Medical Research Council and National Institute for Health Research.

Objectives:To investigate whether serum neurofilament light (NfL) concentration is increased in familial Alzheimer disease (FAD), both pre and post symptom onset, and whether it is associated with markers of disease stage and severity.Methods:We recruited 48 individuals from families with PSEN1 or APP mutations to a cross-sectional study: 18 had symptomatic Alzheimer disease (AD) and 30 were asymptomatic but at 50% risk of carrying a mutation. Serum NfL was measured using an ultrasensitive immunoassay on the single molecule array (Simoa) platform. Cognitive testing and MRI were performed; 33 participants had serial MRI, allowing calculation of atrophy rates. Genetic testing established mutation status. A generalized least squares regression model was used to compare serum NfL among symptomatic mutation carriers, presymptomatic carriers, and noncarriers, adjusting for age and sex. Spearman coefficients assessed associations between serum NfL and (1) estimated years to/from symptom onset (EYO), (2) cognitive measures, and (3) MRI measures of atrophy.Results:Nineteen of the asymptomatic participants were mutation carriers (mean EYO −9.6); 11 were noncarriers. Compared with noncarriers, serum NfL concentration was higher in both symptomatic (p < 0.0001) and presymptomatic mutation carriers (p = 0.007). Across all mutation carriers, serum NfL correlated with EYO (ρ = 0.81, p < 0.0001) and multiple cognitive and imaging measures, including Mini-Mental State Examination (ρ = −0.62, p = 0.0001), Clinical Dementia Rating Scale sum of boxes (ρ = 0.79, p < 0.0001), baseline brain volume (ρ = −0.62, p = 0.0002), and whole-brain atrophy rate (ρ = 0.53, p = 0.01).Conclusions:Serum NfL concentration is increased in FAD prior to symptom onset and correlates with measures of disease stage and severity. Serum NfL may thus be a feasible biomarker of early AD-related neurodegeneration.

Long-term episodic memory deficits in Alzheimer's disease (AD) are well characterised but, until recently, short-term memory (STM) function has attracted far less attention. We employed a recently-developed, delayed reproduction task which requires participants to reproduce precisely the remembered location of items they had seen only seconds previously. This paradigm provides not only a continuous measure of localization error in memory, but also an index of relational binding by determining the frequency with which an object is misplaced to the location of one of the other items held in memory. Such binding errors in STM have previously been found on this task to be sensitive to medial temporal lobe (MTL) damage in focal lesion cases. Twenty individuals with pathological mutations in presenilin 1 or amyloid precursor protein genes for familial Alzheimer's disease (FAD) were tested together with 62 healthy controls. Participants were assessed using the delayed reproduction memory task, a standard neuropsychological battery and structural MRI.Overall, FAD mutation carriers were worse than controls for object identity as well as in gross localization memory performance. Moreover, they showed greater misbinding of object identity and location than healthy controls. Thus they would often mislocalize a correctly-identified item to the location of one of the other items held in memory. Significantly, asymptomatic gene carriers – who performed similarly to healthy controls on standard neuropsychological tests – had a specific impairment in object-location binding, despite intact memory for object identity and location. Consistent with the hypothesis that the hippocampus is critically involved in relational binding regardless of memory duration, decreased hippocampal volume across FAD participants was significantly associated with deficits in object-location binding but not with recall precision for object identity or localization. Object-location binding may therefore provide a sensitive cognitive biomarker for MTL dysfunction in a range of diseases including AD.

Visual short term memory (STM) declines as people get older, but the nature of this deterioration is not well understood. We tested 139 healthy subjects (19–83 years) who were first required to identify a previously seen object and then report its location using a touchscreen. Results demonstrated an age-related decline in both object identification and localization. Deterioration in localization performance was apparent even when only 1 item had to be remembered, worsening disproportionately with increasing memory load. Thus, age-dependent memory degradation cannot be explained simply by a decrease in the number of items that can be held in visual STM but rather by the precision with which they are recalled. More important, there was no evidence for a significant decrease in object-location binding with increasing age. Thus, although precision for object identity and location declines with age, the ability to associate object identity to its location seems to remain unimpaired. As it has been reported that binding deficits in STM might be the first cognitive signs of early Alzheimer’s disease (AD), the finding that object-location binding processes are relatively intact with normal aging supports the possible suitability of using misbinding as an index measures for probing early diagnosis of AD.

SummaryBackgroundTests sensitive to presymptomatic changes in Alzheimer's disease could be valuable for clinical trials. Accelerated long-term forgetting—during which memory impairment becomes apparent over longer periods than usually assessed, despite normal performance on standard cognitive testing—has been identified in other temporal lobe disorders. We assessed whether accelerated long-term forgetting is a feature of presymptomatic autosomal dominant (familial) Alzheimer's disease, and whether there is an association between accelerated long-term forgetting and early subjective memory changes.MethodsThis was a cross-sectional study at the Dementia Research Centre, University College London (London, UK). Participants were recruited from a cohort of autosomal dominant Alzheimer's disease families already involved in research at University College London, and had to have a parent known to be affected by an autosomal dominant Alzheimer's disease mutation, and not report any current symptoms of cognitive decline. Accelerated long-term forgetting of three tasks (list, story, and figure recall) was assessed by comparing 7-day recall with initial learning and 30-min recall. 7-day recognition was also assessed. Subjective memory was assessed using the Everyday Memory Questionnaire. The primary outcome measure for each task was the proportion of material retained at 30 min that was recalled 7 days later (ie, 7-day recall divided by 30-min recall). We used linear regression to compare accelerated long-term forgetting scores between mutation carriers and non-carriers (adjusting for age, IQ, and test set) and, for mutation carriers, to assess whether there was an association between accelerated long-term forgetting and estimated years to symptom onset (EYO). Spearman's correlation was used to examine the association between accelerated long-term forgetting and subjective memory scores.FindingsBetween Feb 17, 2015 and March 30, 2016, we recruited 35 people. 21 participants were mutation carriers (mean EYO 7·2 years, SD 4·5). Across the three tasks, we detected no differences between carriers and non-carriers for initial learning or 30-min recall. The proportion of material recalled at 7 days was lower in carriers than non-carriers for list (estimated difference in mean for list recall −30·94 percentage points, 95% CI −45·16 to −16·73; p=0·0002), story (–20·10, −33·28 to −6·91; p=0·0048), and figure (–15·41, −26·88 to −3·93; p=0·012) recall. Accelerated long-term forgetting was greater in carriers nearer to their estimated age at onset (p≤0·01 for all three tests). Mutation carriers' 7-day recognition memory was also lower across all tasks (list [mean difference −5·80, 95% CI −9·96 to −2·47; p<0·01], story [–6·84, −10·94 to −3·37; p<0·01], and figure [–17·61, −27·68 to −7·72; p<0·01] recognition). Subjective memory scores were poorer in asymptomatic carriers compared with non-carriers (adjusted difference in means 7·88, 95% CI 1·36 to 14·41; p=0·016), and we found a correlation between accelerated long-term forgetting and s...

Background To investigate how serum neurofilament light (NfL) concentration changes through the course of disease in familial Alzheimer’s disease (FAD) and to assess when NfL concentration first increases. Methods NfL was measured using an ultrasensitive immunoassay in 117 serum samples from 61 individuals from families with PSEN1 or APP mutations in a longitudinal study (mean ± SD = 1.9 ± 1.1 visits/patient; inter-visit interval = 1.8 ± 1.1 years). The relationship between NfL concentration and estimated years to/from symptom onset (EYO) was modelled using linear regression, including all time points and robust standard errors to allow for repeated measurements, adjusting for age at visit and sex. Also, for the 27 participants who became symptomatic (during or before the study), NfL concentration was also modelled against known actual years to/from onset (AYO). Results There were 15 non-carriers and 46 mutation carriers (21 symptomatic; 25 presymptomatic). NfL concentration was increased ( p = 0.045) in mutation carriers compared with non-carriers 15 years prior to expected symptom onset, increasing progressively thereafter. There was a significant inter- and intra-individual variability in the longitudinal pattern of change. Modelling NfL for the 27 mutation carriers with known AYO also showed a progressive increase over time. Conclusions There is evidence that serum NfL is increased more than a decade before the onset of clinical symptoms in FAD and rises thereafter. While there is variability in change over time, both within and between individuals, and more work is needed to understand the sources of this variability, serum NfL remains a promising, accessible biomarker of early neurodegeneration in presymptomatic Alzheimer’s disease. Electronic supplementary material The online version of this article (10.1186/s13195-019-0472-5) contains supplementary material, which is available to authorized users.

Objective:To assess regional patterns of gray and white matter atrophy in familial Alzheimer disease (FAD) mutation carriers.Methods:A total of 192 participants with volumetric T1-weighted MRI, genotyping, and clinical diagnosis were available from the Dominantly Inherited Alzheimer Network. Of these, 69 were presymptomatic mutation carriers, 50 were symptomatic carriers (31 with Clinical Dementia Rating [CDR] = 0.5, 19 with CDR > 0.5), and 73 were noncarriers from the same families. Voxel-based morphometry was used to identify cross-sectional group differences in gray matter and white matter volume.Results:Significant differences in gray matter (p < 0.05, family-wise error–corrected) were observed between noncarriers and mildly symptomatic (CDR = 0.5) carriers in the thalamus and putamen, as well as in the temporal lobe, precuneus, and cingulate gyrus; the same pattern, but with more extensive changes, was seen in those with CDR > 0.5. Significant white matter differences between noncarriers and symptomatic carriers were observed in the cingulum and fornix; these form input and output connections to the medial temporal lobe, cingulate, and precuneus. No differences between noncarriers and presymptomatic carriers survived correction for multiple comparisons, but there was a trend for decreased gray matter in the thalamus for carriers closer to their estimated age at onset. There were no significant increases of gray or white matter in asymptomatic or symptomatic carriers compared to noncarriers.Conclusions:Atrophy in FAD is observed early, both in areas commonly associated with sporadic Alzheimer disease and also in the putamen and thalamus, 2 regions associated with early amyloid deposition in FAD mutation carriers.

Objective:To identify a cortical signature pattern of cortical thinning in familial Alzheimer disease (FAD) and assess its utility in detecting and tracking presymptomatic neurodegeneration.Methods:We recruited 43 FAD mutation carriers—36 PSEN1, 7 APP (20 symptomatic, 23 presymptomatic)—and 42 healthy controls to a longitudinal clinical and MRI study. T1-weighted MRI scans were acquired at baseline in all participants; 55 individuals (33 mutation carriers; 22 controls) had multiple (mean 2.9) follow-up scans approximately annually. Cortical thickness was measured using FreeSurfer. A cortical thinning signature was identified from symptomatic FAD participants. We then examined cortical thickness changes in this signature region in presymptomatic carriers and assessed associations with cognitive performance.Results:The cortical signature included 6 regions: entorhinal cortex, inferior parietal cortex, precuneus, superior parietal cortex, superior frontal cortex, and supramarginal gyrus. There were significant differences in mean cortical signature thickness between mutation carriers and controls 3 years before predicted symptom onset. The earliest significant difference in a single region, detectable 4 years preonset, was in the precuneus. Rate of change in cortical thickness became significantly different in the cortical signature at 5 years before predicted onset, and in the precuneus at 8 years preonset. Baseline mean signature thickness predicted rate of subsequent thinning and correlated with presymptomatic cognitive change.Conclusions:The FAD cortical signature appears to be similar to that described for sporadic AD. All component regions showed significant presymptomatic thinning. A composite signature may provide more robust results than a single region and have utility as an outcome measure in presymptomatic trials.