Salloway, Stephen

ObjectivePrevious studies suggest that the brain‐derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer's disease (AD). Our recent cross‐sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in cerebrospinal fluid (CSF) tau and ptau181, and whether these increases are associated with accelerated brain volume loss and memory decline.MethodsA total of 211 subjects (101 mutation noncarriers, 110 mutation carriers), who were cognitively normal, as defined by a Clinical Dementia Rating global score of 0, completed assessments of cognitive function, neuroimaging, and CSF sampling over 3.5 years as part of the Dominantly Inherited Alzheimer's Network.ResultsIn mutation carriers, Met66 carriers showed faster memory decline (4×), hippocampal volume loss (16×), and CSF tau and ptau181increases (6×) than Val66 homozygotes.BDNFdid not influence rates of cortical β‐amyloid accumulation or change in CSF Aβ42levels in mutation carriers. In mutation noncarriers,BDNFgenotype had no effect on change in cognition, brain volume, cortical β‐amyloid accumulation, or change in any CSF measures of tau, ptau181, and CSF Aβ42.InterpretationAs in sporadic AD, the deleterious effects of β‐amyloid on cognitive function, brain volume loss, and CSF tau in DIAD mutation carriers are less in Val66 homozygotes. TheBDNFVal66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in DIAD and sporadic AD. Ann Neurol 2018;84:424–435

Abstract Introduction Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. Methods Serial T1‐weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed‐effects models estimated the change‐points when atrophy rates deviate from normal and the rates of change before and after this point. Results Atrophy increased after the change‐point, which occurred 1–1.5 years (assuming a single step change in atrophy rate) or 3–8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change‐point. Discussion Atrophy rates are pathologically increased up to seven years before “expected onset”. During this period, atrophy rates may be useful for inclusion and tracking of disease progression.

AbstractIntroductionThe objective of this study was to evaluate the relationship between self‐reported exercise levels and Alzheimer's disease (AD) biomarkers, in a cohort of autosomal dominant AD mutation carriers.MethodsIn 139 presymptomatic mutation carriers from the Dominantly Inherited Alzheimer Network, the relationship between self‐reported exercise levels and brain amyloid load, cerebrospinal fluid (CSF) Aβ42, and CSF tau levels was evaluated using linear regression.ResultsNo differences in brain amyloid load, CSF Aβ42, or CSF tau were observed between low and high exercise groups. Nevertheless, when examining only those already accumulating AD pathology (i.e., amyloid positive), low exercisers had higher mean levels of brain amyloid than high exercisers. Furthermore, the interaction between exercise and estimated years from expected symptom onset was a significant predictor of brain amyloid levels.DiscussionOur findings indicate a relationship exists between self‐reported exercise levels and brain amyloid in autosomal dominant AD mutation carriers.