD. This tool may be useful in organizing health care for older adults with cognitive decline or dementia and in the future may help prioritize patients for the use of disease-modifying monoclonal antibody drugs.

Dominantly Inherited Alzheimer Network (DIAN)

A Clinico-Pathological Study of the Correspondence Between 18F-AV-1451 PET Imaging and Post-Mortem Assessment of Tau Pathology