Autosomal Dominant Alzheimer Research Articles

Multimodal MRI and tau PET findings from the Autosomal Dominant Alzheimer’s disease cohort caused by the A431E PSEN1 Jalisco mutation

AbstractBackgroundThe A431E mutation in PSEN1 is a cause of Autosomal Dominant Alzheimer’s disease (ADAD) that represents a founder effect, apparently arising from the state of Jalisco, Mexico, with over 100 superficially distinct families being affected. The median age of symptom onset is 41 years, with about 40% of cases having an atypical presentation of substantial spastic paraparesis. This study aimed to identify the neuroimaging features associated with the A431E PSEN1 Jalisco mutation to elucidate its pathophysiology and to inform future clinical studies.MethodThirty‐one participants with or known to be at‐risk for the A431E PSEN1 mutation were enrolled in a comprehensive genetic, clinical, and imaging protocol including MRI and flortaucipir PET scans. Diffusion MRI and flortaucipir PET studies were conducted on sub‐samples of the cohort along with appropriate control participants.ResultPeak flortaucipir standard uptake value ratio (SUVR) among A431E mutation carriers was predominantly in the lateral parietal cortices relative to the medial temporal lobes with disproportionate signal in motor and sensory cortex relative to persons with late onset AD. Flortaucipir SUVR in 6 brain regions (i.e., medial orbitofrontal, caudal and rostral anterior cingulate, parahippocampal, precuneus, and lateral occipital) were associated with neuropsychiatric symptoms in persons with or at risk for the A431E PSEN1 mutation. Among 21 A431E PSEN1 mutation carriers with available diffusion MRI images, the Ashworth score of spastic paraparesis correlated with mean diffusivity in several brain regions, particularly left inferior parietal, superior parietal, and paracentral lobules (r’s>0.8, p’s< 0.001). In a subset of 10 clinically impaired A431E PSEN1 mutation carriers, mean diffusivity in white matter tracts underlying multiple cortical areas was higher relative to 8 impaired persons with late onset AD or ADAD mutations that do not cause spastic paraparesis.ConclusionThe pattern of flortaucipir distribution was atypical with disproportionate involvement of sensorimotor areas and parietal cortex. Higher flortaucipir signal was associated with more neuropsychiatric symptoms. Microstructural changes in white matter were more pronounced in persons with the A431E PSEN1 mutation and likely underlie the associated spastic paraparesis. The distinct neuroimaging features and associated neuropsychiatric manifestations observed in this cohort highlight the importance of comprehensively characterizing heterogeneous AD subtypes.

APOE3 Christchurch heterozygosity delays clinical onset in autosomal dominant Alzheimer’s disease

AbstractBackgroundWe previously reported a case of a homozygous woman with the APOE3 Christchurch (R136S, APOE3Ch) variant who demonstrated extreme resistance to autosomal dominant Alzheimer’s disease (ADAD) caused by the PSEN1 E280A variant. In this study, we examined the potential protective effects of APOE3Ch against ADAD by characterizing the clinical profile of individuals who were heterozygous for the APOE3Ch variant from the Colombian kindred with the PSEN1 E280A variant.MethodsA total of 421 carriers of the PSEN1 E280A variant were included. Of the 421 carriers, 12 were heterozygous for APOE3Ch (including the previously reported homozygous for APOE3Ch). Clinical and neuropsychological assessments were performed in Spanish at the University of Antioquia in Colombia. Four of the APOE3Ch carriers also donated their brains for postmortem studies. A PSEN1 E280A who is heterozygous for the APOE3Ch variant also underwent structural MRI and amyloid and tau PET imaging.ResultsOur findings showed that PSEN1 E280A carriers who are heterozygous carriers of the APOE3Ch variant had a significantly delayed onset for mild cognitive impairment (MCI, median age of 51 vs. 45 years; p = 0.0048) and dementia (52.5 vs. 48 years; p = 0.016), compared to PSEN1 E280A carriers without the APOE3Ch variant. Specifically, APOE3Ch carriers had seven‐time higher odds of developing MCI and three‐time higher odds of developing dementia at a later age than 75% of all the PSEN1 E280A carriers (odds ratio [OR] = 7.6; 95% confidence interval [CI] 1.9, 29.2, p<0.05); dementia OR = 3.07; 95% CI 1.01, 9.33). Initial characterization of brain imaging of a PSEN1 E280A carrier who is heterozygous for the APOE3Ch variant showed levels of medial temporal lobe tau pathology and hippocampal atrophy that were lower than expected for a typical carrier of their age, and similar to our observations in the previously reported APOE3Ch homozygote case.ConclusionsThese clinical, cognitive, and neuroimaging data provide evidence that APOE3Ch heterozygosity delays the onset of cognitive decline and may have a protective, dose‐dependent effect against tau pathology and neurodegeneration. These results provide support for the potential of the APOE3Ch variant as a target for the development of new treatments for AD.

Associations between aerobic fitness and subsequent memory performance in non‐demented Presenilin‐1 E280A mutation carriers: A preliminary report from the Colombia‐Boston longitudinal biomarker study

AbstractBackgroundGreater aerobic fitness, objectively measured by VO2‐max, is considered a critical component of overall health and a strong predictor of cognitive functioning. It has been associated with less neurodegeneration in Alzheimer’s disease (AD) and greater functional brain connectivity and plasticity in healthy older adults. Yet, less is known about how it relates to AD progression in people at increased risk for dementia. In this study, we examined whether VO2‐max predicted memory decline in non‐demented mutation carriers and non‐carriers from a Colombian kindred with autosomal dominant AD (ADAD), and hypothesized that those with greater VO2‐max levels would exhibit slower cognitive decline.Methods12 Presenilin‐1 E280A mutation carriers (ages: μ = 39.61 years, SD:4.18) and 14 non‐carriers (ages: μ = 37.11 years, SD:6.59) underwent a standard graded maximal exercise test performed on a treadmill to assess their VO2‐max, which is the maximal rate of oxygen consumption during exercise, measured in milliliters of oxygen per minute per kilogram body mass. Participants also completed the CERAD word list learning and delayed recall, a measure of episodic memory, at baseline and again 18‐24 months later. Group differences were tested using the Mann‐Whitney U test. Linear mixed models were used to examine associations among baseline VO2 max and changes in CERAD word list test scores.ResultsVO2‐max levels did not differ between groups (p = .16). Compared to mutation non‐carriers, mutation carriers performed worse in word list learning (p = .008) and recall (p<.001) at baseline. VO2‐max levels were not associated with baseline word list learning (non‐carriers: p = .93; carriers: p = .76) or recall scores (non‐carriers: p = .82; carriers: p = .63). Baseline VO2‐max levels did not predict change in word list learning (non‐carriers: p = .47; carriers: p = .85) or recall scores (non‐carriers: p = .70; carriers: p = .87).ConclusionPreliminary findings suggest that aerobic fitness, which can be increased with exercise and is associated with greater health, does not relate to memory decline in preclinical ADAD. This is an ongoing longitudinal study, and we will continue to collect more physical activity data in this kindred to characterize these associations better. More research with larger samples is needed to elucidate whether physical activity could help delay AD progression regardless of aerobic fitness levels.

Clinical Manifestations.

In recent years, there has been an increase in the number of case reports of families with autosomal dominant Alzheimer's disease (ADAD) in Latin America (LA). Nevertheless, little is known about the clinical phenotypes and demographic characteristics of mutations in each country. Past literature has proved that variants in LA have different and unique characteristics than those reported in Asia, North America, and Europe. Clinical heterogeneity in ADAD supports the need to study clinical phenotypes, especially in preclinical stages, to develop cognitive and clinical markers of the disease. We aimed to describe clinical and cognitive characteristics at baseline assessment of an Argentina PSEN1 p.M146L family enrolled at DIAN. Fifteen Dian Participants living in Buenos Aires and its suburbs and in Taco Pozo, a rural and isolated community from the Province of Salta, positive for the PSEN1 p.M146L mutation, were recruited. DNA was obtained from peripheral blood leukocytes according to standard protocols. In addition, exon 5 of the PSEN1 gene was PCR-amplified, and Sanger sequencing was performed. NACC Uniform Data Set clinical assessment, including the 2.0 UDS Neuropsychological Battery, was administered. Two groups were used to compare cognitive data: Patients with CDR:0 (n:10) and patients with CDR>0 (n:5). The mean age at symptom onset reported in this cohort was 42,90 (SD: 4,62). Significant differences were found in several cognitive measures: Logical Memory Immediate, TMT B and Digit Backward (<0,001); MMSE, Category Fluency Animals, TMT A and Digit Symbol(<0,05). In neurological signs, paraplegia was reported in one of the patients. As expected, differences in neuropsychological tests showed a prevalence of memory deficits, however, dysexecutive symptoms were also present for this mutation. Paraplegia in PSEN1 p.M146L has not been reported in the literature so far. Ongoing longitudinal work will be important in tracking changes in this cohort. Other characteristics, proper of underrepresented groups, such as socioeconomic status, education, race, and ethnicity, deserve appropriate follow-up. Future studies are planned, comparing urban and rural populations in this cohort with the same mutation.

The effect of age and years of schooling on CERAD‐MX performance of Mexican preclinical carriers and non‐carriers’ relatives of the V717I APP mutation

AbstractBackgroundIn a previous study in a sample of young neurotypical adults (18 to 59 years), we found that years of schooling (YoS) have a greater effect than age on the tasks included in the neuropsychological protocol of the Mexican adaptation of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD‐MX).MethodThirty‐eight participants (Mage = 31.08 years; MYoS = 8.27 years), from Jalisco State in Mexico, identified as first‐degree relatives of symptomatic autosomal dominant Alzheimer’s disease (ADAD) carriers of the V71 7I APP mutation were divided into two groups, MC (n = 15) and NC (n = 23). Eight CERAD‐MX tasks were used: the Mini‐mental State Examination (MMSE), Semantic Verbal Fluency (SVF), Verbal Boston Naming (VBN), Word List Memory (WLM) with delayed recall (WLD) and recognition (WLR), as well as Constructional Praxis copy (CPC) and recall (CPR). We used z‐scores, then defined random vectors with Sklar’s theorem and a Gaussian dome from simulations of new samples obtained by inverse transform sampling.ResultIn both groups, YoS had a greater positive effect on the MMSE, WLM, WLD z‐scores. In the MC group only, this same effect was evident in the SVF and CPR scores, while in the NC group this effect was seen in the VBN, and CPC z‐scores. Age effect was more pronounced that YoS in MC performance on the CPC, while in NC, on SVF performance.ConclusionFor both groups, YoS has a greater effect than age on several tasks, showing that YoS is a confounding variable when analyzing performance on CERAD‐MX tasks. Moreover, in the MC group, age has a positive effect on CPC task performance suggesting that graphic abilities are not vulnerable to the presence of V717I APP mutation at the preclinical stage.

Palliative care in Autosomal Dominant Alzheimer’s disease due to PSEN1‐E280A genetic variant in Colombia

AbstractBackgroundAutosomal Dominant Alzheimer’s disease (ADAD) is a subtype of AD in which the symptoms begin before age 65. ADAD is an important subtype of AD as it affects people at productive and reproductive age, has a genetic origin in most of the cases and is one of the 10 causes of years lost to disability (YDLs) (1). Colombia has the largest kindred family with ADAD due to PSEN1‐E280A genetic variant, we aimed to characterize the palliative care need in a subsample of individuals from these families.MethodsWe performed an analytical observational study with one year follow‐up, data obtained from visit 1 (V1) is shown in this first report. Carriers of PSEN1‐E280A variant and GDS/FAST score above 4 were included. NECPAL and Edmonton surveys were conducted to the main carer to assess the need for palliative care and the frequency of symptoms. A complete medical evaluation was also performed.Results36 patients were included in V1. Median age was 53, most of the individuals were women (63.89%), lived in urban areas (88.89%) and the most common level of education was elementary‐middle school (47.22%). Clinical variables are listed in Table 2. Results of the poisson regression showed that dysphagia, pressure ulcers, asthenia perceived by the main carer, not being surprised if the patient died in the following 12 months (Surprise question of NECPAL scale), functional decline, use of medical services (2 visits in the past year), PAINAD scale and GDS/FAST scale were associated with the need for palliative care when adjusted by number of persons involved in caring, type of carer, hours of care per week and caregiver training.ConclusionADAD is a neurodegenerative disease that requires follow‐up by palliative care services. The health perception of the main carer should be taken into consideration when deciding the need for palliative care in these patients.

Production of a PSEN1 genetically engineered marmoset model of early‐onset Alzheimer’s Disease

AbstractBackgroundThe lack of an adequate animal model of Alzheimer’s disease (AD) that mirrors the natural onset and progression of the human disorder has been a substantial barrier to basic and translational research into AD. Consequently, many fundamental questions remain about the key mechanisms that initiate the disease and the factors that promote its progression. While rodents are valuable AD models, nonhuman primates (NHPs) offer many advantages and have greater translational relevance. The common marmoset (Callithrix jacchus) is a small, prolific New World NHP that is amenable to genetic engineering and is rapidly becoming a valuable model organism, especially for neuroscience research.MethodWe used CRISPR/Cas9 technology to generate marmosets with C410Y or A426P point mutations in the PSEN1 gene. In humans, these mutations lead to familial early‐onset autosomal dominant Alzheimer’s Disease. Briefly, we designed, synthesized, and injected CRISPR/Cas9 reagents into single‐cell embryos that were subsequently transferred to synchronized recipient females. One adult C410Y founder animal was bred to a wild‐type mate.ResultTo date, we have produced seven live‐born marmosets harboring the PSEN1 C410Y (3 males, 1 female) or A426P (1 male, 2 females) mutations. One male founder animal, a compound heterozygote harboring C410Y and 1bp insertion PSEN1 alleles, has successfully sired three litters and transmitted the C410Y substitution (n = 6) and the 1bp insertion (n = 5) alleles to F1 offspring. We are currently characterizing the founders and F1 offspring using fluid‐based biomarkers, non‐invasive neuroimaging, and behavioral assessment to identify early markers of disease progression.ConclusionCRISPR/Cas9 gene editing was used to successfully establish a line of genetically engineered marmosets expected to model early‐onset AD. This nonhuman primate model will bridge the rodent‐to‐human translational gap and enable detailed studies of the early‐life molecular determinants of AD pathogenesis.

Striatal Amyloid deposition in sporadic Alzheimer’s Disease

AbstractBackgroundIt has been shown that disorders associated with early‐life alterations in amyloid production or processing such as in autosomal dominant Alzheimer’s disease (AD) and down syndrome‐associated dementia have a different pattern of Aβ deposition, with early striatal accumulation, as compared to sporadic late‐onset cases, in which striatal deposition has been suggested to be a marker of late and advanced amyloidosis. It is not clear, however, if the pattern of amyloid accumulation is related to any other factors or if it has any impact on brain metabolism. We aimed to determine if there are any clinical or demographic predictors of striatal tau accumulation in sporadic AD and whether its presence affects the subjects´ brain metabolism.MethodSubjects that underwent positron emission tomography (PET) scans with 18F‐FDG and 11C‐PIB were analyzed retrospectively. Only those with clinical diagnosis of AD and mild cognitive impairment (MCI) due to AD were considered for the analysis. Visual analyses were performed to exclude subjects without cortical amyloid accumulation. Mean values from cortical volumes of interest (VOIs) and striatum were obtained. Amyloid deposition was correlated with age and disease duration via Pearson’s correlations. Amyloid deposition was also correlated to brain metabolism as assessed by FDG PET.Result150 subjects were included in this study. Neither age nor disease duration was correlated with striatal amyloid accumulation. Subjects with striatal Pib accumulation showed higher cortical amyloid burden. Moreover, higher striatal amyloid burden was positively correlated with higher frontal amyloid burden specifically. Amyloid burden in the striatum did not seem to have an impact on the glucose metabolism in the striatum itself. However, variations in cortical glucose metabolism could be observed. A higher striatal amyloid burden was correlated with cortical glucose hypometabolism, specifically in the precuneus and temporal areas (Figure 1).ConclusionThere seems to be a stage of sporadic Alzheimer’s disease in which amyloid accumulates in the striatum. This, in turn, appears to have an impact on brain functioning. Whether this has a real impact on cognitive performance remains to be elucidated.

Longitudinal analysis of qEEG in subjects with autosomal dominant Alzheimer’s disease due to PSEN1‐E280A variant

AbstractBackgroundAlzheimer’s disease (AD) is the leading cause of dementia in the world. Synaptic dysfunction is a pathophysiological event that alters neuronal connections at multiple scales: molecular, cellular, brain networks, cerebral cortex, among others. There are different mechanisms that interact to trigger alterations in the homeostasis of synaptic function, among them the most prominent are amyloidosis, tauopathy and inflammation. EEG has been used in recent years as a cost‐effective, portable, and noninvasive alternative for the study of biomarkers in Alzheimer’s disease.MethodAll participants were members of families with PSEN1‐E280A genetic variant and healthy controls recruited voluntarily. A longitudinal follow‐up was planned, this study collects data from the initial visit and in the first year of follow‐up. At each visit, neurological and neuropsychological evaluation and electroencephalogram were performed. We analyzed the resting state EEG spectral power bands and the Alpha/Theta reactivity index.ResultAlpha1 and Alpha2 frequency bands did not have significant changes in the follow‐up year, in the Beta3 frequency band in component 20 and Beta2 in component 22 statistically significant differences were found. However, the distribution of the data in the shift graphs for the Beta frequency band presents some slopes, which indicates a modest effect sizes and low precision.ConclusionThe Beta frequency band is a potential neurophysiological marker that in preclinical stages of ADAD show statistically significant differences between asymptomatic carriers and non‐ carriers. This signal is related to components whose origin is estimated in posterior regions, which highlights the importance of previous findings in the precuneus. However, the effect sizes were modest and with low precision. It would recommend larger samples and longer following in future research.

Advanced measures of cortical microstructural change and associations with cognitive and blood‐based biomarkers in autosomal dominant Alzheimer’s disease

AbstractBackgroundIn Alzheimer’s disease (AD), dysfunction and loss of cortical neurons occurs prior to symptom onset. Diffusion tensor imaging, measuring mean diffusivity (MD), provides a metric of microscopic change but lacks specificity for different underlying microstructural processes. We used Neurite Orientation Dispersion and Density Imaging (NODDI) to investigate specific cortical microstructural features across the disease course in autosomal dominant AD (ADAD).MethodSixty‐three ADAD family members (36 mutation carriers) (Table 1) underwent T1w and multi‐shell diffusion MRI (dMRI). Cortical thickness and cortical MD were estimated, with NODDI providing measures of tissue fraction (TF), neurite density index (NDI) and orientation dispersion index (ODI) (a proxy measure of dendritic complexity). Imaging metrics were sampled across six cortical regions of interest (ROIs) known to be particularly vulnerable to early neurodegeneration. Associations between dMRI measures and 1) disease stage as measured by estimated years to onset (EYO), 2) AD blood biomarkers, and 3) cognitive measures were assessed.ResultAcross mutation carriers, ODI (Figure 1) and TF (Figure 2) demonstrated negative associations (p&lt;0.05) with EYO in most ROIs, while MD demonstrated positive correlations. Most associations remained after adjusting for cortical thickness. The association between ODI and EYO in the supramarginal gyrus also remained after adjustment for MD (p = 0.002). In presymptomatic carriers, EYO appeared most prominently associated with ODI (p&lt;0.05 in 3/6 regions). ODI, TF and MD showed widespread associations with MMSE and CDR sum of boxes. TF was negatively, and MD positively, associated with serum NfL across ROIs, but for ODI this was only the case in the supramarginal gyrus. ptau181 demonstrated significant associations with ODI in the supramarginal (p = 0.0089) and inferior parietal (p = 0.033) cortices, and with MD in the entorhinal cortex (p = 0.015).ConclusionCortical dendritic complexity (modelled by ODI) and cortical tissue fraction decrease, while overall diffusivity increases as individuals approach symptom onset. ODI appears to be the metric most closely associated with presymptomatic disease stage, possibly reflecting early dendritic pruning, and is associated with ptau – a measure of early pathology – while MD and TF may be more sensitive to later larger scale changes, given their associations with serum NfL and cognitive measures.

Advanced measures of cortical microstructural change and associations with cognitive and blood‐based biomarkers in autosomal dominant Alzheimer’s disease

AbstractBackgroundIn Alzheimer’s disease (AD), dysfunction and loss of cortical neurons occurs prior to symptom onset. Diffusion tensor imaging, measuring mean diffusivity (MD), provides a metric of microscopic change but lacks specificity for different underlying microstructural processes. We used Neurite Orientation Dispersion and Density Imaging (NODDI) to investigate specific cortical microstructural features across the disease course in autosomal dominant AD (ADAD).MethodSixty‐three ADAD family members (36 mutation carriers) (Table 1) underwent T1w and multi‐shell diffusion MRI (dMRI). Cortical thickness and cortical MD were estimated, with NODDI providing measures of tissue fraction (TF), neurite density index (NDI) and orientation dispersion index (ODI) (a proxy measure of dendritic complexity). Imaging metrics were sampled across six cortical regions of interest (ROIs) known to be particularly vulnerable to early neurodegeneration. Associations between dMRI measures and 1) disease stage as measured by estimated years to onset (EYO), 2) AD blood biomarkers, and 3) cognitive measures were assessed.ResultAcross mutation carriers, ODI (Figure 1) and TF (Figure 2) demonstrated negative associations (p&lt;0.05) with EYO in most ROIs, while MD demonstrated positive correlations. Most associations remained after adjusting for cortical thickness. The association between ODI and EYO in the supramarginal gyrus also remained after adjustment for MD (p = 0.002). In presymptomatic carriers, EYO appeared most prominently associated with ODI (p&lt;0.05 in 3/6 regions). ODI, TF and MD showed widespread associations with MMSE and CDR sum of boxes. TF was negatively, and MD positively, associated with serum NfL across ROIs, but for ODI this was only the case in the supramarginal gyrus. ptau181 demonstrated significant associations with ODI in the supramarginal (p = 0.0089) and inferior parietal (p = 0.033) cortices, and with MD in the entorhinal cortex (p = 0.015).ConclusionCortical dendritic complexity (modelled by ODI) and cortical tissue fraction decrease, while overall diffusivity increases as individuals approach symptom onset. ODI appears to be the metric most closely associated with presymptomatic disease stage, possibly reflecting early dendritic pruning, and is associated with ptau – a measure of early pathology – while MD and TF may be more sensitive to later larger scale changes, given their associations with serum NfL and cognitive measures.

Leveraging systems biology approaches and single‐nucleus RNA‐seq to study sex differences in AD

AbstractBackgroundThere is increasing evidence indicating sex‐specific patterns in disease manifestation and sex differences in the rates of cognitive decline and brain atrophy. Sex‐related differences in AD‐associated genes are starting to emerge, but these have not been systematically studied at cell‐type‐specific transcriptome‐wide expression levels. We leveraged single‐nucleus RNA‐seq (snRNA‐seq) and systems biology approaches to identify transcriptomic modules in human brains and determine the modules associated with sex‐AD interactions.MethodsWe studied snRNA‐seq data from the parietal cortex of 67 pathologically confirmed controls, sporadic AD (sAD), autosomal dominant AD (ADAD), and other neurodegenerative samples from the Knight ADRC and DIAN cohorts1, and used Celda2 to co‐cluster cells and genes into subpopulations and modules. This approach identified clusters that correspond to previously described cell types1. We used linear mixed models to identify those modules associated with a sex‐AD interaction. For each nominally significant (P&lt;0.05) module, we isolated the top genes that accounted for 80% of the module expression signature and tested each for a sex‐AD interaction.ResultsWhen run on 38,584 astrocytes, Celda split 13,302 genes into 65 gene modules. Module L17 was nominally significant (P = 0.04), with 55 out of 194 genes accounting for ∼80% of the module signature. After multiple testing correction, two genes, ENTREP1/FAM189A2 (Adj.P = 1.57´10−2) and CD38 (Adj.P = 1.80´10−2), showed a significant sex‐sAD interaction in expression (Figure 1, Table 1). ENTREP1 facilitates the removal of the chemokine receptor CXCR4 from the plasma membrane reducing the downstream effects of CXCL12/CXCR4 signaling3 including astrocytic inflammation response4 and release of glutamate as a gliotransmitter5. Studies have linked ENTREP16 and CXCL12/CXCR47 to neurodegeneration. CD38 expression is influenced by cytokine and chemokines released by senescent cells, which increase with age, AD, and other neurodegenerative diseases8. Increased expression of CD38 increases proinflammatory cytokine release and reduces NAD‐dependent enzyme activity, increasing DNA mutations, mitochondrial dysfunction, and oxidative stress. Knockouts of CD38 in mouse showed significant decreases in Aβ plaque load and soluble Aβ levels9.ConclusionThese results suggest that the known neurodegenerative genes ENTREP1 and CD38 are uniquely modulated by biological sex in relation to AD within astrocytes potentially contributing to the clinical differences seen between males and females.

Atypical presentations of autosomal dominant familial Alzheimer’s disease: insights into genetic, neuropathological and clinical heterogeneity

AbstractBackgroundAutosomal dominant familial Alzheimer’s disease (ADAD), caused by APP, PSEN1 and PSEN2 mutations, is clinically and pathologically similar to sporadic AD, with both typically presenting with memory impairment. However as in sporadic AD, atypical phenotypes and neuropathological heterogeneity occur, including variable vascular Aβ deposition as cerebral amyloid angiopathy (CAA). Investigating relationships between clinical, genetic and neuropathological heterogeneity in ADAD may provide insights into pathophysiological pathways relevant to AD in general.Methods256 symptomatic individuals from ADAD families seen at our Centre were included in a survival analysis, with detailed clinical phenotype data available for 138 (101 PSEN1, 37 APP). 33 of these individuals underwent brain donation (24 PSEN1, 9 APP), all demonstrating end‐stage AD pathology. Frontal and occipital cortex sections were stained immunohistochemically for Aβ and vessel counts used to determine the proportion of cortical and leptomeningeal blood vessels affected by CAA.ResultsAge at onset was, on average, seven years younger for PSEN1 than APP mutations and was influenced by mutation much more than survival was. Atypical (non‐amnestic) cognitive presentations with initial behavioral, language, dyscalculic or dysexecutive symptoms, and atypical clinical features (pyramidal, extrapyramidal and cerebellar signs) were more common in PSEN1 than APP cases, particularly those with post‐codon 200 mutations. Atypical cognitive presentations were associated with longer survival. There was some indication that APOE4 carriers had longer survival and that this effect may be restricted to PSEN1. In the post‐mortem cohort, atypical cognitive presentations occurred in 15%. Additional neurological features comprised myoclonus (45%), seizures (21%), pyramidal signs (21%) and extrapyramidal signs (15%), one individual had cerebellar signs. Increased frontal cortical and leptomeningeal CAA occurred in individuals with pyramidal and extrapyramidal signs, and in PSEN1 post‐codon 200 compared to pre‐codon 200 mutations. Atypical cognitive presentations were associated with increased frontal cortical CAA.ConclusionsPhenotypic heterogeneity in ADAD is influenced by causative gene and mutation type, and atypical clinical presentations are associated with increased CAA. Exploring mechanisms by which certain mutations drive Aβ deposition towards the vasculature, and how these may be impacted by other genetic factors and by therapies targeting Aβ, is an important direction for future research.

Neuropathological characterization of PiB binding in postmortem striatum in Down syndrome

AbstractBackgroundAmyloid‐beta plaques form in the brain throughout life in people with Down syndrome (DS) and are one of the hallmarks of Alzheimer disease (AD) neuropathology. The regional progression of amyloid buildup in DS is similar to that of late onset AD (LOAD) in the neurotypical population. The development of positron emission tomography (PET) ligands like Pittsburgh Compound B (PiB) has allowed researchers and clinicians to visualize and track amyloid accumulation in the brain throughout life. Using this technology, a unique pattern emerges in people with DS, where the earliest and strongest PiB PET retention is in the striatum, unlike LOAD but similar to autosomal dominant AD. Frontal cortex PiB PET retention is similar in all groups. We used a fluorescent derivative of PiB, cyano‐PiB (CN‐PiB), to investigate PiB labeling postmortem in DS striatum. We hypothesized that striatal CN‐PiB load increases with age and is greater than in the frontal cortex, similar to observations from PiB PET studies of adults with DS.MethodWe conducted CN‐PiB labeling in postmortem striatum and frontal cortex from 44 cases with DS ages ranging from 42 to 70 years (25F/19M, mean PMI 7.4 hours). Whole slide imaging and automated image analysis were used to derive individual plaque‐level information regarding load, size, and distribution of CN‐PiB+ plaques in DS with age.ResultCN‐PiB labeled plaques in both the striatum and frontal cortex were also positive for amyloid‐beta antibodies targeting epitopes 1‐16, 17‐24, and x‐42. Preliminary data suggest that striatal CN‐PiB load (median = 2.3%) is not higher compared to the frontal cortex in DS (median = 10%). Striatal CN‐PiB load did not change with age from 42 to 70 years, suggesting an early saturation (IQR = 3.5%).ConclusionCN‐PiB labeled amyloid‐beta plaque load in the striatum in DS is comparable to conventional neuropathologic analysis and does not differ from frontal cortical load. Other aspects of PiB‐binding or pathologies may contribute to the early and prominent striatal PiB PET retention reported in DS. It will be important in future studies to include younger cases with DS.

Phonetic‐phonological disturbances of spontaneous speech in autosomal dominant Alzheimer disease due to A431E PSEN1 mutation

AbstractBackgroundConsiderable cognitive research in Alzheimer Disease (AD) has focused on memory as it is often the primary symptom; nevertheless, in A431E PSEN1 mutation carriers in Jalisco, a rapidly language impairment and verbal fluency decrease during the disease is reported (Petersen‐Dumois, et al., 2020) though this deficit is not well‐characterized. The aim of this study was to identify and characterize phonetic‐phonological abnormalities in the spontaneous speech through different stages of A431E PSEN1 mutation‐related AD.MethodEleven symptomatic A431E PSEN1 mutation carriers, with a mean age of 42.54 years (DE = 4.17) participated in the study: five with Mild Cognitive Impairment (MCI), three with Mild Dementia (MiD) and five with Moderate Dementia (MoD). We used three language tasks: trip planning, picture description, and narrative discourse of a risky and happy moment of their lives which were recorded and transcribed. For each participant, we computed the frequency of phonetic‐phonological features: stuttering, unintelligible productions, phonological paraphasias, fillers and pauses (≥2 seconds) and then converted into percentages dividing the number of occurrences of each feature by the number of words used on the speech sample (for pauses, time in seconds). Then, we obtained the percentage mean of each feature per group.ResultWe analyzed a total of 134.65 minutes of speech sample. Regarding verbal fluency, words per minute (means) varied across the groups MCI: 85.55 (SD = 39.34); MiD: 128.56 (SD = 34.14) MoD: 67.80. (SD = 32.71). All phonological features were present, stuttering: MCI: 1.38%; MiD: 3.2%; MoD: 4.05%; unintelligible productions: MCI: .22%; MiD: .64%; MoD: .76%; phonological paraphasias; MCI: 0.002%; MiD: .01% MoD: .01%; fillers: MCI: 2.05%; MiD: .29%; MoD: 2.88%; number of pauses: MCI: .04%; MiD: .05%; MoD: .03%. and pauses average: MCI: 3.42 (SD = .62); MiD: 2.55 (SD = .03) MoD = 3.43. (SD: 1.61).ConclusionWe found that A431E PSEN1 mutation carriers present phonetic‐phonological traits even in the earliest stage (MCI) and for three of them (stuttering, unintelligible productions, and phonological paraphasias) their frequency is greater the more severe the impairment (MoD). Stuttering is their most prominent feature. These disturbances in the spontaneous speech could be a phenotype trait of this ADAD mutation.

Longitudinal effects of sex on pathology accumulation, neurodegeneration and cognitive decline in Presenilin‐1 E280A mutation carriers: preliminary findings from the Colombia‐Boston (COLBOS) biomarker study

AbstractBackgroundPrevious work showed that females at risk for autosomal dominant Alzheimer’s disease (AD) due to a single mutation (E280A) in the Presenilin‐1 gene (PSEN1) may have greater cognitive resilience to AD‐pathology and neurodegeneration than males. However, more research is needed to clarify the effect of sex on AD risk and progression. We investigated the effects of sex on rates of amyloid and tau accumulation, neurodegeneration, and memory decline in PSEN1 mutation carriers with and without cognitive impairment, who are genetically determined to develop early‐onset dementia.MethodA total of 66 cognitively unimpaired mutation carriers (mean age of 34.41 +/‐ 4.86 years; 38 females), and 23 cognitively impaired mutation carriers (mean age of 44.91 +/‐ 2.83 years; 17 females) from the Colombia‐Boston Biomarker (COLBOS) study completed baseline cognitive assessments. A subset of 52 participants also completed florbetapir‐ and flortaucipir‐PET, and structural MRI. Cognitive and neuroimaging follow‐up visits were completed at 2‐ (n = 29) and 4‐year (n = 13) intervals. We used linear mixed‐effects models, with random intercepts, to predict rate of change in MMSE scores, CERAD word list delayed recall, cortical amyloid burden, tau in the entorhinal, inferior temporal, and precuneus cortices, and hippocampal volume by sex, controlling for education.ResultOver time, carriers exhibited greater cortical amyloid burden (p&lt;.001), inferior temporal tau (p = .019), precuneus tau (p = .003), lower hippocampal volume (p = .005), and showed a trend towards lower MMSE scores (p = .059) and word list delayed recall (p&lt;.080); entorhinal tau did not significantly increase (p = .137). Female carriers showed a steeper decline in word list delayed recall than male carriers (p = .021). There were no sex differences in the rate of accumulation of mean cortical amyloid or regional tau, hippocampal atrophy, or change in MMSE scores (all ps&gt;.05).ConclusionPreliminary findings of this ongoing study suggest that despite similar rates of pathology accumulation or atrophy between female and male PSEN1 E280A carriers, female mutation carriers may have faster memory decline. Future analyses with additional participants and follow‐up intervals are needed to characterize sex differences in ADAD risk and resilience, as well as inform development of treatments and interventions.

Functional variations in gamma‐secretase processing of APP are critical determinants of the clinical, biomarker, and cognitive progression of autosomal dominant Alzheimer’s disease

AbstractBackgroundThe balance between production, clearance, and toxicity of Ab peptides is central to AD pathobiology. Though highly variable in terms of age of symptom onset (AAO), hundreds of pathogenic variants in Presenilin‐1 (PSEN1) cause autosomal dominant forms of AD (ADAD). PSEN1 forms the catalytic core of the γ‐secretase complex and thereby directly mediates the production of longer, aggregation‐prone Aβ peptides relative to shorter, non‐aggregating peptides. We hypothesized that the broad AAO and biomarker heterogeneity seen across ADAD would be predictable based on mutation‐specific differences in γ‐secretase function, as measured by a ratio of production of shorter vs. longer Aβ species.MethodsAβ‐37, 38, 40, 42, and 43 production was quantified from 162 unique PSEN1 variants expressed in HEK293 cells engineered to lack endogenous wild‐type PSEN1/2 (Figure 1). Prediction of AAO was carried out in 107 PSEN1 variants (characterized by Liu et al, 2022) and then replicated with a set 55 unique PSEN1 variants represented in the Dominantly Inherited Alzheimer Network (DIAN; n = 190 corresponding variant carriers with detailed cognitive and biomarker data; Figure 2).ResultsMutation‐level variations in Aβ production, including a novel composite representing γ‐secretase function (lower score = less g‐processivity), from the cellular model were highly predictive of actual AAO across the 162 mutants examined (Non‐DIAN variants [N = 107]: r = 0.71, p &lt;2.2e‐16; DIAN variants [N = 55]: r = 0.61, p = 6.10e‐07). Our cell‐based γ‐secretase function composite was strongly associated with cerebral PiB‐PET β‐amyloid burden (B[SE] = ‐0.03[0.01], p = 4.06e‐07), MRI gray matter volume (B[SE] = 44.22[6.4], p = 5.15e‐01), cerebrospinal fluid Aβ42/40 (B[SE] = 6.3e‐04[1.5e‐04], p = 4.46e‐05) and phosphorylated tau‐217 (B[SE] = ‐0.01[0.002], p = 1.98e‐05), Clinical Dementia Rating®‐ Sum of Boxes (B[SE] = ‐0.07[0.02], p = 4.86e‐05), and Mini‐Mental State Exam (B[SE] = 0.11[.03], p = 2.17e‐04).ConclusionsBiochemical variations in γ‐secretase function across PSEN1 pathogenic variants broadly predicted the cross‐sectional clinical, cognitive, and biomarker course of ADAD, including AAO. These findings elucidate the critical link between γ‐secretase function, Aβ production, and severity of AD. The novel approach designed here also represents a tool to account for heterogeneity in ADAD clinical trials and to assess the pathogenicity of PSEN1 variants of unknown significance or with limited family history.

Impact of reference region on longitudinal florbetapir PET SUVR changes from the API ADAD Colombia Trial

AbstractBackgroundWe previously examined the impact of using a cerebellar, pons, or cerebral white matter (WM) reference region (RR) on the ability of each to distinguish cortical measures of fibrillar amyloid‐(Aβ) deposition with baseline data in unimpaired presenilin (PSEN1) E280A mutation carriers and non‐carriers (NC) from the Alzheimer’s Prevention Initiative Autosomal Dominant Alzheimer’s Disease (API ADAD) Colombia Trial (NCT01998841). In this study, we extend our findings by comparing these RRs on their ability to distinguish longitudinal changes in cortical measures of serial Aβ‐PET scans from the completed clinical trial.MethodWe estimated template‐based (SPM12) cortical mean change using baseline, 2, and 5‐year florbetapir PET standard‐uptake value ratios (SUVRs) with three different RRs (whole cerebellum, pons, and WM) and compared carriers on placebo (placebo‐carriers, n = 82) with NC all on placebo (NC, n = 83). We calculated Cohen’s D with [95% CI] and standard deviation of NC as effect‐sizes for 2 and 5‐year cortical changes. Additionally, we characterized cerebellar Aβ burden in carriers on crenezumab (treatment‐carriers, n = 81), placebo‐carriers, and NC, using our previously reported method targeting the whole cerebellum region‐of‐interest (ROI) with pons as RR to estimate cerebellar‐to‐pons‐SUVRs and compare using a mixed‐model repeated‐measures ANOVA adjusted for age but not multiple comparisons.ResultAs expected, placebo‐carriers had significantly greater SUVR change compared with NC for all three RRs. However, the pons RR was best at detecting 2‐year changes (d = 1.75[1.39‐2.11]), and WM and pons were best at detecting 5‐year changes in cortical‐Aβ levels between placebo‐carriers and NC (pons d = 2.01[1.64‐2.39], WM d = 2.51[2.10‐2.92]). Additionally, treatment‐carriers had higher cerebellar‐to‐pons‐SUVRs compared with placebo‐carriers at baseline and 2‐years, but not 5‐years (p = .034, p = .027,&amp; p = .06,respectively), both carrier groups had higher cerebellar‐to‐pons‐SUVRs compared to NC at each interval(p&lt;.001). Cerebellar‐to‐pons‐SUVRs continued to increase within carrier groups at each interval(5‐year&gt;2‐year&gt;baseline,p&lt;.05) and remained constant within the NC‐group(p&gt;.05).ConclusionUse of pons for 2‐year and WM or pons RRs for 5‐year changes may improve the power to track longitudinal increases and evaluate Aβ‐modifying treatments in 2 and 5‐year studies, in this ADAD population. A cerebellar RR may be confounded by early Aβ deposition in the cerebellum which can artificially reduce average cortical Aβ‐PET SUVRs even in preclinical stages of ADAD.

A perspective on data sharing from potentially registrational trials

AbstractIt is well recognized that sharing rich and rigorously collected clinical trial data with researchers who were not conducting the study has the potential to accelerate progress in Alzheimer’s disease.. Such data sharing can contribute to an understanding of pathophysiology, natural history, performance of outcome measures, and the profile of response to treatments, and can help researchers to design better studies and health authorities and payors to evaluate the benefits of therapies. The complexities involved in such data sharing include the need to keep up with evolving patient privacy laws, protecting participant anonymity, ensuring trial integrity, and balancing regulatory and publication requirements. In 2012 Roche/Genentech made a commitment to Banner Alzheimer’s Institute and the NIH to share baseline and longitudinal trial data from the Alzheimer’s Prevention Initiative Autosomal Dominant AD trial, a public‐private partnership. We will describe the mechanisms developed to share data from the API ADAD Trial (baseline data now available; longitudinal clinical, imaging, and biomarker data to follow) including methods employed to protect confidentiality and anonymity of participants, and the process for requesting and accessing baseline data. We will also offer learnings from our experiences in sharing data from other neurodegeneration trials.The API ADAD trial was funded by NIA grants RF1‐AG041705, R01‐AG055444, Genentech, Roche, philanthropic contributions to Banner Alzheimer’s Foundation. Florbetapir PET was partly supported by Avid and Lilly.

TMS and imaging correlates of spasticity in persons at‐risk for the A431E PSEN1 mutation

AbstractBackgroundSpastic paraparesis (SP) occurs in approximately 45% of carriers of the A431E PSEN1 mutation (MCs), sometimes preceding cognitive decline. SP is typically caused by reduced cortical excitatory output to spinal motor neurons resulting from delayed cortical conduction time or increased inhibitory output from cortex. Previous studies have observed that people with spasticity have increased corticospinal inhibition at rest and altered interhemispheric inhibitory control (amount of inhibition and conduction time) during isometric contraction. Hence, in this study, we sought to identify transcranial magnetic stimulation (TMS) and diffusion MRI and flortaucipir PET imaging predictors of SP using these inhibitory measures captured using TMS.MethodWe included 19 persons known to be at‐risk for the A431E PSEN1 mutation (15 MCs, 3 NCs) and one person affected by the F388S PSEN1 mutation who participated in a comprehensive study of autosomal dominant AD including TMS, diffusion MRI, and flortaucipir PET. We measured cosrticospinal inhibition for lower limbs at rest by targeting tibialis anterior muscle representation at primary motor cortex. For inter‐hemispheric inhbition (extent of inhibition and transcallosal conduction time), we stimulated the hemisphere ipsilateral to the limb performing isometric contraction. We ran a non‐parametric regression model for prediction using the gsm function from the npreg package in R© because several variables were not normally distributed (Shapiro‐Wilk test, p&lt;0.05).ResultSpasticity score (Ashworth scale) was positively associated with interhemispheric inhibition, transcallosal conduction time, and DTI measures of the corticospinal tract and pre‐post‐para central lobes of both hemispheres (Spearman rank correlation, p&lt; 0.05). Among all inhibitory TMS measures and DTI variables, the transcallosal conduction time for the lower limbs (β = 2.87) and suvr_rh_paracentral (β = ‐25.92) independently predicted increased spasticity scores. The interaction effect between these measures was insignificant. The prediction model had an adjusted R2 value of 0.89.ConclusionWe show increased transcallosal conduction time and decreased white matter integrity around the right‐hemisphere paracentral lobule is associated with increased mean spasticity scores in people with A431E PSEN1 mutations. This is consistent with other studies showing altered interhemispheric control in SP. Delay in transcallosal conduction time in A431E PSEN1 MCs may compromise inter‐hemispheric control limiting smooth movement control.