Inherited Alzheimer Disease Research Articles

Association of Longitudinal Changes in Cerebrospinal Fluid Total Tau and Phosphorylated Tau 181 and Brain Atrophy With Disease Progression in Patients With Alzheimer Disease

The amyloid/tau/neurodegeneration (A/T/N) framework uses cerebrospinal fluid (CSF) levels of total tau (tTau) as a marker of neurodegeneration and CSF levels of phosphorylated tau 181 (pTau181) as a marker of tau tangles. However, it is unclear whether CSF levels of tTau and pTau181 have similar or different trajectories over the course of Alzheimer disease. To examine the rates of change in CSF levels of tTau and pTau181 across the Alzheimer disease course and how the rates of change are associated with brain atrophy as measured by magnetic resonance imaging. This cohort study was set in tertiary research clinics. Each participant was a member of a pedigree with a known mutation for dominantly inherited Alzheimer disease. Participants were divided into 3 groups on the basis of the presence of a mutation and their Clinical Dementia Rating score. Data analysis was performed in June 2019. Rates of change of CSF tTau and pTau181 levels and their association with the rate of change of brain volume. Data from 465 participants (283 mutation carriers and 182 noncarriers) were analyzed. The mean (SD) age of the cohort was 37.8 (11.3) years, and 262 (56.3%) were women. The mean (SD) follow-up duration was 2.7 (1.5) years. Two or more longitudinal CSF and magnetic resonance imaging assessments were available for 160 and 247 participants, respectively. Sixty-five percent of mutation carriers (183) did not have symptoms at baseline (Clinical Dementia Rating score, 0). For mutation carriers, the annual rates of change for CSF tTau and pTau181 became significantly different from 0 approximately 10 years before the estimated year of onset (mean [SE] rates of change, 5.5 [2.8] for tTau [P = .05] and 0.7 [0.3] for pTau 181 [P = .04]) and 15 years before onset (mean [SE] rates of change, 5.4 [3.9] for tTau [P = .17] and 1.1 [0.5] for pTau181 [P = .03]), respectively. The rate of change of pTau181 was positive and increased at the early stages of the disease, showing a positive rate of change starting at 15 estimated years before onset until 5 estimated years before onset (mean [SE], 0.4 [0.3]), followed by a positive but decreasing rate of change at year 0 (mean [SE], 0.1 [0.3]) and then negative rates of change at 5 years (mean [SE], -0.3 [0.4]) and 10 years (mean [SE], -0.6 [0.6]) after symptom onset. In individuals without symptoms (Clinical Dementia Rating score, 0), the rates of change of CSF tTau and pTau181 were negatively associated with brain atrophy (high rates of change in CSF measures were associated with low rates of change in brain volume in asymptomatic stages). After symptom onset (Clinical Dementia Rating score, >0), an increased rate of brain atrophy was not associated with rates of change of levels of both CSF tTau and pTau181. These findings suggest that CSF tTau and pTau181 may have different associations with brain atrophy across the disease time course. These results have implications for understanding the dynamics of disease pathobiology and interpreting neuronal injury biomarker concentrations in response to Alzheimer disease progression and disease-modifying therapies.

Understanding the Amyloid Hypothesis in Alzheimer's Disease.

The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer's disease (IAD). However, despite the neuropathological overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, we suggested that amyloid-β (Aβ) peptides production and AP formation is a physiological aging process resulting from a systemic age-related decrease in the efficiency of the proteins catabolism/clearance machinery. In this pathogenetic model Aβ peptides act as neurotoxic molecules, but only above a critical concentration [Aβ]c. A threshold mechanism triggers IAD/NIAD onset only when [Aβ]≥[Aβ]c. In this process, APOE modifies [Aβ]c threshold in an isoform-specific way. Consequently, all factors influencing Aβ anabolism, such as amyloid beta precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) gene mutations, and/or Aβ catabolism/clearance could contribute to exceed the threshold [Aβ]c, being characteristic of each individual. In this model, AP formation does not depend on [Aβ]c. The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be observed in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD.

Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease.

To assess the onset, sequence, and rate of progression of comprehensive biomarker and clinical measures across the spectrum of Alzheimer disease (AD) using the Dominantly Inherited Alzheimer Network (DIAN) study and compare these to cross-sectional estimates. We conducted longitudinal clinical, cognitive, CSF, and neuroimaging assessments (mean of 2.7 [±1.1] visits) in 217 DIAN participants. Linear mixed effects models were used to assess changes in each measure relative to individuals' estimated years to symptom onset and to compare mutation carriers and noncarriers. Longitudinal β-amyloid measures changed first (starting 25 years before estimated symptom onset), followed by declines in measures of cortical metabolism (approximately 7-10 years later), then cognition and hippocampal atrophy (approximately 20 years later). There were significant differences in the estimates of CSF p-tau181 and tau, with elevations from cross-sectional estimates preceding longitudinal estimates by over 10 years; further, longitudinal estimates identified a significant decline in CSF p-tau181 near symptom onset as opposed to continued elevations. These longitudinal estimates clarify the sequence and temporal dynamics of presymptomatic pathologic changes in autosomal dominant AD, information critical to a better understanding of the disease. The pattern of biomarker changes identified here also suggests that once β-amyloidosis begins, additional pathologies may begin to develop less than 10 years later, but more than 15 years before symptom onset, an important consideration for interventions meant to alter the disease course.

Seizures in dominantly inherited Alzheimer disease.

To assess seizure frequency in a large French cohort of autosomal dominant early-onset Alzheimer disease (ADEOAD) and to determine possible correlations with causative mutations. A national multicentric study was performed in patients with ADEOAD harboring a pathogenic mutation within PSEN1, PSEN2, APP, or a duplication of APP, and a minimal follow-up of 5 years. Clinical, EEG, and imaging data were systematically recorded. We included 132 patients from 77 families: 94 PSEN1 mutation carriers (MCs), 16 APP duplication carriers, 15 APP MCs, and 7 PSEN2 MCs. Seizure frequency was 47.7% after a mean follow-up of 8.4 years (range 5-25). After 5-year follow-up and using a Cox model analysis, the percentages of patients with seizures were respectively 19.1% (10.8%-26.7%) for PSEN1, 28.6% (0%-55.3%) for PSEN2, 31.2% (4.3%-50.6%) for APP duplications, and no patient for APP mutation. APP duplication carriers showed a significantly increased seizure risk compared to both APP MCs (hazard ratio [HR] = 5.55 [95% confidence interval 1.87-16.44]) and PSEN1 MCs (HR = 4.46 [2.11-9.44]). Among all PSEN1 mutations, those within the domains of protein hydrophilic I, transmembrane II (TM-II), TM-III, TM-IV, and TM-VII were associated with a significant increase in seizure frequency compared to other domains (HR = 4.53 [1.93-10.65], p = 0.0005). Seizures are a common feature of ADEOAD. In this population, risk was significantly higher in the APP duplication group than in all other groups. Within PSEN1, 5 specific domains were associated with a higher seizure risk indicating specific correlations between causative mutation and seizures.

The 7th Leonard Berg Symposium, Part 3

One question that pervaded the 7th Leonard Berg Symposium is whether dominantly inherited AD really is the same disease as the common late-onset forms that afflict some 35 million people around the globe, according to a recent report. “Can we generalize from FAD to all AD?” asked Martin Rossor of University College, London. The question is important in part because the interest drug developers take in testing prevention in families with strong AD genetics hinges on their confidence that success in the few will translate into success in the many. In private, some industry leaders express doubt about that point, and some companies exclude eFAD families from their trials for this reason. That eFAD indeed models late-onset AD (LOAD) to a great extent, if not in all aspects, is a premise of DIAN, and the comparison of DIAN and ADNI data may settle the issue definitively. In the meantime, scientists at the Symposium discussed what clues they have so far. See below for talks taking stock of LOAD/eFAD similarities and differences in the clinic, pathology, biochemistry, genetics, and imaging. First, a word about nomenclature. Autosomaldominant AD is the form in which a child of an affected parent faces 50-50 odds of inheriting a pathogenic mutation in either the AβPP or the presenilin 1 or 2 genes. It is variously referred to as “familial” or “FAD,” “earlyonset” or “EOAD,” “early-onset familial” or “eFAD.” Strictly speaking, none of the terms is interchangeable. Familial AD often is merely a clustering, not a Mendelian autosomal-dominant inheritance pattern; early-onset AD is often sporadic in the sense that neither affected relatives, much less a gene mutation, is known. The term used in the Alzforum section on this set of aggressive forms of AD – eFAD – does not quite catch all people it means to include, either, because recently, autosomal-dominant pathogenic presenilin mutations were spotted in some rare families who get this form of AD in their seventies, i.e., with a late onset [1, 2]. The WashU researchers sidestepped this confusing nameology by using yet another term: “dominantly inherited Alzheimer disease.” DIAD conveniently stands opposite LOAD and echoes DIAN, making DIAN the network for the DIAD crowd. At the Leonard Berg Symposium, speakers stressed that DIAD/eFAD overall appears to model LOAD quite closely. However, it is not a carbon copy, and for the sake of discussion, the differences got center stage for a session. DIAD is heterogeneous. The way people decline can vary a bit from person to person, said Rossor, whose center follows members of 10 families with AβPP mutations and 34 families with presenilin 1 mutations. Certain clinical differences do track with genetic ones. For example, people who get DIAD because their AβPP gene is duplicated frequently have seizures, brain hemorrhages, and white matter changes. In these extremely rare families, some affected relatives start having seizures when they are teenagers, and depression and then dementia follow within a decade thereafter. With presenilin, some 175 different mutations are published, but clinicians have no comprehensive description of how their preclinical period unfolds. DIAN is aiming to accomplish that and in the process may match up genotypes to phenotypes. Based on what clinicians observe, it is already clear that some presenilin cases come with added signs that are atypical for AD.