Identification of common human TMEM173 genotypes associated with Alzheimer's disease.

Mutations in APP, PSEN1, and PSEN2 lead to early-onset Alzheimer disease (EOAD) but account for only approximately 11% of EOAD overall, leaving most of the genetic risk for the most severe form of Alzheimer disease unexplained. This extreme phenotype likely harbors highly penetrant risk variants, making it primed for discovery of novel risk genes and pathways for AD. To search for rare variants contributing to the risk for EOAD. In this case-control study, whole-exome sequencing (WES) was performed in 51 non-Hispanic white (NHW) patients with EOAD (age at onset <65 years) and 19 Caribbean Hispanic families previously screened as negative for established APP, PSEN1, and PSEN2 causal variants. Participants were recruited from John P. Hussman Institute for Human Genomics, Case Western Reserve University, and Columbia University. Rare, deleterious, nonsynonymous, or loss-of-function variants were filtered to identify variants in known and suspected AD genes, variants in multiple unrelated NHW patients, variants present in 19 Hispanic EOAD WES families, and genes with variants in multiple unrelated NHW patients. These variants/genes were tested for association in an independent cohort of 1524 patients with EOAD, 7046 patients with late-onset AD (LOAD), and 7001 cognitively intact controls (age at examination, >65 years) from the Alzheimer's Disease Genetics Consortium. The study was conducted from January 21, 2013, to October 13, 2016. Alzheimer disease diagnosed according to standard National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer Disease and Related Disorders Association criteria. Association between Alzheimer disease and genetic variants and genes was measured using logistic regression and sequence kernel association test-optimal gene tests, respectively. Of the 1524 NHW patients with EOAD, 765 (50.2%) were women and mean (SD) age was 60.0 (4.9) years; of the 7046 NHW patients with LOAD, 4171 (59.2%) were women and mean (SD) age was 77.4 (8.6) years; and of the 7001 NHW controls, 4215 (60.2%) were women and mean (SD) age was 77.4 (8.6) years. The gene PSD2, for which multiple unrelated NHW cases had rare missense variants, was significantly associated with EOAD (P = 2.05 × 10-6; Bonferroni-corrected P value [BP] = 1.3 × 10-3) and LOAD (P = 6.22 × 10-6; BP = 4.1 × 10-3). A missense variant in TCIRG1, present in a NHW patient and segregating in 3 cases of a Hispanic family, was more frequent in EOAD cases (odds ratio [OR], 2.13; 95% CI, 0.99-4.55; P = .06; BP = 0.413), and significantly associated with LOAD (OR, 2.23; 95% CI, 1.37-3.62; P = 7.2 × 10-4; BP = 5.0 × 10-3). A missense variant in the LOAD risk gene RIN3 showed suggestive evidence of association with EOAD after Bonferroni correction (OR, 4.56; 95% CI, 1.26-16.48; P = .02, BP = 0.091). In addition, a missense variant in RUFY1 identified in 2 NHW EOAD cases showed suggestive evidence of an association with EOAD as well (OR, 18.63; 95% CI, 1.62-213.45; P = .003; BP = 0.129). The genes PSD2, TCIRG1, RIN3, and RUFY1 all may be involved in endolysosomal transport-a process known to be important to development of AD. Furthermore, this study identified shared risk genes between EOAD and LOAD similar to previously reported genes, such as SORL1, PSEN2, and TREM2.

The Genetics of Alzheimer Disease: Back to the Future

The aims of this cross-sectional study were (i) to compare the overall glucose metabolism between early onset and late onset Alzheimer's disease in a large sample of patients; and (ii) to investigate the pattern of glucose metabolism as a function of dementia severity in early onset versus late onset Alzheimer's disease, using a statistical parametric mapping (SPM) analysis. Subjects consisted of four groups: 74 patients with early onset Alzheimer's disease, 46 patients with late onset of the disease, and two control groups age matched to each patient group. All the subjects underwent 2-[(18)F]fluoro-2-deoxy-d-glucose (FDG)-PET under the same scanning conditions. Severity of dementia was rated with the Clincial Dementia Rating (CDR). Voxel-based SPM99 was used for statistical analyses. Overall glucose hypometabolism of early onset Alzheimer's disease patients was much greater in magnitude and extent than that of late onset patients, though both groups were similar in dementia severity: the early onset group showed more severe hypometabolism in parietal, frontal and subcortical (basal ganglia and thalamus) areas. When the decline of glucose metabolism was compared as a function of CDR stage, the slope was steeper in early onset than in late onset Alzheimer's disease. The rapid decline occurred at CDR 0.5-1 in the early onset group, whereas similar changes occurred at CDR 2-3 in the late onset group. The greater hypometabolism in early onset than in late onset patients is required to reach the same severity of dementia, probably reflecting greater functional reserve in younger than in older subjects. Alternatively, the metabolic decline curve suggests that the early onset patients may take a more rapid course in the reduction of glucose metabolism than the late onset patients.

Tau accumulation in the nucleus basalis of Meynert (nbM) has been documented in Alzheimer's disease (AD), but its relationship to neuropathological changes in other brain regions and cognitive deficits remains unclear, particularly between early-onset AD (EOAD) and late-onset AD (LOAD). To evaluate tau accumulation patterns in the nbM and other brain regions in EOAD and LOAD using 18F-florzolotau PET and examine correlations with cognitive function. Thirty-eight amyloid-positive AD patients (15 EOAD, 23 LOAD) and 46 healthy controls underwent 18F-florzolotau PET. Tau levels were quantified in the nbM and Braak-staging regions. Postmortem brain samples were examined to assess 18F-florzolotau binding to tau deposits. EOAD showed a higher overall tau burden, including in the nbM, compared with LOAD. However, nbM tau levels correlated more strongly with cognitive decline in LOAD than EOAD. The relationship between nbM tau and neocortical tau differed between EOAD and LOAD. Histopathology revealed abundant 18F-florzolotau labeling of neurofibrillary tangles (NFTs) and ghost tangles in AD nbM samples. This study provides the first in vivo PET evidence of differential nbM tau pathology between EOAD and LOAD, with higher accumulation but weaker correlation to cognition in EOAD. The distinct relationships between nbM and cortical tau in EOAD and LOAD suggest divergent pathological trajectories. 18F-florzolotau PET successfully visualized NFTs and extracellular ghost tangles in the nbM across AD stages. These findings highlight the importance of considering age of onset when evaluating tau pathology and its clinical correlates in AD.

Temporoparietal cortical thickness outperforms hippocampal volume as a biomarker for atypical and early-onset Alzheimer's disease

Objective: Early-onset Alzheimer's disease (EAD) shows distinct features from late-onset Alzheimer's disease (LAD). To explore the characteristics of EAD, clinical, neuropsychological, and functional imaging studies have been conducted. However, differences between EAD and LAD are not clear, especially in terms of brain connectivity and networks. In this study, we investigated the differences in metabolic connectivity between EAD and LAD by adopting graph theory measures.Methods: We analyzed 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) images to investigate the distinct features of metabolic connectivity between EAD and LAD. Using metabolic connectivity and graph theory analysis, metabolic network differences between LAD and EAD were explored.Results: Results showed the decreased connectivity centered in the cingulate gyri and occipital regions in EAD, whereas decreased connectivity in the occipital and temporal regions as well as increased connectivity in the supplementary motor area were observed in LAD when compared with age-matched control groups. Global efficiency and clustering coefficients were decreased in EAD but not in LAD. EAD showed progressive network deterioration as a function of disease severity and clinical dementia rating (CDR) scores, mainly in terms of connectivity between the cingulate gyri and occipital regions. Global efficiency and clustering coefficients were also decreased along with disease severity.Conclusion: These results indicate that EAD and LAD have distinguished features in terms of metabolic connectivity, with EAD demonstrating more extensive and progressive deterioration.

Rodent models of Alzheimer's disease (AD) have provide invaluable insights on AD pathophysiology in the past decades. Therefore, the evaluation of similarities between models and human pathology can improve AD research. Here, we compared hippocampal transcriptomic profiles of human late onset-AD (LOAD) and early-onset AD (EOAD) individuals with three mouse models (hAβ-KI, APP/PS1 and 5xFAD) to evaluate transcriptomic similarities between these animal models and human pathology. While APP/PS1 and 5xFAD are well established EOAD models, hAβ-KI was recently introduced as a potential LOAD model. We hypothesized that APP/PS1 and 5xFAD will have more similiatires to EOAD human AD and hAβ-KI with human LOAD. Five publicly available human AD/cognitively unimpaired transcriptomic profiles were collected from GEO (https://www.ncbi.nlm.nih.gov/geo/), merged and submitted to differential expression analysis (DEA) and functional enrichment analysis (FEA) using R. APP/PS1 mouse model RNAseq data from two datasets (GSE149661 and GSE145907) were also collected. Finally, RNAseq data of 5xFAD and hAβ-KI mouse models were obtained from AMP-AD Knowledge Portal (https://www.synapse.org/) using synapser and synapserutils packages. All animal models were submitted to DEA and FEA. DEA identified 1164, 3261 and 1782 differentially expressed genes (DEGs) for the comparisons between hAβ-KI, 5xFAD and APP/PS1 mutants versus wild type controls, respectively. The hAβ-KI mice model exhibited more DEGs in common with LOAD than with EOAD patients. Interestingly, APP/PS1 and 5xFAD mice also presented more DEGs in common with LOAD than with EOAD patients. However, 5xFAD showed significantly higher DEGs intersection with EOAD than with hAβ-KI and APP/PS1. FEA of Gene Ontology biological processes revealed 92% overlap of terms enriched in hAβ-KI with LOAD, but only 32% with EOAD. Unexpectedly, both 5xFAD and APP/PS1 presented more than 75% of their enriched terms in common with LOAD patients compared to ∼45% in EOAD. New animal models are being introduced constantly to better simulate AD pathology. Hence, the evaluation of their overlap with human pathology is paramount. We found that the new hAβ-KI shows a good fit towards LOAD, as was its original purpose. APP/PS1 and 5xFAD on the other hand, were less optimal than expected to model EOAD.

Early-onset Alzheimer's disease constitutes ∼5-10% of Alzheimer's disease. Its clinical characteristics and biomarker profiles are not well documented. To compare the characteristics covering clinical, neuropsychological and biomarker profiles between patients with early- and late-onset Alzheimer's disease, we enrolled 203 patients (late-onset Alzheimer's disease = 99; early-onset Alzheimer's disease = 104) from a Chinese hospital-based cohort, the Shanghai Memory Study. A full panel of plasma biomarkers under the amyloid/tau/neurodegeneration framework including plasma amyloid beta 40, amyloid beta 42, total-tau, neurofilament light chain and phosphorylated tau 181 were assayed using ultra-sensitive Simoa technology. Seventy-five patients underwent an amyloid molecular positron emission tomography scan whereas 43 received comprehensive amyloid, Tau deposition and hypometabolism analysis. Clinical features, plasma and imaging biomarkers were compared cross-sectionally. Compared to those with late-onset Alzheimer's disease, patients with early-onset Alzheimer's disease presented more severe impairment in language function, lower frequency of APOE ɛ4 and lower levels of plasma neurofilament light chain (all P < 0.05). The plasma phosphorylated tau 181 concentration and phosphorylated tau 181/amyloid beta 42 ratios were higher in early-onset Alzheimer's disease than in late-onset Alzheimer's disease (all P < 0.05). More severe Tau deposition as indicated by 18F-florzolotau binding in the precuneus, posterior cingulate cortex and angular gyrus was observed in the early-onset Alzheimer's disease group. Plasma phosphorylated tau 181 was associated with earlier age at onset and domain-specific cognitive impairment, especially in patients with early-onset Alzheimer's disease. We concluded that patients with early-onset Alzheimer's disease differed from late-onset Alzheimer's disease in cognitive performance and biomarker profile. A higher burden of pathological tau was observed in early-onset Alzheimer's disease and was associated with earlier age at onset and more profound cognitive impairment.

Early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) share similar amyloid etiology, but evidence from smaller-scale studies suggests that they manifest differently clinically. Current analyses sought to contrast the cognitive profiles of EOAD and LOAD. Z-score cognitive-domain composites for 311 amyloid-positive sporadic EOAD and 314 amyloid-positive LOAD participants were calculated from baseline data from age-appropriate control cohorts. Z-score composites were compared between AD groups for each domain. After controlling for cognitive status, EOAD displayed worse visuospatial, executive functioning, and processing speed/attention skills relative to LOAD, and LOAD displayed worse language, episodic immediate memory, and episodic delayed memory. Sporadic EOAD possesses distinct cognitive profiles relative to LOAD. Clinicians should be alert for non-amnestic impairments in younger patients to ensure proper identification and intervention using disease-modifying treatments. Both early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) participants displayed widespread cognitive impairments relative to their same-aged peers. Cognitive impairments were more severe for EOAD than for LOAD participants in visuospatial and executive domains. Memory and language impairments were more severe for LOAD than for EOAD participants Results were comparable after removing clinical phenotypes of posterior cortical atrophy (PCA), primary progressive aphasia (lv-PPA), and frontal-variant AD.

Early-onset Alzheimer's disease is associated with a distinct neuropsychological profile

BackgroundDown syndrome (DS) is strongly associated with Alzheimer’s disease (AD), attributable to APP overexpression, displaying common features with early‐onset AD (EOAD) and late‐onset AD (LOAD) like Amyloid‐β (Aβ) and tau pathology. Here, we evaluated the Aβ plaques proteome of DS, EOAD and LOAD.MethodWe used unbiased localized proteomics to analyze amyloid plaques and the adjacent plaque‐devoid tissue (‘AD non‐plaque’) from post‐mortem paraffin‐embedded tissues in three subtypes of AD (n = 20/group): DS (59.8 ±4.99 y/o), EOAD (63 ±4.07 y/o), and LOAD (82.1 ±6.37 y/o). Functional associations were analyzed using Gene Ontology (GO) enrichment and protein interaction networks.ResultWe identified 132, 192 and 128 differentially abundant proteins in DS, EOAD and LOAD Aβ plaques (FDR&lt;5%, fold‐change&lt;1.5). Common plaque‐associated proteins constituted 14% across all groups, with 15% only in DS, 32% in EOAD, and 17% in LOAD. Significant correlations (p&lt;0.0001) existed between DS and EOAD (R2 = 0.77) and DS and LOAD (R2 = 0.73), compared to EOAD and LOAD (R2 = 0.67). Top BP GO terms (p&lt;0.0001) were lysosomal transport, regulation of the immune system process and lysosome organization for DS, EOAD and LOAD, respectively. Protein networks revealed a characteristic signature across all AD subtypes involving APP metabolism, immune response, and lysosomal pathways. We identified 263, 269, and 301 differentially abundant proteins in DS, EOAD and LOAD non‐plaques. Common differentially abundant proteins constituted 12% across AD subtypes, with 24% only in DS, 14% in EOAD and 26% in LOAD. DS correlated significantly (p&lt;0.0001) with EOAD (R2 = 0.59) and with LOAD (R2 = 0.33), compared to EOAD and LOAD (R2 = 0.79). The top BP GO term for all three subtypes was chromatin remodeling (p = 0.0013, p = 5.79 × 10‐9, and p = 1.69 × 10‐10, respectively). Additional GO terms for DS included extracellular matrix and integrin‐mediated signaling (p = 0.0068), while EOAD and LOAD were associated with protein‐DNA complexes and regulation of gene expression (p&lt;0.0001).ConclusionWe identified proteome differences in Aβ plaques across AD subtypes. Correlation and functional analyses revealed that DS and LOAD plaque‐associated proteins primarily participate in lysosomal pathways, while EOAD proteins are linked to immune response. In contrast, EOAD and LOAD non‐plaque proteins correlated better compared to DS, with functional differences reflected in the top GO terms.

Thirty‐one patients with early onset Alzheimer's disease (EAD) and 44 with late onset Alzheimer's disease (LAD) were examined with regard to symptoms reflecting disturbances in various brain regions, ie frontal, parietal and subcortical symptoms. Clinical vascular factors were recorded. The albumin ratio (CSF albumin/serum albumin) was used as a measure of the blood‐brain barrier (BBB) function. Parietal symptoms were more common in EAD than in LAD, both among mildly demented patients (60% in EAD, 10% in LAD; p&lt;0.01) and among moderately demented patients (93% in EAD, 58% in LAD; p&lt;0.01). Among moderately and severely demented patients, predominance parietal symptoms was more common in EAD (93%) than in LAD (26%) (p&lt;0.01). Patients with predominant parietal symptoms had significantly lower age at onset, absence of concomitant diseases, and normal BBB function, and we suggest that they constitute the classical AD group. A symptom profile without parietal predominance was found to be associated with higher age at onset, presence of clinical vascular factors and impaired BBB function, suggesting that age‐related and/or vascular factors may influence the symptomatology in this group.

Early-onset (age < 65) Alzheimer's disease is associated with greater non-amnestic cognitive symptoms and neuropathological burden than late-onset disease. It is not fully understood whether these groups also differ in the associations between molecular pathology, neurodegeneration and cognitive performance. We studied amyloid-positive patients with early-onset (n = 60, mean age 58 ± 4, MMSE 21 ± 6, 58% female) and late-onset (n = 53, mean age 74 ± 6, MMSE 23 ± 5, 45% female) Alzheimer's disease who underwent neurological evaluation, neuropsychological testing, 11C-Pittsburgh compound B PET (amyloid-PET) and 18F-flortaucipir PET (tau-PET). 18F-fluorodeoxyglucose PET (brain glucose metabolism PET) was also available in 74% (n = 84) of participants. Composite scores for episodic memory, semantic memory, language, executive function and visuospatial domains were calculated based on cognitively unimpaired controls. Voxel-wise regressions evaluated correlations between PET biomarkers and cognitive scores and early-onset versus late-onset differences were tested with a PET × Age group interaction. Mediation analyses estimated direct and indirect (18F-fluorodeoxyglucose mediated) local associations between 18F-flortaucipir binding and cognitive scores in domain-specific regions of interest. We found that early-onset patients had higher 18F-flortaucipir binding in parietal, lateral temporal and lateral frontal cortex; more severe 18F-fluorodeoxyglucose hypometabolism in the precuneus and angular gyrus; and greater 11C-Pittsburgh compound B binding in occipital regions compared to late-onset patients. In our primary analyses, PET-cognition correlations did not meaningfully differ between age groups.18F-flortaucipir and 18F-fluorodeoxyglucose, but not 11C-Pittsburgh compound B, were significantly associated with cognition in expected domain-specific patterns in both age groups (e.g. left perisylvian/language, frontal/executive, occipital/visuospatial). 18F-fluorodeoxyglucose mediated the relationship between 18F-flortaucipir and cognition in both age groups across all domains except episodic memory in late-onset patients. Additional direct effects of 18F-flortaucipir were observed for executive function in all age groups, language in early-onset Alzheimer's disease and in the total sample and visuospatial function in the total sample. In conclusion, tau and neurodegeneration, but not amyloid, were similarly associated with cognition in both early and late-onset Alzheimer's disease. Tau had an association with cognition independent of neurodegeneration in language, executive and visuospatial functions in the total sample. Our findings support tau PET as a biomarker that captures both the clinical severity and molecular pathology specific to Alzheimer's disease across the broad spectrum of ages and clinical phenotypes in Alzheimer's disease.

Early-onset Alzheimer’s disease (AD) patients present a different clinical profile than late-onset AD patients. This can be partially explained by cortical atrophy, although brain organization might provide more insight. The aim of this study was to examine functional connectivity in early-onset and late-onset AD patients. Resting-state fMRI scans of 20 early-onset (<65 years old), 28 late-onset (≥65 years old) AD patients and 15 “young” (<65 years old) and 31 “old” (≥65 years old) age-matched controls were available. Resting-state network-masks were used to create subject-specific maps. Group differences were examined using a non-parametric permutation test, accounting for gray-matter. Performance on five cognitive domains were used in a correlation analysis with functional connectivity in AD patients. Functional connectivity was not different in any of the RSNs when comparing the two control groups (young vs. old controls), which implies that there is no general effect of aging on functional connectivity. Functional connectivity in early-onset AD was lower in all networks compared to age-matched controls, where late-onset AD showed lower functional connectivity in the default-mode network. Functional connectivity was lower in early-onset compared to late-onset AD in auditory-, sensory-motor, dorsal-visual systems and the default mode network. Across patients, an association of functional connectivity of the default mode network was found with visuoconstruction. Functional connectivity of the right dorsal visual system was associated with attention across patients. In late-onset AD patients alone, higher functional connectivity of the sensory-motor system was associated with poorer memory performance. Functional brain organization was more widely disrupted in early-onset AD when compared to late-onset AD. This could possibly explain different clinical profiles, although more research into the relationship of functional connectivity and cognitive performance is needed.

Patients with Alzheimer's disease can present with different clinical phenotypes. Individuals with late-onset Alzheimer's disease (>65 years) typically present with medial temporal lobe neurodegeneration and predominantly amnestic symptomatology, while patients with early-onset Alzheimer's disease (<65 years) exhibit greater neocortical involvement associated with a clinical presentation including dyspraxia, executive dysfunction, or visuospatial impairment. We recruited 20 patients with early-onset Alzheimer's disease, 21 with late-onset Alzheimer's disease, three with prodromal early-onset Alzheimer's disease and 13 with prodromal late-onset Alzheimer's disease, as well as 30 cognitively healthy elderly controls, that had undergone 18F-AV-1451 tau positron emission tomography and structural magnetic resonance imaging to explore whether early- and late-onset Alzheimer's disease exhibit differential regional tau pathology and atrophy patterns. Strong associations of lower age at symptom onset with higher 18F-AV-1451 uptake were observed in several neocortical regions, while higher age did not yield positive associations in neither patient group. Comparing patients with early-onset Alzheimer's disease with controls resulted in significantly higher 18F-AV-1451 retention throughout the neocortex, while comparing healthy controls with late-onset Alzheimer's disease patients yielded a distinct pattern of higher 18F-AV-1451 retention, predominantly confined to temporal lobe regions. When compared against each other, the early-onset Alzheimer's disease group exhibited greater uptake than the late-onset group in prefrontal and premotor, as well as in inferior parietal cortex. These preliminary findings indicate that age may constitute an important contributor to Alzheimer's disease heterogeneity highlighting the potential of tau positron emission tomography to capture phenotypic variation across patients with Alzheimer's disease.