Biomarkers in preclinical familial Alzheimer disease

Background: Alzheimer disease (AD) is a neurodegenerative disorder, characterized by the accumulation of b-amyloid (Ab) plaques and tangles consisting of hyperphosphorylated tauprotein in the brain. It accounts for 60-70% of dementia cases, making it the most common cause of dementia. In rare cases the disease is inherited in autosomal dominant early onset form caused by mutations in APP, PSEN1 or PSEN2. These familial forms of AD (FAD) allow for studies of the long preclinical stage of the disease and may thereby address unanswered questions about the natural history of AD which can be used to develop optimal tools for early diagnosis and for monitoring treatment response, as well as finding new possible treatment targets. To this end we conducted a prospective study, involving repeated clinical evaluations and collection of biomarkers from asymptomatic carriers of mutations leading to FAD with non-carriers (NC) from the same families as controls. The asymptomatic mutation carriers (MC) are good representatives of the preclinical stage of AD as they will develop symptoms of the disease in the future at an age which can be estimated based on the age at symptom onset in their family members who have already become symptomatic. Aims: To map biomarker changes in preclinical AD, as well as their temporal trajectories and sequence, through repeated collection and analysis of biomarkers in asymptomatic FAD MC and NC. Results: There were significant differences in the levels of the cerebrospinal fluid (CSF) biomarkers Ab42, total-tau protein (t-tau) and phosphorylated tau-protein (p-tau), as well as in the Ab42/p-tau ratio when comparing MC to NC, more than 7 years before the expected onset of symptoms in the MC. Ab42 and the Ab42/p-tau ratio were lower in MC than NC, while ttau and p-tau were higher in MC than NC. There was a trend of Ab42 and the Ab42/p-tau ratio decreasing as the onset of symptoms approached in MC, while t-tau and p-tau showed a trend of increasing with approaching symptom onset. On structural magnetic resonance imaging (MRI) of the brain, the MC had reduced volume of the left precuneus, left superior temporal gyrus and left fusiform gyrus, 9 years before the expected symptom onset. However, there was no observable decline in grey matter thickness or volume as the onset of symptoms approached, making the temporality of these changes difficult to assess. In the same group of subjects there was no significant difference on neuropsychological assessments between MC and NC, but a trend of poorer results was observed in the MC regarding immediate memory, episodic memory and attention/executive function. The CSF biomarkers YKL-40, reflecting glial activation, and neurogranin, a synaptic marker, were compared between asymptomatic MC and NC and found not to differ between the groups. A longitudinal study of changes in YKL-40 and neurogranin with approaching symptom onset was also conducted, revealing an increase in YKL-40 in both MC and NC as the age of symptom onset drew nearer, with a steeper increase in MC than NC. No such correlation to years to symptom onset was found for neurogranin. The APP processing products sAPPa, sAPPb, Ab42, Ab40 and Ab38 were compared both between the MC group as a whole and the NC and between subgroups of MC carrying specific mutations and the NC. The whole MC group had lower levels of Ab42, Ab40 and Ab38, as well as a lower Ab42/Ab40 ratio than NC. No significant correlation was observed between any of the aforementioned APP processing products and years to symptom onset in MC. When comparing different MC subgroups to each other, the whole MC group and the NC group, some mutation specific differences in the levels of the APP processing products and their temporality emerged. During the biomarker studies presented above the presence of a statistical outlier came to our attention, an MC carrying the PSEN1 H163Y mutation who had passed the age at symptom onset in his family but displayed no cognitive decline and no abnormalities in CSF biomarkers. This individual had been followed-up within the FAD study for 22 years and had opted for a presymptomatic genetic test, making his mutation status known to him and to the researchers involved in the study. His clinical case was characterized in paper III, with his brother serving as a control. The brother was only one year older than the outlier but had already passed away from AD at the end of the follow-up time, having displayed typical signs and symptoms of the disease in the preceding years. Conclusions: The study revealed early preclinical changes in CSF biomarkers, reflecting Ab aggregation, glial activation, tau phosphorylation and neurodegeneration, as well as loss of volume in specific areas in the left hemisphere of the brain on structural MRI in asymptomatic carriers of FAD mutations. When assessing the temporality of specific biomarkers in the CSF, Ab42 and the Ab42/p-tau ratio seemed to decrease with approaching symptom onset, while ttau and p-tau increased as symptom onset drew nearer. These results are based on crosssectional data, but only longitudinal studies can properly assess temporal changes, as we did for CSF neurogranin and YKL-40 (with YKL-40 increasing at a faster rate in MC than in NC). However, the overall results give an important indication of the true nature of these preclinical temporal changes. We also observed mutation specific differences in APP processing products in the CSF and characterized a case of reduced penetrance of the PSEN1 H163Y mutation. In conclusion, the study sheds light on preclinical biomarker changes in FAD and the possible sequence of these changes. It also emphasizes the differences in phenotype between specific FAD mutations and the presence of reduced penetrance which affects the estimation of symptom onset in these families and has an impact on genetic counseling and possibly on the design of clinical trials in this population

Early astrocytosis in autosomal dominant Alzheimer's disease measured in vivo by multi-tracer positron emission tomography

Studying autosomal dominant Alzheimer's disease (ADAD), caused by gene mutations yielding nearly complete penetrance and a distinct age of symptom onset, allows investigation of presymptomatic pathological processes that can identify a therapeutic window for disease-modifying therapies. Astrocyte activation may occur in presymptomatic Alzheimer's disease (AD) because reactive astrocytes surround beta-amyloid (A beta) plaques in autopsy brain tissue. Positron emission tomography was performed to investigate fibrillar A beta, astrocytosis and cerebral glucose metabolism with the radiotracers C-11-Pittsburgh compound-B (PIB), C-11-deuterium-L-deprenyl (DED) and F-18-fluorodeoxyglucose (FDG) respectively in presymptomatic and symptomatic ADAD participants (n = 21), patients with mild cognitive impairment (n = 11) and sporadic AD (n = 7). Multivariate analysis using the combined data from all radiotracers clearly separated the different groups along the first and second principal components according to increased PIB retention/decreased FDG uptake (component 1) and increased DED binding (component 2). Presymptomatic ADAD mutation carriers showed significantly higher PIB retention than non-carriers in all brain regions except the hippocampus. DED binding was highest in presymptomatic ADAD mutation carriers. This suggests that non-fibrillar A beta or early stage plaque depostion might interact with inflammatory responses indicating astrocytosis as an early contributory driving force in AD pathology. The novelty of this finding will be investigated in longitudinal follow-up studies

Early astrocytosis in autosomal dominant Alzheimer's disease measured in vivo by multi-tracer positron emission tomography

Studying autosomal dominant Alzheimer's disease (ADAD), caused by gene mutations yielding nearly complete penetrance and a distinct age of symptom onset, allows investigation of presymptomatic pathological processes that can identify a therapeutic window for disease-modifying therapies. Astrocyte activation may occur in presymptomatic Alzheimer's disease (AD) because reactive astrocytes surround beta-amyloid (A beta) plaques in autopsy brain tissue. Positron emission tomography was performed to investigate fibrillar A beta, astrocytosis and cerebral glucose metabolism with the radiotracers C-11-Pittsburgh compound-B (PIB), C-11-deuterium-L-deprenyl (DED) and F-18-fluorodeoxyglucose (FDG) respectively in presymptomatic and symptomatic ADAD participants (n = 21), patients with mild cognitive impairment (n = 11) and sporadic AD (n = 7). Multivariate analysis using the combined data from all radiotracers clearly separated the different groups along the first and second principal components according to increased PIB retention/decreased FDG uptake (component 1) and increased DED binding (component 2). Presymptomatic ADAD mutation carriers showed significantly higher PIB retention than non-carriers in all brain regions except the hippocampus. DED binding was highest in presymptomatic ADAD mutation carriers. This suggests that non-fibrillar A beta or early stage plaque depostion might interact with inflammatory responses indicating astrocytosis as an early contributory driving force in AD pathology. The novelty of this finding will be investigated in longitudinal follow-up studies

Identification and description of three families with familial Alzheimer disease that segregate variants in the SORL1 gene

Abstract Alzheimer disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. The majority of AD cases are sporadic, while up to 5% are families with an early onset AD (EOAD). Mutations in one of the three genes: amyloid beta precursor protein (APP), presenilin 1 (PSEN1) or presenilin 2 (PSEN2) can be disease causing. However, most EOAD families do not carry mutations in any of these three genes, and candidate genes, such as the sortilin-related receptor 1 (SORL1), have been suggested to be potentially causative. To identify AD causative variants, we performed whole-exome sequencing on five individuals from a family with EOAD and a missense variant, p.Arg1303Cys (c.3907C > T) was identified in SORL1 which segregated with disease and was further characterized with immunohistochemistry on two post mortem autopsy cases from the same family. In a targeted re-sequencing effort on independent index patients from 35 EOAD-families, a second SORL1 variant, c.3050-2A > G, was found which segregated with the disease in 3 affected and was absent in one unaffected family member. The c.3050-2A > G variant is located two nucleotides upstream of exon 22 and was shown to cause exon 22 skipping, resulting in a deletion of amino acids Gly1017- Glu1074 of SORL1. Furthermore, a third SORL1 variant, c.5195G > C, recently identified in a Swedish case control cohort included in the European Early-Onset Dementia (EU EOD) consortium study, was detected in two affected siblings in a third family with familial EOAD. The finding of three SORL1-variants that segregate with disease in three separate families with EOAD supports the involvement of SORL1 in AD pathology. The cause of these rare monogenic forms of EOAD has proven difficult to find and the use of exome and genome sequencing may be a successful route to target them

Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease

The relationships between pathophysiological processes in Alzheimer's disease remain largely unclear. In a longitudinal, multitracer PET study, Rodriguez-Vieitez et al. reveal that progression of autosomal dominant Alzheimer's disease is accompanied by prominent early and then declining astrocytosis, increasing amyloid plaque deposition and decreasing glucose metabolism. Astrocyte activation may initiate Alzheimer pathology.See Schott and Fox (doi: 10.1093/brain/awv405) for a scientific commentary on this article. The relationships between pathophysiological processes in Alzheimer's disease remain largely unclear. In a longitudinal, multitracer PET study, Rodriguez-Vieitez et al. reveal that progression of autosomal dominant Alzheimer's disease is accompanied by prominent early and then declining astrocytosis, increasing amyloid plaque deposition and decreasing glucose metabolism. Astrocyte activation may initiate Alzheimer pathology.Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-beta, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer C-11-deuterium-L-deprenyl), fibrillar amyloid-beta plaque deposition (C-11-Pittsburgh compound B), and glucose metabolism (F-18-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 +/- 10.3 years old) and non-carriers (n = 16; 51.1 +/- 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 +/- 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 +/- 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into C-11-Pittsburgh compound B-positive (n = 13; 62.0 +/- 6.4; seven male) and C-11-Pittsburgh compound B-negative (n = 4; 61.8 +/- 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants underwent clinical and imaging follow-up examinations after 2.8 +/- 0.6 years. By using linear mixed-effects models, fibrillar amyloid-beta plaque deposition was first observed in the striatum of presymptomatic autosomal dominant Alzheimer's disease carriers from 17 years before expected symptom onset; at about the same time, astrocytosis was significantly elevated and then steadily declined. Diverging from the astrocytosis pattern, amyloid-beta plaque deposition increased with disease progression. Glucose metabolism steadily declined from 10 years after initial amyloid-beta plaque deposition. Patients with sporadic mild cognitive impairment who were C-11-Pittsburgh compound B-positive at baseline showed increasing amyloid-beta plaque deposition and decreasing glucose metabolism but, in contrast to autosomal dominant Alzheimer's disease carriers, there was no significant longitudinal decline in astrocytosis over time. The prominent initially high and then declining astrocytosis in autosomal dominant Alzheimer's disease carriers, contrasting with the increasing amyloid-beta plaque load during disease progression, suggests astrocyte activation is implicated in the early stages of Alzheimer's disease pathology