Alzheimer's Disease Mutation Carriers Research Articles

Plasma and cerebrospinal fluid glial fibrillary acidic protein levels in adults with Down syndrome: a longitudinal cohort study.

The diagnosis of symptomatic Alzheimer's disease is a clinical challenge in adults with Down syndrome. Blood biomarkers would be of particular clinical importance in this population. The astrocytic Glial Fibrillary Acidic Protein (GFAP) is a marker of astrogliosis associated with amyloid pathology, but its longitudinal changes, association with other biomarkers and cognitive performance have not been studied in individuals with Down syndrome. We performed a three-centre study of adults with Down syndrome, autosomal dominant Alzheimer's disease and euploid individuals enrolled in Hospital Sant Pau, Barcelona (Spain), Hospital Clinic, Barcelona (Spain) and Ludwig-Maximilians-Universität, Munich (Germany). Cerebrospinal fluid (CSF) and plasma GFAP concentrations were quantified using Simoa. A subset of participants had PET 18F-fluorodeoxyglucose, amyloid tracers and MRI measurements. This study included 997 individuals, 585 participants with Down syndrome, 61 Familial Alzheimer's disease mutation carriers and 351 euploid individuals along the Alzheimer's disease continuum, recruited between November 2008 and May 2022. Participants with Down syndrome were clinically classified at baseline as asymptomatic, prodromal Alzheimer's disease and Alzheimer's disease dementia. Plasma GFAP levels were significantly increased in prodromal and Alzheimer's disease dementia compared to asymptomatic individuals and increased in parallel to CSF Aβ changes, ten years prior to amyloid PET positivity. Plasma GFAP presented the highest diagnostic performance to discriminate symptomatic from asymptomatic groups (AUC=0.93, 95% CI 0.9-0.95) and its concentrations were significantly higher in progressors vs non-progressors (p<0.001), showing an increase of 19.8% (11.8-33.0) per year in participants with dementia. Finally, plasma GFAP levels were highly correlated with cortical thinning and brain amyloid pathology. Our findings support the utility of plasma GFAP as a biomarker of Alzheimer's disease in adults with Down syndrome, with possible applications in clinical practice and clinical trials. AC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, Alzheimer's Association, National Institute for Health Research, EU Joint Programme-Neurodegenerative Disease Research, Alzheimer's Society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens, Fundación Tatiana Pérez de Guzmán el Bueno & European Union's Horizon 2020 und Umwelteinflüssen auf die menschliche Gesundheit.

Brain network decoupling with increased serum neurofilament and reduced cognitive function in Alzheimer's disease.

Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer's disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer's disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer's disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer's disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer's disease.

Translating network activity in an Alzheimer mouse model to human Alzheimer's disease mutation carriers

AbstractBackgroundAlzheimer’s disease (AD) mouse models allow for the identification of cellular and molecular processes underlying neuronal network imbalance. In order to interpret these processes in a disease context, we need to link network changes in AD animals to those in human patients. Brain oscillations reflect neuronal network (im)balance and offer a tool to translate findings from mice to men. In this preliminary study, we investigate and compare cortical and hippocampal oscillatory activity using magnetoencephalography (MEG) in human patients and longitudinal electrophysiology recordings in AD mice.MethodsSource reconstructed resting state whole‐brain MEG of ten APP and PSEN1 mutation carriers and ten age‐ and gender‐matched control subjects were acquired. Carriers did not show objectively impaired cognitive functioning on any of the composite scores after extensive neuropsychological testing. Longitudinal local field potential recordings were obtained by implanted electrodes in APP/PS1 transgenic and wildtype controls from 3 until 10 months of age in different brain regions of the left hemisphere: hippocampus, prefrontal and parietal cortex. MEG analyses were constrained to similar brain regions. We estimated peak frequency, total (absolute broadband) and relative power across canonical frequency bands and compared these between human or mice mutation carriers and controls.ResultsHuman APP and PSEN1 mutation carriers showed lower peak frequency in the hippocampus and lower relative alpha 2 power in the precuneus and frontal cortex compared to controls (Fig1.). APP/PS1 mice also showed specific network alterations compared to wildtype control mice, but these seem to have more faster oscillations instead.ConclusionIn cognitively unimpaired human APP and PS1 mutation carriers we find oscillatory activity changes in the cortex and hippocampus, indicating network imbalance. However, opposite network changes are observed in the APP/PS1 AD mouse model compared to human mutation carriers using spectral measures. Future studies should explore other measures of network imbalance to identify potential cross‐species mechanistic links of early stage AD.

Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer's disease.

IntroductionAsymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD‐MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD‐MC and could help predict risk for dementia during trial enrollment.MethodsWe created a dementia risk score by entering standardized gray‐matter volumes from 231 DIAD‐MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD‐MC followed longitudinally.ResultsOur risk score separated asymptomatic versus demented DIAD‐MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%–98.2%]) and improved prediction beyond established methods based on familial age of onset.DiscussionIndividualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD‐MC participants for prevention trials.

BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer's disease.

SEE ROGAEVA AND SCHMITT-ULMS DOI101093/AWW201 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-β-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-β in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) ε4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val66 homozygotes, 48 Met66 carriers). Among preclinical mutation carriers, Met66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val66 homozygotes. Cortical amyloid-β and cerebrospinal fluid amyloid-β42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val66 homozygotes and Met66 carriers. There was an effect of APOE on amyloid-β levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-β on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-β in autosomal dominant Alzheimer's disease.

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

Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-β, 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 (11)C-deuterium-L-deprenyl), fibrillar amyloid-β plaque deposition ((11)C-Pittsburgh compound B), and glucose metabolism ((18)F-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 (11)C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and (11)C-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-β 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-β plaque deposition increased with disease progression. Glucose metabolism steadily declined from 10 years after initial amyloid-β plaque deposition. Patients with sporadic mild cognitive impairment who were (11)C-Pittsburgh compound B-positive at baseline showed increasing amyloid-β 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-β plaque load during disease progression, suggests astrocyte activation is implicated in the early stages of Alzheimer's disease pathology.

Early behavioural changes in familial Alzheimer's disease in the Dominantly Inherited Alzheimer Network.

Prior studies indicate psychiatric symptoms such as depression, apathy and anxiety are risk factors for or prodromal symptoms of incipient Alzheimer's disease. The study of persons at 50% risk for inheriting autosomal dominant Alzheimer's disease mutations allows characterization of these symptoms before progressive decline in a population destined to develop illness. We sought to characterize early behavioural features in carriers of autosomal dominant Alzheimer's disease mutations. Two hundred and sixty-one persons unaware of their mutation status enrolled in the Dominantly Inherited Alzheimer Network, a study of persons with or at-risk for autosomal dominant Alzheimer's disease, were evaluated with the Neuropsychiatric Inventory-Questionnaire, the 15-item Geriatric Depression Scale and the Clinical Dementia Rating Scale (CDR). Ninety-seven asymptomatic (CDR = 0), 25 mildly symptomatic (CDR = 0.5), and 33 overtly affected (CDR > 0.5) autosomal dominant Alzheimer's disease mutation carriers were compared to 106 non-carriers with regard to frequency of behavioural symptoms on the Neuropsychiatric Inventory-Questionnaire and severity of depressive symptoms on the Geriatric Depression Scale using generalized linear regression models with appropriate distributions and link functions. Results from the adjusted analyses indicated that depressive symptoms on the Neuropsychiatric Inventory-Questionnaire were less common in cognitively asymptomatic mutation carriers than in non-carriers (5% versus 17%, P = 0.014) and the odds of experiencing at least one behavioural sign in cognitively asymptomatic mutation carriers was lower than in non-carriers (odds ratio = 0.50, 95% confidence interval: 0.26-0.98, P = 0.042). Depression (56% versus 17%, P = 0.0003), apathy (40% versus 4%, P < 0.0001), disinhibition (16% versus 2%, P = 0.009), irritability (48% versus 9%, P = 0.0001), sleep changes (28% versus 7%, P = 0.003), and agitation (24% versus 6%, P = 0.008) were more common and the degree of self-rated depression more severe (mean Geriatric Depression Scale score of 2.8 versus 1.4, P = 0.006) in mildly symptomatic mutation carriers relative to non-carriers. Anxiety, appetite changes, delusions, and repetitive motor activity were additionally more common in overtly impaired mutation carriers. Similar to studies of late-onset Alzheimer's disease, we demonstrated increased rates of depression, apathy, and other behavioural symptoms in the mildly symptomatic, prodromal phase of autosomal dominant Alzheimer's disease that increased with disease severity. We did not identify any increased psychopathology in mutation carriers over non-carriers during the presymptomatic stage, suggesting these symptoms result when a threshold of neurodegeneration is reached rather than as life-long qualities. Unexpectedly, we found lower rates of depressive symptoms in cognitively asymptomatic mutation carriers.

The Alzheimer's prevention initiative composite cognitive test score: sample size estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers.

To identify a cognitive composite that is sensitive to tracking preclinical Alzheimer's disease decline to be used as a primary end point in treatment trials. We capitalized on longitudinal data collected from 1995 to 2010 from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the world's largest known early-onset autosomal dominant Alzheimer's disease kindred to identify a composite cognitive test with the greatest statistical power to track preclinical Alzheimer's disease decline and estimate the number of carriers age 30 years and older needed to detect a treatment effect in the Alzheimer's Prevention Initiative's (API) preclinical Alzheimer's disease treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of 1 to 7 cognitive tests/subtests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a 2- and 5-year follow-up period (n = 78 and 57), using data from noncarriers (n = 31 and 56) during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top-performing combinations, and representation of relevant cognitive domains. The optimal test combination included Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Recall, CERAD Boston Naming Test (high frequency items), Mini-Mental State Examination (MMSE) Orientation to Time, CERAD Constructional Praxis, and Raven's Progressive Matrices (Set A), with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR = 0.38) or the entire CERAD-Col battery (MSDR = 0.76). A sample size of 75 cognitively normal PSEN1 E280A mutation carriers aged 30 years and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, P = .05). We have identified a composite cognitive test score representing multiple cognitive domains that, compared to the most sensitive single test item, has improved power to track preclinical Alzheimer's disease decline in autosomal dominant Alzheimer's disease mutation carriers and to evaluate preclinical Alzheimer's disease treatments. This API composite cognitive test score will be used as the primary end point in the first API trial in cognitively unimpaired autosomal dominant Alzheimer's disease carriers within 15 years of their estimated age at clinical onset. We have independently confirmed our findings in a separate cohort of cognitively healthy older adults who progressed to the clinical stages of late-onset Alzheimer's disease, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytic approaches.

Decreased Expression of Peptidase Inhibitors in Peripheral Blood from Familial Alzheimer's Disease Mutation Carriers (S34.004)

Decreased Expression of Peptidase Inhibitors in Peripheral Blood from Familial Alzheimer's Disease Mutation Carriers (S34.004)

P1‐015: Brain and hippocampal rates of atrophy in familial Alzheimer's disease mutation carriers: Preliminary findings from the DIAN study

The Dominantly Inherited Alzheimer Network (http://dian-info.org/) study is an international clinical, biomarker and multi-modality imaging study of individuals at risk for autosomal dominant Alzheimer's disease and those already mildly affected. This prospective study of these individuals provides an opportunity to follow these individuals through different stages of the disease process, starting several years before symptoms are evident. We report here the first longitudinal analyses of cerebral and hippocampal atrophy rates from the DIAN cohort. All DIAN participants have T1-weighted volumetric MRI scanning at baseline. We analysed data from the first 22 participants with a follow-up MRI scan (mean ± sd interval 12.7 ± 0.9 months). Seventeen subjects were symptomatic mutation carriers (sMut+) with Clinical Dementia Rating (CDR) scores >0 aged 46.4 ± 9.6 years; three were asymptomatic carriers (aMut+) with CDR = 0; and two were non-carriers (NC). The aMut+ and NC were combined into one group for this initial analysis (age: 34.5 ± 5.4 years). The whole brain and hippocampi were first delineated using an automated procedure. Annualized atrophy rates were measured by volumetric difference as well as the Boundary Shift Integral (BSI). Two sample t-tests assuming unequal variances were performed between the annualized atrophy rates of the sMut+ group and the combined NC/aMut+ group. Brain BSI atrophy rates were higher (see Table) in the symptomatic subjects (1.9% vs. 0%/year; P = 0.003). However, the difference in hippocampal atrophy rates was not statistically significant (2.5% vs. 0.5%/year; P = 0.057 for volumetric). Initial analysis of atrophy rates from this cohort indicates that brain atrophy rates are higher in symptomatic mutation carriers than in asymptomatic carriers or non-carriers. The lack of a detectable difference in hippocampal atrophy rates may reflect the small sample size and that these preliminary analyses included presymptomatic mutation carriers in the control group who may have already had increasing rates of hippocampal atrophy. Over 200 subjects will be followed longitudinally, so as more data are acquired, we will separately analyze atrophy rates in asymptomatic carriers and non-mutation carriers, estimate sample sizes for trials and assess the relationship between atrophy rates and symptom onset.

IC‐P‐138: Brain and hippocampal rates of atrophy in familial Alzheimer's disease mutation carriers: Preliminary findings from the DIAN study

IC‐P‐138: Brain and hippocampal rates of atrophy in familial Alzheimer's disease mutation carriers: Preliminary findings from the DIAN study

Peripheral white blood cell count may be diminished in familial Alzheimer's disease mutation carriers

Peripheral white blood cell count may be diminished in familial Alzheimer's disease mutation carriers

Increased fMRI signal with age in familial Alzheimer's disease mutation carriers

Although many Alzheimer's disease (AD) patients have a family history of the disease, it is rarely inherited in a predictable way. Functional magnetic resonance imaging (fMRI) studies of nondemented adults carrying familial AD mutations provide an opportunity to prospectively identify brain differences associated with early AD-related changes. We compared fMRI activity of 18 nondemented autosomal dominant AD mutation carriers with fMRI activity in eight of their noncarrier relatives as they performed a novelty encoding task in which they viewed novel and repeated images. Because age of disease onset is relatively consistent within families, we also correlated fMRI activity with subjects' distance from the median age of diagnosis for their family. Mutation carriers did not show significantly different voxelwise fMRI activity from noncarriers as a group. However, as they approached their family age of disease diagnosis, only mutation carriers showed increased fMRI activity in the fusiform and middle temporal gyri. This suggests that during novelty encoding, increased fMRI activity in the temporal lobe may relate to incipient AD processes.

Increased fMRI Activity with Age in Left Temporal Lobe of Familial Alzheimer's Disease Mutation Carriers

regard to APOE-related volumetric changes in mild cognitive impairment (MCI) and normal aging. The MTL is the earliest site of AD pathology, and autopsy studies have demonstrated that MTL pathophysiological changes occur in AD prodromal stages. Thus, we examined for APOE genotypic differences in cortical thickness in normally aging and MCI individuals in the following MTL structures: hippocampus, entorhinal cortex, fusiform gyrus, and parahippocampal gyrus. Methods: Fifty-nine nondemented participants were divided into demographically similar groups based on cognitive status (MCI: n 1⁄4 28; NC: n 1⁄4 29). APOE genotyping was conducted and Freesurfer-derived volumetric and cortical thickness values of MTL structures were compared across groups. Results: Despite no differences in hippocampal volumes or cortical thickness, participants possessing the e4 allele demonstrated significantly decreased thickness of the fusiform gyrus (p 1⁄4 .01), entorhinal cortex (p1⁄4 .002), and parahippocampal gyrus (p1⁄4 .04) relative to those without the e4 allele. Additionally, findings were considerably stronger in the right versus left hemisphere for all significant cortical thickness volumes (all pvalues < .01). Further, APOE-e4 status was predictive of MTL substructure thickness after adjusting for age, stroke risk, and hippocampal volumes. Conclusions: Possession of the APOE-e4 allele was strongly associated with cortical thickness of MTL substructures within our sample of nondemented older adults. Findings were independent of MCI status, hippocampal volumes, and stroke risk, suggesting that, even in the context of normal aging, possession of the APOE-e4 allele is associated with subtle alterations in cortical thickness in MTL structures implicated in the pathogenesis of AD. Interestingly, results revealed hemispheric differences by regional cortical thickness of MTL structures, suggesting a possible right hemisphere predilection for neurobiological changes associated with the APOE-e4 allele.

Acceleration of cortical thinning in familial Alzheimer's disease

MRI in presymptomatic autosomal dominant Alzheimer's disease mutation carriers (MC) provides an opportunity to detect changes that pre-date symptoms or clinical diagnosis. We used automated cortical thickness (CTh) measurement to compare the grey matter of such a group with cognitively normal controls. 9 presymptomatic mutation carriers (4 PSEN1, 5 APP) and 25 healthy, age and sex-matched controls underwent longitudinal volumetric MRI brain imaging. CTh measurement was performed across the whole brain using a validated, automated technique. Four regions of interest (ROI) (entorhinal cortex (ERC), parahippocampal gyrus (PHG), posterior cingulate cortex and precuneus) and two control regions (paracentral and pericalcarine) were selected on the basis of imaging data in existing Alzheimer's disease (AD) literature. Linear mixed models were used to describe normal ageing in controls and the extent to which mean CTh in cases differed from controls according to time since clinical diagnosis, adjusting for normal ageing. An accelerating decline in CTh was observed across all ROI in the MC group. No such decline was demonstrated in the control regions for the MC group. Relative to controls, and adjusting for normal ageing, there was evidence (p=0.05, one-sided test) of lower CTh in the posterior cingulate up to 1.8 years prior to diagnosis and in the precuneus up to 4.1 years prior to diagnosis in the MC group. Automated CTh analysis is a relatively practical, rapid and effective technique for assessing subtle structural change in AD. There is evidence that cortical thickness is reduced in mutation carriers a number of years prior to clinical diagnosis.

P1-282: Decreased activation in the left medial parietal lobe in presymptomatic familial Alzheimer's disease mutation carriers in FMRI during an unrelated word pair memory task

P1-282: Decreased activation in the left medial parietal lobe in presymptomatic familial Alzheimer's disease mutation carriers in FMRI during an unrelated word pair memory task

Mixtures of Wild-type and a Pathogenic (E22G) Form of Aβ40 in Vitro Accumulate Protofibrils, Including Amyloid Pores

Although APP mutations associated with inherited forms of Alzheimer's disease (AD) are relatively rare, detailed studies of these mutations may prove critical for gaining important insights into the mechanism(s) and etiology of AD. Here, we present a detailed biophysical characterization of the structural properties of protofibrils formed by the Arctic variant (E22G) of amyloid-β protein (Aβ40 ARC) as well as the effect of Aβ40 WT on the distribution of the protofibrillar species formed by Aβ40 ARC by characterizing biologically relevant mixtures of both proteins that may mimic the situation in the heterozygous patients. These studies revealed that the Arctic mutation accelerates both Aβ oligomerization and fibrillogenesis in vitro. In addition, Aβ40 ARC was observed to affect both the morphology and the size distribution of Aβ protofibrils. Electron microscopy examination of the protofibrils formed by Aβ40 ARC revealed several morphologies, including: (1) relatively compact spherical particles roughly 4–5 nm in diameter; (2) annular pore-like protofibrils; (3) large spherical particles 18–25 nm in diameter; and (4) short filaments with chain-like morphology. Conversion of Aβ40 ARC protofibrils to fibrils occurred more rapidly than protofibrils formed in mixed solutions of Aβ40 WT/Aβ40 ARC, suggesting that co-incubation of Aβ40 ARC with Aβ40 WT leads to kinetic stabilization of Aβ40 ARC protofibrils. An increase in the ratio of Aβ WT/Aβ MUT(Arctic), therefore, may result in the accumulation of potential neurotoxic protofibrils and acceleration of disease progression in familial Alzheimer's disease mutation carriers.