Inherited Alzheimer Disease Research Articles

Association of Resilience-Related Life Experiences on Variability on Age of Onset in Dominantly Inherited Alzheimer Disease.

It remains unknown whether the associations between protective lifestyles and sporadic dementia risk reported in observational studies also affect age at symptom onset (AAO) in autosomal dominant Alzheimer disease (ADAD) with predominant genetic influences. We investigated the associations between resilience-related life experiences and interindividual AAO variability in ADAD. We performed a longitudinal and confirmatory analysis of the Dominantly Inherited Alzheimer Network prospective observational cohort (January 2009-June 2018, follow-up duration 2.13 ± 2.22 years), involving clinical, CSF, and lifestyle/behavioral assessments. We performed a 2-pronged comprehensive resilience assessment in each cohort. Cohort 1, incorporating the general resilience definition (cognitive maintenance [Clinical Dementia Rating = 0] despite high pathology), included carriers during the periods of significant CSFp-tau181 variability and grouped into resilience/resistance outcome bins according to the dichotomous pathologic and cognitive statuses, subcategorized by the estimated years from expected symptom onset (EYO). Cohort 2, focused on ADAD-specific genetically determined time frame characterizing the onset predictability, included asymptomatic participants with available preclinical lifestyle data and AAO outcomes and grouped into delayed or earlier AAO relative to the parental AAO. Associations of cognitive, CSFp-tau181, and lifestyle/behavioral predictors with binary outcomes were investigated using logistic regression. Of 320 carriers (age 38.19 ± 10.94 years, female 56.25%), cohort 1 included 218 participants (39.00 ± 9.37 years, 57.34%) and cohort 2 included 28 participants (43.34 ± 7.40 years, 71.43%). In cohort 1, 218 carriers after -20 EYO, when the interindividual variability (SD) of CSFp-tau181 first became more than twice greater in carriers than in noncarriers, were grouped into low-risk control (asymptomatic, low pathology, n = 103), high-resilience (asymptomatic despite high pathology, n = 60), low-resilience (symptomatic despite low pathology, n = 15), and susceptible control (symptomatic, high pathology, n = 40) groups. Multivariable predictors of high resilience, controlling for age and depression, included higher conscientiousness (odds ratio 1.051 [95% CI 1.016-1.086], p = 0.004), openness to experience (1.068 [1.005-1.135], p = 0.03) (vs. susceptible controls), and agreeableness (1.082 [1.015-1.153], p = 0.02) (vs. low resilience). From 1 to 3 years before parental AAO (cohort 2), the multivariable predictor of delayed AAO, controlling for CSFp-tau181, was higher conscientiousness (0.916 [0.845-0.994], p = 0.036). Among the cognitively and socially integrated life experiences associated with resilience, measures of conscientiousness were useful indicators for evaluating resilience and predicting future dementia onset in late preclinical ADAD.

Cryo-EM structures of cotton wool plaques’ amyloid β and of tau filaments in dominantly inherited Alzheimer disease

Cotton wool plaques (CWPs) have been described as features of the neuropathologic phenotype of dominantly inherited Alzheimer disease (DIAD) caused by some missense and deletion mutations in the presenilin 1 (PSEN1) gene. CWPs are round, eosinophilic amyloid-β (Aβ) plaques that lack an amyloid core and are recognizable, but not fluorescent, in Thioflavin S (ThS) preparations. Amino-terminally truncated and post-translationally modified Aβ peptide species are the main component of CWPs. Tau immunopositive neurites may be present in CWPs. In addition, neurofibrillary tangles coexist with CWPs. Herein, we report the structure of Aβ and tau filaments isolated from brain tissue of individuals affected by DIAD caused by the PSEN1 V261I and A431E mutations, with the CWP neuropathologic phenotype. CWPs are predominantly composed of type I Aβ filaments present in two novel arrangements, type Ic and type Id; additionally, CWPs contain type I and type Ib Aβ filaments. Tau filaments have the AD fold, which has been previously reported in sporadic AD and DIAD. The formation of type Ic and type Id Aβ filaments may be the basis for the phenotype of CWPs. Our data are relevant for the development of PET imaging methodologies to best detect CWPs in DIAD.

Downstream Biomarker Effects of Gantenerumab or Solanezumab in Dominantly Inherited Alzheimer Disease

Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = -242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = -0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = -0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = -0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. ClinicalTrials.gov Identifier: NCT04623242.

White matter injury mediates the effects of PS1 mutation position on clinical measures in late disease stage

AbstractBackgroundClinical presentation of dominantly inherited Alzheimer disease (DIAD) varies across individuals with Presenilin‐1 (PS1) pathogenic mutations. Previous findings suggest that individuals with a PS1 mutation after codon 200 have more small vessel disease (SVD) pathology (Mann et al., 2001; Ryan et al., 2015). We investigated the effect of mutation position on clinical measures, including indirect effects via SVD as estimated by imaging markers of white matter injury.MethodWe evaluated 393 individuals with DIAD family history of PS1 mutations who underwent clinical and imaging assessments from the DIAN study. Among them, 245 carried a mutation before (Pre‐200MC, n = 83) or after codon‐200 (Post‐200MC, n = 162) and the remaining were non‐carriers (NC, n = 148). We assessed clinical disease stage with the Clinical Dementia Rating® Sum of Boxes (CDR®‐SB) scale and the estimated years to symptoms onset (EYO). White matter injury metrics included periventricular white matter hyperintensity (PVWMH) volumes from T2‐FLAIR and the peak width of skeletonized mean diffusivity (PSMD) from DTI (Shirzadi et al., 2022). Accounting for age of onset, sex, education, and APOE‐ɛ4 status, linear mixed‐effects models evaluated mutation position by EYO effect on SVD and on dementia in all participants. Further mediation analysis evaluated these effects within the carrier groups. Missing values were imputed using random forest algorithm.ResultPost‐200MC had more white matter injury with advanced EYO compared to Pre‐200MC (estimatesPVWMH = 65.3±31.8, P‐value&lt;.05, estimatesPSMD = 0.01±0.003, P‐value&lt;.0005) and to non‐carriers (estimatesPVWMH = 61.5±27.4, P‐value&lt;.05, estimatesPSMD = 0.01±0.003, P‐value&lt;.0005; Figure 1A). Post‐200MC presented higher CDR‐SB scores with advanced EYO compared to Pre‐200MC (estimatesCDR‐SB = 0.08±0.03, P‐value&lt;.005) and to non‐carriers (estimatesCDR‐SB = 0.19±0.02, P‐value&lt;.0001; Figure 1B). When EYO&gt;0, the effects of mutation position on CDR‐SB were significantly mediated by PVWMH (e.g., average causal mediation effect at EYO = 0.5: estimatesCDR‐SB = 0.06[0.;0.14], P‐value&lt;.05) or PSMD (e.g., average causal mediation effect at EYO = 0.5: estimatesCDR‐SB = 0.2[0.05;0.37], P‐value&lt;.05; Table1).ConclusionThese findings give further insights on how mutation position within the PS1 gene influences clinical disease presentation in DIAD. This characterization may inform future clinical trials in this population as the presence of small vessel disease contributes to a more severe disease course, which may influence treatment outcome and decisions. Funding: AARFD‐20‐681815; U19AG032438.

Model on Impingement and consequences of Alzheimer’s disease in community‐ introductory study.

AbstractBackgroundAlzheimer disease demands salutation and envisioning the cause for the disease. Despite the evolving scientific discoveries, the inhabitation among the global population reminds hiking alarmingly. The track of ways the spread of disease should leave a hint for the further research on the origin of the disease.MethodThis is a speculation much closure to current environment, to analyze effect and the pace of spread over a community. Penna model of biological aging [1] and model of colonization (lattice model) [2] are primitive base. For the model both inherited and non‐ inherited Alzheimer disease is taken into account and is obtruded into the lattice simulated on external factors such as age, genome, genetic mutation, mating partner, offspring and visualizing the change in population, symptoms and progress of the disease.ResultOutcome helps in providing an introductory knowledge on the impact Alzheimer creates in the society. It shows the growth on the level of symptoms in the population, the influence of the inheritance on the population and their progress during the course of time. The symptom to analyze the level of disease at respective age of the individual is monitored. The executions for variations in the input arguments are studied to determine the effect of disease from different perspectives.ConclusionThe Preliminary results show reasonable changes on the level of symptoms for the inherited Alzheimer’s disease. The results shell out some introductory ideas about growth of the level of symptoms of AD in the population during the course of the disease increasing number of offspring and number of mating will give a greater view of the consequences in the model and is predictable for the current scenario.1. Stauffer, D. (2007). The Penna model of biological aging. Bioinformatics and Biology Insights, 1, 117793220700100005.2. Mroz, I., &amp;Pękalski, A. (1999). Model of populations colonizing a new habitat. The European Physical Journal B‐Condensed Matter and Complex Systems, 10(1), 181‐186.

Longitudinal cerebrospinal fluid phosphorylated tau181 and total tau do not reflect tau PET retention in dominantly inherited Alzheimer disease

AbstractBackgroundAlthough Alzheimer disease (AD) related changes of tau can be measured in fluids and by positron emission tomography (PET), it remains unclear how these two are associated across the AD spectrum. To further explore the association between soluble tau related biomarkers‐ cerebrospinal fluid (CSF) total tau and p‐tau181‐ and neurofibrillary tangles (NFT) (flortaucipir PET), we compared longitudinal change of each in the dominantly inherited AD trials unit (DIAN‐TU) trial of solanezumab and gantenerumab.Method73 Mutation carriers (MC) (31 CDR&gt;0) from the DIAN‐TU‐001 study (30 gantenerumab, 20 solanezumab, 23 shared placebo) underwent longitudinal collection of CSF for measurement of p‐tau181 and total tau, and flortaucipir tau PET over 2.3 (0.92) mean (SD) years; tau PET was available at baseline for 26% of participants. Individual rates of change for CSF measures and tau PET retention were estimated using the method of least squares. Spearman correlations of the rate of change were used to assess the association between CSF and tau PET.ResultFor all MCs the change of CSF p‐tau181 and tau had no association with change in tau PET standard uptake value ratio SUVR (r = 0.01, p‐0.95 and r = 0.10, p‐0.43), figure. When limiting the correlations to those in the gantenerumab arm, where a significant reduction in p‐tau181 and total tau was previously identified, there remained no clear association between a reduction in soluble tau measures in CSF and change in tau PET SUVR (r=‐0.21, p‐0.27 and r= ‐0.08, p‐0.71).ConclusionIn dominantly inherited AD, soluble p‐tau181 and total tau changes in CSF appear to reflect disease processes that are distinct from the change in NFT pathology measured by tau PET. These results suggest the need for caution in extrapolating treatment related changes of soluble tau to those of NFT pathology.

Discovery and validation of dominantly Inherited Alzheimer’s Disease mutations in populations from Latin America.

AbstractBackgroundMore than 300 variants in the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes have been reported to cause Dominantly Inherited Alzheimer Disease (DIAD). However, most of these reports come from non‐Hispanic whites and the full extent of DIAD remains understudied in Latin American (LatAm) countries. Here we describe five AD affected families from LatAm carrying novel DIAD variants.MethodsFive novel variants in the presenilin1 (PSEN1) gene were identified in Brazilian (p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se and p.Ala275Thr) and Mexican families (p.Ile414Thr). To assign the likelihood of pathogenicity among these variants of unknown significance, we report pedigree information, frequency in control populations, in silico predictions, and cell‐based models.ResultThe mean age at onset in newly identified families was 43.5 years (range 36‐54). The novel variants were absent from gnomAD genome and exome databases. Two PSEN1 variants (p.Val103_Ser104delinsGly and p.Lys395Ile) showed segregation with the disease status; segregation studies were not possible in the other three families. Additionally, PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr produced Aβ profiles consistent with known AD pathogenic mutations (i.e. increased extracellular Aβ42/40); thus, we consider them as likely pathogenic. PSEN1 p.Ile414Thr did not alter Aβ in a manner consistent with a known pathogenic mutation; therefore, PSEN1 p.Ile414Thr likely represents an AD risk factor or benign polymorphism.ConclusionOur study provides further insights into the genetics of AD in LatAm by identifying novel DIAD pathogenic variants in Brazil and Mexico, two countries with distinct genetic admixtures. Expanding the families eligible to participate in observational and clinical trials of DIAD enhances the generalizability of diagnosis and treatment approaches.

Amyloid-Related Imaging Abnormalities in the DIAN-TU-001 Trial of Gantenerumab and Solanezumab: Lessons from a Trial in Dominantly Inherited Alzheimer Disease.

To determine the characteristics of participants with amyloid-related imaging abnormalities (ARIA) in a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease (DIAD). 142 DIAD mutation carriers received either gantenerumab SC (n=52), solanezumab IV (n=50), or placebo (n=40). Participants underwent assessments with the Clinical Dementia Rating® (CDR®), neuropsychological testing, CSF biomarkers, β-amyloid positron emission tomography (PET), and magnetic resonance imaging (MRI) to monitor ARIA. Cross-sectional and longitudinal analyses evaluated potential ARIA-related risk factors. Eleven participants developed ARIA-E, including 3 with mild symptoms. No ARIA-E was reported under solanezumab while gantenerumab was associated with ARIA-E compared to placebo (odds ratio [OR]=9.1, confidence interval [CI][1.2, 412.3]; p= 0.021). Under gantenerumab, APOE-ɛ4 carriers were more likely to develop ARIA-E (OR=5.0, CI[1.0, 30.4]; p= 0.055), as were individuals with microhemorrhage at baseline (OR=13.7, CI[1.2, 163.2]; p= 0.039). No ARIA-E was observed at the initial 225 mg/month gantenerumab dose, and most cases were observed at doses >675 mg. At first ARIA-E occurrence, all ARIA-E participants were amyloid-PET+, 60% were CDR >0, 60% were past their estimated year to symptom onset, and 60% had also incident ARIA-H. Most ARIA-E radiologically resolved after dose adjustment and developing ARIA-E did not significantly increase odds of trial discontinuation. ARIA-E was more frequently observed in the occipital lobe (90%). ARIA-E severity was associated with age at time of ARIA-E. In DIAD, solanezumab was not associated with ARIA. Gantenerumab dose over 225 mg increased ARIA-E risk, with additional risk for individuals APOE-ɛ4(+) or with microhemorrhage. ARIA-E was reversible on MRI in most cases, generally asymptomatic, without additional risk for trial discontinuation. ANN NEUROL 2022;92:729-744.

Association of BDNF Val66Met With Tau Hyperphosphorylation and Cognition in Dominantly Inherited Alzheimer Disease

Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism moderates increases in cerebrospinal fluid (CSF) levels of tau and phosphorylated tau 181 (p-tau181), measured using immunoassay, and cognitive decline in presymptomatic dominantly inherited Alzheimer disease (DIAD). Advances in mass spectrometry show that CSF tau phosphorylation occupancy at threonine 181 and 217 (p-tau181/tau181, p-tau217/tau217) increases with initial β-amyloid (Aβ) aggregation, while phosphorylation occupancy at threonine 205 (p-tau205/tau205) and level of total tau increase when brain atrophy and clinical symptoms become evident. To determine whether site-specific tau phosphorylation occupancy (ratio of phosphorylated to unphosphorylated tau) is associated with BDNF Val66Met in presymptomatic and symptomatic DIAD. This cross-sectional cohort study included participants from the Dominantly Inherited Alzheimer Network (DIAN) and Aβ-positive cognitively normal older adults in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Data were collected from 2009 through 2018 at multicenter clinical sites in the United States, United Kingdom, and Australia, with no follow-up. DIAN participants provided a CSF sample and completed clinical and cognitive assessments. Data analysis was conducted between March 2020 and March 2021. Mass spectrometry analysis was used to determine site-specific tau phosphorylation level; tau levels were also measured using immunoassay. Episodic memory and global cognitive composites were computed. Of 374 study participants, 144 were mutation noncarriers, 156 were presymptomatic mutation carriers, and 74 were symptomatic carriers. Of the 527 participants in the network, 153 were excluded because their CSF sample, BDNF status, or both were unavailable. Also included were 125 Aβ-positive cognitively normal older adults in the ADNI. The mean (SD) age of DIAD participants was 38.7 (10.9) years; 43% were women. The mean (SD) age of participants with preclinical sporadic AD was 74.8 (5.6) years; 52% were women. In presymptomatic mutation carriers, compared with Val66 homozygotes, Met66 carriers showed significantly poorer episodic memory (d = 0.62; 95% CI, 0.28-0.95), lower hippocampal volume (d = 0.40; 95% CI, 0.09-0.71), and higher p-tau217/tau217 (d = 0.64; 95% CI, 0.30-0.97), p-tau181/tau181 (d = 0.65; 95% CI, 0.32-0.99), and mass spectrometry total tau (d = 0.43; 95% CI, 0.10-0.76). In symptomatic mutation carriers, Met66 carriers showed significantly poorer global cognition (d = 1.17; 95% CI, 0.65-1.66) and higher p-tau217/tau217 (d = 0.53; 95% CI, 0.05-1.01), mass spectrometry total tau (d = 0.78; 95% CI, 0.28-1.25), and p-tau205/tau205 (d = 0.97; 95% CI, 0.46-1.45), when compared with Val66 homozygotes. In preclinical sporadic AD, Met66 carriers showed poorer episodic memory (d = 0.39; 95% CI, 0.00-0.77) and higher total tau (d = 0.45; 95% CI, 0.07-0.84) and p-tau181 (d = 0.46; 95% CI, 0.07-0.85). In DIAD, clinical disease stage and BDNF Met66 were associated with cognitive impairment and levels of site-specific tau phosphorylation. This suggests that pharmacological strategies designed to increase neurotrophic support in the presymptomatic stages of AD may be beneficial.

Presence of co‐pathology in sporadic early‐onset Alzheimer disease versus dominantly inherited Alzheimer disease

A small proportion of Alzheimer disease (AD), known as early onset AD (EOAD), has symptomatic age at onset (AAO) before age 65. About 5-10% of EOAD is dominantly inherited (DIAD); the rest is termed to be sporadic (sEOAD). Although DIAD and sEOAD share the hallmark plaques and tangles that define AD neuropathologic change (ADNC), the relative burdens of these lesions and the frequencies of non-AD co-pathologies in sEOAD relative to DIAD remain unknown.We compared the neuropathological burden of AD and the frequency of AD and non-AD pathologies in 363 sEOAD cases from the National Alzheimer's Coordinating Center (NACC) and in 62 DIAD cases (45 from the Dominantly Inherited Alzheimer Network (DIAN); 17 from NACC). Operational criteria for the classification of AD and other co-pathologies followed accepted NACC guidelines. Only cases with AAO under 65 and a primary pathological diagnosis of 'high ADNC' were included.DIAD participants [mean AAO = 42.9 ± 8.1 years] had higher CERAD scores than sEOAD cases [mean AAO = 57.1 ±7.2 years] [p=0.03]. Braak stages were similar for both cohorts. The frequency and severity of cerebral amyloid angiopathy (CAA) was higher in DIAD versus sEOAD [CAA: 100% vs 83.7%, p=0.001; severe CAA: 40.3% versus 20.1%, p<0.001, respectively]. The frequency of at least one non-AD/non-CAA pathology was similar between DIAD and sEOAD [63.9% vs 59.7%, p=0.61], but the frequency of multiple pathologies (two or more) was lower in DIAD [3.2%] than in sEOAD [21.0%, p<0.001]. Lewy body disease (LBD) was the most prevalent non-AD/non-CAA pathology in both cohorts [58.1% in DIAD, 51.2% in sEOAD; p=0.39]. Hippocampal sclerosis [14.5%] and argyrophilic grain disease [2.5%], were observed in sEOAD, but were absent from DIAD.DIAD cases show greater neuritic plaque density and more severe CAA than sEOAD cases, but comparable Braak NFT stages. The similar frequencies of LBD in both cohorts may be linked to severe AD neuropathological change, rather than co-incident age-related pathologies. Future studies should include methodologically uniform assessments of both cohorts to explore age-related and non-age-related mechanisms that may account for differences in the burdens of ADNC lesions and non-AD co-pathologies.

Characterization of amyloid‐related imaging abnormality in the DIAN‐TU‐001 trial

AbstractBackgroundAmyloid‐related imaging abnormalities (ARIA), edema (E) or hemorrhagic (H) type, have been reported in trials of anti‐β‐amyloid passive immunotherapies in sporadic and dominantly inherited Alzheimer Disease (DIAD). However, beyond APOE‐ɛ4 the risk factors and clinical implications of ARIA are not well understood, especially in DIAD populations. Here we characterize ARIA, focusing on ARIA‐E in the DIAN‐TU‐001 trial evaluating gantenerumab and solanezumab in DIAD.MethodThe DIAN‐TU‐001 trial enrolled 194 participants, including 144 DIAD mutation‐carriers receiving gantenerumab (n=52), solanezumab (n=52), or a placebo (n=40). Clinical assessments included the Clinical Dementia Rating (CDR). Imaging assessments included PiB‐PET and safety MR, including T2‐FLAIR and T2*‐GRE. Treatment dosage and APOE‐ɛ4 status were also reported.ResultEleven participants developed a total of 14 ARIA‐E episodes (discovered on scheduled safety MR) and three had associated mild symptoms reported in retrospect (e.g. headache, imbalance disorder). Though one ARIA‐E case was observed in the solanezumab arm, the following results focus on the gantenerumab arm to prevent unblinding. Recipients of gantenerumab were more likely to develop ARIA‐E compared to placebo (odds ratio (OR)=9.29, 95% confidence interval (CI)=[1.1,75.9], p‐value&lt;0.05). ARIA‐E participants were PiB‐PET+ and 60% were CDR&gt;0. APOE‐ɛ4 tends to be associated with risk for developing ARIA‐E (OR=5.0, 95%CI=[1.0,30.4], p‐value=0.055). ARIA‐E were not observed at initial 225mg dose and were first observed after a titration step (within 4‐24 weeks, after 1‐6 injections, Table 1). Time‐to‐resolution of ARIA‐E was 10.4±6.2weeks. Seven of ten ARIA‐E patients paused/reduced dose escalation and three discontinued treatment. Overall, developing ARIA‐E did not increase the odds of trial discontinuation (OR=1.57, 95%CI=[0.34,7.33], p‐value=0.57). ARIA‐E occurred primarily in the occipital lobe (71%) with associated incident ARIA‐H (microhemorrhages or superficial siderosis) in 60% of ARIA‐E participants. ARIA‐E size was associated with microhemorrhage count (Spearman’s rho=0.72, p‐value&lt;0.05), rate of change (rho=0.78, p‐value&lt;0.01), and baseline PiB‐PET (rho=0.68, p‐value&lt;0.05). Normalizing by baseline, PiB‐PET decreased similarly in ARIA‐E+ (‐0.21±0.20) and ARIA‐E‐ (‐0.16±0.20) participants.ConclusionIn DIAD, gantenerumab dose over 225mg increased ARIA‐E risk, possibly more for APOE‐ɛ4 carriers. ARIA‐E was reversible, generally asymptomatic, and without increased odds of trial discontinuation. These aspects of drug response give insights for managing ARIA‐E occurrence in future trials.

The design of Dominantly Inherited Alzheimer Disease Trial of the anti‐tau antibody, E‐2814, on the DIAN‐TU Tau Next Generation Platform

AbstractBackgroundTau pathology is closely associated with the onset and progression of Alzheimer’s disease. Recent advances in drugs that target tau suggest the potential to prevent or attenuate the pathophysiology and pathology of tau. Novel CSF and blood tau species including specific phospho‐tau (p‐tau) and truncated species containing the microtubule binding region of tau (MTBR‐tau) which aggregates in tau tangles, increases 10 years or more before tau tangles are detected by tau‐PET. Two stages of AD are identified and studied using soluble p‐tau and MTBR‐tau forms in the asymptomatic stage and Tau PET in the post‐tangle symptomatic stage. E2814, an anti‐tau monoclonal antibody targets MTBR‐tau and decreases tau pathology in animal models.MethodWe designed an anti‐tau trial to target soluble tau species in two cohorts including pre‐tangle asymptomatic and post‐tangle symptomatic participants in dominantly inherited AD (DIAD). We analyzed longitudinal clinical, cognitive, tau PET and CSF measures of tau species including, multiple p‐tau species (e.g., p‐tau217, 231, 181, 205), total tau, MTBR‐tau (e.g., MTBR‐tau243, MTBR‐tau299, and MTBR‐tau354), and NfL in DIAD cohorts from DIAN and DIAN‐TU. Novel trial design and statistical approaches have been developed to address primary and secondary outcomes, magnitude of effect by stage of disease (pre‐tangle vs. post‐tangle), and potential for prevention.ResultWe designed a trial of two cohorts, each powered, with different biomarker outcomes: in the pre‐tangle, tau‐PET negative cohort, CSF ptau217/tau217 is the endpoint; for the post‐tangle tau‐PET positive cohort, tau‐PET is the endpoint. Further, each cohort will measure target engagement by CSF MTBR‐tau and downstream effects on soluble total tau, p‐tau and MTBR tau with common measures of neurodegeneration by CSF and blood NfL, atrophy by MRI, hypometabolism by FDG‐PET, effects on amyloid by abeta42/40 and amyloid‐PET, and cognitive and clinical measures. This design is facilitated by the predictable pattern of biomarker changes observed in DIAD allowing appropriate powering of the study even in this rare condition.ConclusionThe Tau Next Generation Platform will address disease progression, before and after tangle formation begins, assessing when an anti‐MTBR tau monoclonal antibody will have the largest effects. It is the first anti‐tau trial for DIAD.

PS1 mutation position influences regional PiB‐uptake and white matter lesion volume

AbstractBackgroundMutations in the Presenilin‐1 (PS1) gene account for 80% of dominantly inherited Alzheimer disease (DIAD). Previous findings suggest PS1 mutation position relative to codon 200 may impact the distribution and amount of cerebral β‐amyloid pathology (Mann et al., 2001; Ryan et al., 2015). We investigated the effect of mutation position on imaging markers of β‐amyloidosis and small vessel disease with a focus on regional variability and disease progression.MethodIndividuals with PS1 mutations before (Pre‐200MC, n=76) or after codon‐200 (Post‐200MC, n=126) and non‐carriers of these mutations (n=129) from the same families were assessed with the Clinical Dementia Rating (CDR) scale and underwent neuroimaging including PiB‐PET to assess β‐amyloid burden and T2‐FLAIR MRI to assess white matter lesions. A subset (52 non‐carriers, 63 Pre‐200MC, 73 Post‐200MC) had longitudinal data available. Accounting for estimated year to symptom onset (EYO) and APOE‐ɛ4 status, cross‐sectional and longitudinal linear mixed‐effects models evaluated the effect of mutation positions on PiB‐uptake (SUVR) in 40 FreeSurfer regions, white matter hyperintensity (WMH) volumes in periventricular and deep areas, and their associations with dementia.ResultPre‐200MC had earlier age of symptom onset versus Post‐200MC (43.34±8.97 versus 46.81±7.55 years, p&lt;0.0001). Pre‐200MC presented with higher amyloid burden (mean cortical SUVR of 2.28±1.27 versus 1.91±1.0, p&lt;0.02). Differences were observed mostly in frontal, temporal, and subcortical regions. Stronger associations between PiB‐uptake and EYO were observed in Pre‐200MC versus Post‐200MC in nearly all regions (precuneus: F(1,192)=9.37, p&lt;0.01; caudate: F(1,192)=17.65, p&lt;0.001; Figure 1A). In contrast, Post‐200MC presented with stronger associations of periventricular WMH with EYO (F(1,25)=5.02, p&lt;0.05) and deep WMH with dementia as measured by CDR‐SB (F(1,25)=14.01, p=0.01). Longitudinal analyses showed higher rates of change in PiB uptake in Pre‐200MC versus Post‐200MC in several frontal, temporal, and striatal regions (inferior temporal: F(1,171)=13.71, p&lt;0.0005; caudate: F(1,171)=8.22, p&lt;0.005; Figure 1B). Mutation position did not influence rates of change in WMH volumes nor cognitive decline.ConclusionThese findings confirm that mutation position within the PS1 gene influences disease presentation in DIAD. Improved characterization of heterogeneity in disease progression may inform further clinical trials in this population. Further investigation into biological mechanisms responsible for these differences is necessary. Funding: AARFD‐20‐681815;U19AG032438.

Longitudinal changes of multiple CSF phosphorylated tau sites in dominantly inherited Alzheimer disease

AbstractBackgroundRecent analyses of tau phosphorylation in cerebrospinal fluid (CSF) from dominantly inherited Alzheimer disease (DIAD) patients have pinpointed early modification of phosphorylated tau (p‐tau) at 217 (pT217) occurring simultaneously with emergence of amyloid plaques. This has opened new perspective in diagnosing AD pathology at preclinical stages using ptau in CSF and plasma. Tau is phosphorylated at many sites in brain and a subset of them is detectable in CSF. To date, we have investigated four p‐tau sites and demonstrated the modifications of pT217, pT181 and pT205 start respectively 21, 19 and 13 years before estimated year to symptom onset (EYO) when pS202 remained unchanged. We extend the list of monitored ptau sites in the DIAN cohort to ten tau residues.Method589 CSF samples from 370 participants in DIAD families were analyzed by tau immunopurification and multiplex‐targeted mass spectrometry using nanoLC‐Q‐LTQ‐Orbitrap instrument. We measured phosphorylation occupancy and ptau level at T111, T153, T175, T181, S199, S202, T205, S208, T217 and T231. For each ptau, we calculated area under curve (AUC) of receiver operating characteristic (ROC) to detect amyloidosis as measured by PiB‐PET. We determined phosphorylation amount and rate of change over the course of the disease based on EYO.ResultThe most to least sensitive phosphorylated sites for detecting amyloidosis in mutation carriers were T217, T181, T153, T111, T231, S208 and T205 with AUC ranging from 0.96 to 0.87. T175, S199 and S202 were not significantly modified. For the newly investigated sites pT111, pT153, pS208 and T231, we found significant hyperphosphorylation compared to non‐carriers at EYOs ranging from ‐22 to ‐19 years. Longitudinal analyses of pT153, pS208 and pT231 demonstrated a decreasing of the phosphorylation after symptoms as previously observed for pT217 and pT181. Separately, pT111 continued to increase after onset.ConclusionThis study corroborates the distinct response of tau residues to hyperphosphorylation over AD process. We confirm pT217 is the earliest abnormally modified phosphorylated site in AD amongst the 10 sites investigated in CSF. Our results support the use of pT153, pT111 pT231 and pS208 as additional ptau biomarkers for the diagnosis of asymptomatic AD.

Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease.

ObjectiveTo investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD).MethodsMutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease.ResultsThree percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. APOE ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year).ConclusionOur study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs.

A time‐embedding network model captures dynamic longitudinal pathology changes in a dominantly inherited Alzheimer disease population

AbstractBackgroundPopulation‐level analyses of autosomal dominant Alzheimer disease (ADAD) cohorts have revealed a roadmap of neuropathological and volumetric changes that increase over disease‐time and culminate in severe cognitive impairment. Traditional statistical analysis approaches struggle to integrate these cohort‐level dynamics with patient data to inform disease trajectory predictions at the individual level. Current machine learning approaches excel at this integration of population and individual level information, but require much larger sample sizes than current Alzheimer disease research cohorts can provide. The current work introduces a time‐embedding neural network in order to accurately represent known disease‐time dependent patterns among neuroimaging variables. The network is trained to predict ADAD carrier status to demonstrate the ability of this framework to make actionable predictions within ADAD populations.Method468 participants from families carrying gene mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) enrolled in the Dominantly Inherited Alzheimer Network (DIAN) were selected for analysis. Structural MRI, [11C] Pittsburgh Compound B (PiB) PET, and [18F] Fluorodeoxyglucose (FDG) PET region of interest imaging data was utilized (Table 1). DIAN estimated years to symptom onset (EYO) was used as disease‐time. The time‐embedding network learns EYO‐dependent representations of all imaging data in both mutation carrier and non‐carrier groups. These representations are combined with control variables and passed to a decoder network trained to output carrier status predictions (Figure 1).ResultThe time‐embedding network captures three main longitudinal pathology dynamics that correspond to known longitudinal PiB PET, FDG PET, and volumetric pathology changes in ADAD populations (Figure 2A). The network was successfully trained to predict ADAD carrier status in individual participants (Figure 2B). Prediction accuracy increases as the time of prediction moves closer to onset of clinical symptoms (Figure 2C).ConclusionThe time‐embedding network model is able to accurately represent nonlinear time‐dependent processes in a low‐dimensional, sparsely sampled embedding. This embedding provides an interpretable framework that is consistent with known longitudinal pathology changes when applied to an ADAD population, and can be trained to make accurate longitudinal predictions with currently available data sets.

Dominantly inherited Alzheimer disease: Frequency, genetic heterogeneity, and clinical phenotype in Latin America

AbstractBackgroundMore than 300 pathogenic variants in APP, PSEN1 and PSEN2 genes have been reported causing Dominant Inhered Alzheimer Disease (DIAD); most of these reports come from Northern hemisphere countries. In recent years, a growing number of familial AD cases have become known in Central and South American countries; however, little is known about epidemiology and clinical‐genetic profile of DIAD in Latin American (LatAm) countries. We aimed to systematically review and describe DIAD cases reported in LatAm populations.MethodA systematic review for all DIAD cases reported in LatAm was completed between September 2019 to December 2019. The search strategy included the following major databases: MedLine, SciELO, Cochrane, and LILACS. More than 927 records were screened and 106 peer‐reviewed publications on DIAD families from LATAM were included in the final analysis. We extracted individual‐level data on the age at onset(AAO), disease course, and the presence/absence of neurological findings. Findings extracted from literature were updated by local researchers . The combined dataset included 843 family members, of whom 237 were affected by DIAD. Analyses were done using descriptive statistics, comparisons of means and frequencies.Result24 DIAD pathogenic variants have been reported in LatAm countries, including 21 PSEN1, two PSEN2 and one APP variant. Countries with higher DIAD frequency were Colombia, Puerto Rico, Mexico, and Cuba, usually related to founders' effects on these regions. AAO differed by causing gene, with a younger age at onset for individuals harboring PSEN1 variants, followed by APP and PSEN2 carriers (43.8 ± 8.9 years vs 48.6 ± 1.6 years vs 52.2 ± 2.1 years respectively, p &lt; 0.0001). The most common clinical presentation was amnestic. Atypical features were described with M146V‐PSEN1(Argentina) and A431E‐PSEN1 (Mexico) presenting with FTD‐like syndrome and spastic paraparesis respectively. We found that affected individuals carrying PSEN1 mutations also experience myoclonus, pyramidal, and cerebellar signs (p &lt; 0.001, p = 0.002, and p = 0.003, respectively).ConclusionThis work describes an initial overview of DIAD in LatAm. The discovery and clinical characterization of DIAD families from Lain America will inform the development of the DIAN‐observational study in the region and will create a cohort ready population for clinical the upcoming trials.

Longitudinal 18F-FDG Images in Patients With Alzheimer Disease Over More Than 9 Years From a Preclinical Stage.

Brain F-FDG uptake reportedly starts to decline more than 10 years before the onset of cognitive decline in dominantly inherited Alzheimer disease (AD). We compared longitudinal F-FDG images in sporadic AD to aging data from a large sample size to expand the current knowledge of F-FDG reduction for AD progression. Participants comprised 2 individuals (subjects A and B at ages 65 and 68 years, respectively) and 107 control subjects (67.9 [SD, 4.9] years). Subject A underwent F-FDG PET a total of 8 times over 9 years from the preclinical to early dementia stages. Subject B underwent F-FDG PET a total of 11 times over 12 years from the preclinical to mild cognitive impairment stages. Control subjects underwent F-FDG PET twice over a mean follow-up period of 7.8 years. After placing the volume of interest on the AD-related hypometabolic regions, the longitudinal F-FDG images were compared among the subjects and control subjects. For the control group, the rate of F-FDG reduction was 2.2% per decade (ie, aging effects). The rates of F-FDG reduction were 9.41% over 9 years and 9.07% over 12 years in subjects A and B, respectively. We estimated that F-FDG uptake started to decrease 4 and 2 years before indications of memory loss in subjects A and B, respectively. The present study suggests that the time between the beginning of F-FDG reduction and the onset of cognitive decline may be shorter in elderly individuals with AD compared with the recently estimated period in dominantly inherited AD.

Autosomal dominantly inherited alzheimer disease: Analysis of genetic subgroups by machine learning

Despite subjects with Dominantly-Inherited Alzheimer’s Disease (DIAD) represent less than 1% of all Alzheimer’s Disease (AD) cases, the Dominantly Inherited Alzheimer Network (DIAN) initiative constitutes a strong impact in the understanding of AD disease course with special emphasis on the presyptomatic disease phase. Until now, the 3 genes involved in DIAD pathogenesis (PSEN1, PSEN2 and APP) have been commonly merged into one group (Mutation Carriers, MC) and studied using conventional statistical analysis. Comparisons between groups using null-hypothesis testing or longitudinal regression procedures, such as the linear-mixed-effects models, have been assessed in the extant literature.Within this context, the work presented here performs a comparison between different groups of subjects by considering the 3 genes, either jointly or separately, and using tools based on Machine Learning (ML). This involves a feature selection step which makes use of ANOVA followed by Principal Component Analysis (PCA) to determine which features would be realiable for further comparison purposes. Then, the selected predictors are classified using a Support-Vector-Machine (SVM) in a nested k-Fold cross-validation resulting in maximum classification rates of 72–74% using PiB PET features, specially when comparing asymptomatic Non-Carriers (NC) subjects with asymptomatic PSEN1 Mutation-Carriers (PSEN1-MC). Results obtained from these experiments led to the idea that PSEN1-MC might be considered as a mixture of two different subgroups including: a first group whose patterns were very close to NC subjects, and a second group much more different in terms of imaging patterns. Thus, using a k-Means clustering algorithm it was determined both subgroups and a new classification scenario was conducted to validate this process. The comparison between each subgroup vs. NC subjects resulted in classification rates around 80% underscoring the importance of considering DIAN as an heterogeneous entity.

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.