We aimed to identify new candidate genes potentially involved in early-onset Alzheimer's disease (EOAD). Exome sequencing was conducted on 45 EOAD patients with either a family history of Alzheimer's disease (AD, <65 years) or an extremely early age at the onset (≤55 years) followed by multiple variant filtering according to different modes of inheritance. We identified 29 candidate genes potentially involved in EOAD, of which the gene TYROBP, previously implicated in AD, was selected for genetic and functional follow-up. Using 3 patient cohorts, we observed rare coding TYROBP variants in 9 out of 1110 EOAD patients, whereas no such variants were detected in 1826 controls (p = 0.0001), suggesting that at least some rare TYROBP variants might contribute to EOAD risk. Overexpression of the p.D50_L51ins14 TYROBP mutant led to a profound reduction of TREM2 expression, a well-established risk factor for AD. This is the first study supporting a role for genetic variation in TYROBP in EOAD, with in vitro support for a functional effect of the p.D50_L51ins14 TYROBP mutation on TREM2 expression.

We and others have recently reported an association between amyotrophic lateral sclerosis (ALS) and single nucleotide polymorphisms on chromosome 9p21 in several populations. Here we show that the associated haplotype is the same in all populations and that several families previously shown to have genetic linkage to this region also share this haplotype. The most parsimonious explanation of these data are that there is a single founder for this form of disease.

Many patients with dementia with Lewy bodies (DLB) have overlapping Alzheimer's disease (AD)-related pathology, which may contribute to white matter (WM) diffusivity alterations on diffusion tensor imaging (DTI). Consecutive patients with DLB (n = 30), age- and sex-matched AD patients (n = 30), and cognitively normal controls (n = 60) were recruited. All subjects underwent DTI, 18F 2-fluoro-deoxy-d-glucose, and (11)C Pittsburgh compound B positron emission tomography scans. DLB patients had reduced fractional anisotropy (FA) in the parietooccipital WM but not elsewhere compared with cognitively normal controls, and elevated FA in parahippocampal WM compared with AD patients, which persisted after controlling for β-amyloid load in DLB. The pattern of WM FA alterations on DTI was consistent with the more diffuse posterior parietal and occipital glucose hypometabolism of 2-fluoro-deoxy-d-glucose positron emission tomography in the cortex. DLB is characterized by a loss of parietooccipital WM integrity, independent of concomitant AD-related β-amyloid load. Cortical glucose hypometabolism accompanies WM FA alterations with a concordant pattern of gray and WM involvement in the parietooccipital lobes in DLB.

Our objective was to examine associations between glucose metabolism, as measured by (18)F-fluorodeoxyglucose positron emission tomography (FDG PET), and age and to evaluate the impact of carriage of an apolipoprotein E (APOE) ε4 allele on glucose metabolism and on the associations between glucose metabolism and age. We studied 806 cognitively normal (CN) and 70 amyloid-imaging-positive cognitively impaired participants (35 with mild cognitive impairment and 35 with Alzheimer's disease [AD] dementia) from the Mayo Clinic Study of Aging, Mayo Alzheimer's Disease Research Center and an ancillary study who had undergone structural MRI, FDG PET, and (11)C-Pittsburgh compound B (PiB) PET. Using partial volume corrected and uncorrected FDG PET glucose uptake ratios, we evaluated associations of regional FDG ratios with age and carriage of an APOE ε4 allele in CN participants between the ages of 30 and 95 years, and compared those findings with the cognitively impaired participants. In region-of-interest (ROI) analyses, we found modest but statistically significant declines in FDG ratio in most cortical and subcortical regions as a function of age. We also found a main effect of APOE ε4 genotype on FDG ratio, with greater uptake in ε4 noncarriers compared with carriers but only in the posterior cingulate and/or precuneus, lateral parietal, and AD-signature meta-ROI. The latter consisted of voxels from posterior cingulate and/or precuneus, lateral parietal, and inferior temporal. In age- and sex-matched CN participants the magnitude of the difference in partial volume corrected FDG ratio in the AD-signature meta-ROI for APOE ε4 carriers compared with noncarriers was about 4 times smaller than the magnitude of the difference between age- and sex-matched elderly APOE ε4 carrier CN compared with AD dementia participants. In an analysis in participants older than 70 years (31.3% of whom had elevated PiB), there was no interaction between PiB status and APOE ε4 genotype with respect to glucose metabolism. Glucose metabolism declines with age in many brain regions. Carriage of an APOE ε4 allele was associated with reductions in FDG ratio in the posterior cingulate and/or precuneus, lateral parietal, and AD-signature ROIs, and there was no interaction between age and APOE ε4 status. The posterior cingulate and/or precuneus and lateral parietal regions have a unique vulnerability to reductions in glucose metabolic rate as a function both of age and carriage of an APOE ε4 allele.

In 1164 cognitively unimpaired persons, aged 50-95 years, from the population-based Mayo Clinic Study of Aging, we examined the relationships of baseline cognition and cognitive changes across the full range of cortical thickness of an Alzheimer signature region of interest and global β-amyloid levels measured by Pittsburgh compound B positron emission tomography (PIB PET) standardized uptake value ratio (SUVR). In machine-learning models accounting for both biomarkers simultaneously, worsening biomarker values were additive and associated with lower baseline global cognition and greater subsequent decline in global cognition. Associations between Alzheimer's disease signature cortical thickness or PIB PET β-amyloid SUVR and baseline cognition were mainly linear. Lower Alzheimer's disease signature cortical thickness values across the entire range of thickness predicted future decline in global cognitive scores, demonstrating its close relationship to cognitive functioning. PIB PET β-amyloid SUVR also predicted cognitive decline across its full range, even when cortical thickness was accounted for. PIB PET β-amyloid's relationship to cognitive decline was nonlinear, more prominent at lower β-amyloid levels and less prominent at higher β-amyloid levels.

Loss-of-function mutations in the progranulin gene (GRN) are one of the major causes of familial frontotemporal lobar degeneration. Our objective was to determine the rates and trajectories of lobar cortical atrophy from longitudinal structural magnetic resonance imaging in both asymptomatic and symptomatic GRN mutation carriers. Individuals in this study were from the ADRC and LEFFTDS studies at the Mayo Clinic. We identified 13 GRN mutation carriers (8 asymptomatic, 5 symptomatic) and noncarriers (n = 10) who had at least 2 serial T1-weighted structural magnetic resonance images and were followed annually with a median of 3 years (range 1.0-9.8 years). Longitudinal changes in lobar cortical volume were analyzed using the tensor-based morphometry with symmetric normalization (TBM-SyN) algorithm. Linear mixed-effect models were used to model cortical volume change over time among 3 groups. The annual rates of frontal (p < 0.05) and parietal (p < 0.01) lobe cortical atrophy were higher in asymptomatic GRN mutation carriers than noncarriers. The symptomatic GRN mutation carriers also had increased rates of atrophy in the frontal (p < 0.01) and parietal lobe (p < 0.01) cortices than noncarriers. In addition, greater rates of cortical atrophy were observed in the temporal lobe cortices of symptomatic GRN mutation carriers than noncarriers (p < 0.001). We found that a decline in frontal and parietal lobar cortical volume occurs in asymptomatic GRN mutation carriers and continues in the symptomatic GRN mutation carriers, whereas an increased rate of temporal lobe cortical atrophy is observed only in symptomatic GRN mutation carriers. This sequential pattern of cortical involvement in GRN mutation carriers has important implications for using imaging biomarkers of neurodegeneration as an outcome measure in potential treatment trials involving GRN mutation carriers.

Next-generation sequencing has contributed to our understanding of the genetics of Alzheimer's disease (AD) and has explained a substantial part of the missing heritability of familial AD. We sequenced 19 exomes from 8 Dutch families with a high AD burden and identified EIF2AK3, encoding for protein kinase RNA-like endoplasmic reticulum kinase (PERK), as a candidate gene. Gene-based burden analysis in a Dutch AD exome cohort containing 547 cases and 1070 controls showed a significant association of EIF2AK3 with AD (OR 1.84 [95% CI 1.07-3.17], p-value 0.03), mainly driven by the variant p.R240H. Genotyping of this variant in an additional cohort from the Rotterdam Study showed a trend toward association with AD (p-value 0.1). Immunohistochemical staining with pPERK and peIF2α of 3 EIF2AK3 AD carriers showed an increase in hippocampal neuronal cells expressing these proteins compared with nondemented controls, but no difference was observed in AD noncarriers. This study suggests that rare variants in EIF2AK3 may be associated with disease risk in AD.

Reduced nigrostriatal uptake on N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-[123I]iodophenyl) nortropane (123I-FP-CIT) SPECT reflects dopamine dysfunction, while other imaging markers could be complementary when used together. We assessed how well 123I-FP-CIT SPECT differentiates dementia with Lewy bodies (DLBs) from Alzheimer's disease dementia (ADem) and whether multimodal imaging provides additional value. 123I-FP-CIT SPECT, magnetic resonance imaging, [18F]2-fluoro-deoxy-D-glucose-positron emission tomography (PET), and 11C-Pittsburgh compound B (PiB)-PET were assessed in 35 participants with DLBs and 14 participants with ADem (autopsy confirmation in 9 DLBs and 4 ADem). Nigrostriatal dopamine transporter uptake was evaluated with 123I-FP-CIT SPECT using DaTQUANT software. Hippocampal volume was calculated with magnetic resonance imaging, cingulate island sign ratio with FDG-PET, and global cortical PiB retention with PiB-PET. The DaTQUANT z-scores of the putamen showed the highest c-statistic of 0.916 in differentiating DLBs from ADem among the analyzed imaging biomarkers. Adding another imaging modality to 123I-FP-CIT SPECT had c-statistics ranging from 0.968 to 0.975, and 123I-FP-CIT SPECT in combination with 2 other imaging modalities presented c-statistics ranging from 0.987 to 0.996. These findings suggest that multimodal imaging with 123I-FP-CIT SPECT aids in differentiating DLBs and ADem and in detecting comorbid Lewy-related and Alzheimer's disease pathology in patients with DLBs and ADem.

Alzheimer's disease (AD) can present with non-amnestic clinical syndromes. We investigated whether there is an imaging signature of AD pathology in these atypical subjects. We identified 14 subjects that had pathological AD, a non-amnestic presentation (i.e. atypical AD), and MRI. These subjects were matched to 14 with clinical and pathological AD (i.e. typical AD), 14 with the same non-amnestic presentations with frontotemporal lobar degeneration (FTLD) pathology, and 20 controls. Voxel-based morphometry and region-of-interest (ROI) analysis were used to assess patterns of grey matter loss. Loss was observed in the temporoparietal cortex in both typical and atypical AD, and showed significantly greater loss than FTLD. However, the medial temporal lobes were more severely affected in typical AD and FTLD compared to atypical AD. A ratio of hippocampal and temporoparietal volumes provided excellent discrimination of atypical AD from FTLD subjects. Temporoparietal atrophy may therefore provide a useful marker of the presence of AD pathology even in subjects with atypical clinical presentations, especially in the context of relative sparing of the hippocampus.

Posterior cortical atrophy (PCA) is an understudied visual impairment syndrome most often due to "posterior Alzheimer's disease (AD)" pathology. Case studies detected mutations in PSEN1, PSEN2, GRN, MAPT, and PRNP in subjects with clinical PCA. To detect the frequency and spectrum of mutations in known dementia genes in PCA, we screened 124 European-American subjects with clinical PCA (n = 67) or posterior AD neuropathology (n = 57) for variants in genes implicated in AD, frontotemporal dementia, and prion disease using NeuroX, a customized exome array. Frequencies in PCA of the variants annotated as pathogenic or potentially pathogenic were compared against ∼ 4300 European-American population controls from the NHLBI Exome Sequencing Project. We identified 2 rare variants not previously reported in PCA, TREM2 Arg47His, and PSEN2 Ser130Leu. No other pathogenic or potentially pathogenic variants were detected in the screened dementia genes. In this first systematic variant screen of a PCA cohort, we report 2 rare mutations in TREM2 and PSEN2, validate our previously reported APOE ε4 association, and demonstrate the utility of NeuroX.

Argyrophilic grains (AG) are silver-positive spindle-shaped lesions found at postmortem. Their significance is controversial.

The aim of this study was to compare the patterns of grey and white matter atrophy on MRI in autopsy confirmed progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), and to determine whether the patterns vary depending on the clinical syndrome. Voxel-based morphometry was used to compare patterns of atrophy in 13 PSP and 11 CBD subjects and 24 controls. PSP and CBD subjects were also subdivided into those with a dominant dementia or extrapyramidal syndrome. PSP subjects showed brainstem atrophy with involvement of the cortex and underlying white matter. Frontoparietal grey and subcortical grey matter atrophy occurred in CBD. When subdivided, PSP subjects with an extrapyramidal syndrome had more brainstem atrophy and less cortical atrophy than CBD subjects with an extrapyramidal syndrome. PSP subjects with a dementia syndrome had more subcortical white matter atrophy than CBD subjects with a dementia syndrome. These results show regional differences between PSP and CBD that are useful in predicting the underlying pathology, and help to shed light on the in vivo distribution of regional atrophy in PSP and CBD.

The aim of this study was to compare patterns of cerebral atrophy on MRI, and neurochemistry on magnetic resonance spectroscopy (MRS), in patients with posterior cortical atrophy (PCA) and typical Alzheimer's disease (AD). Voxel-based morphometry was used to assess grey matter atrophy in 38 patients with PCA, 38 patients with typical AD, and 38 controls. Clinical data was assessed in all PCA patients. Single voxel (1)H MRS located in the posterior cingulate was analyzed in a subset of patients with PCA, typical AD, and control subjects. PCA showed a pattern of atrophy affecting occipital, parietal and posterior temporal lobes, compared to controls. The pattern was bilateral, but more severe on the right. Patients with PCA showed greater atrophy in the right visual association cortex than patients with typical AD, whereas those with AD showed greater atrophy in the left hippocampus than those with PCA. (1)H MRS suggested loss of neuronal integrity and glial activation in subjects with PCA and typical AD. The differing patterns of atrophy on MRI suggest that PCA should be considered a distinct entity from typical AD.

Frontotemporal lobar degeneration (FTLD) is now recognised as a common form of early onset dementia. Up to 40% of patients have a family history of disease demonstrating a large genetic component to its etiology. Linkage to chromosome 9p21 has recently been reported in families with this disorder. We undertook a large scale two-stage linkage disequilibrium mapping approach of this region in the Manchester FTLD cohort. We identified association of ubiquitin associated protein 1 (UBAP1; OR 1.42 95% CI 1.08-1.88, P=0.013) with FTLD in this cohort and we replicated this finding in an additional two independent cohorts from the Netherlands (OR 1.33 95% CI 1.04-1.69, P=0.022), the USA (OR 1.4 95% CI 1.02-1.92, P=0.032) and a forth Spanish cohort approached significant association (OR 1.45 95% CI 0.97-2.17, P=0.064). However, we failed to replicate in a fifth cohort from London (OR 0.99 95% CI 0.72-1.37, P=0.989). Quantitative analysis of UBAP1 mRNA extracted from tissue from the Manchester cases demonstrated a significant reduction of expression from the disease-associated haplotype. In addition, we identified a case of familial FTLD that demonstrated colocalisation of UBAP1 and TDP-43 in the neuronal cytoplasmic inclusions in the brain of this individual. Our data for the first time identifies UBAP1 as a genetic risk factor for FTLD and suggests a mechanistic relationship between this protein and TDP-43.

Frontotemporal dementia (FTD) presents with a wide variability in clinical syndromes, genetic etiologies, and underlying pathologies. Despite the discovery of pathogenic variants in several genes, many familial cases remain unsolved. In a large FTD cohort of 198 familial patients, we aimed to determine the types and frequencies of variants in genes related to FTD. Pathogenic or likely pathogenic variants were revealed in 74 (37%) patients, including 4 novel variants. The repeat expansion in C9orf72 was most common (21%), followed by variants in MAPT (6%), GRN (4.5%), and TARDBP (3.5%). Other pathogenic variants were found in VCP, TBK1, PSEN1, and a novel homozygous variant in OPTN. Furthermore, we identified 15 variants of uncertain significance, including a promising variant in TUBA4A and a frameshift in VCP, for which additional research is needed to confirm pathogenicity. The patients without identified genetic cause demonstrated a wide clinical and pathological variety. Our study contributes to the clinical characterization of the genetic subtypes and confirms the value of whole-exome sequencing in identifying novel genetic variants.

Association between the transactive response DNA-binding protein of 43 kDa (TDP-43), its newly described types (type α/type β), and resilience to Alzheimer's disease neuropathological change (ADNC) defined as preservation of normal cognitive functioning despite advanced ADNC has been evaluated in this case-control study of 63 older adults. Twenty-one resilient to ADNC individuals were matched 1:2 to nonresilient (Alzheimer's dementia) using propensity scores, accounting for age at death, neuritic plaque density, and neurofibrillary tangle stage. Resilient and matched nonresilient participants were similar in terms of gender, apolipoprotein E ε4 carriership, education, occupation, AD, and other pathologies. Resilient participants had lower frequency of TDP-43 co-pathology compared to nonresilient (19% vs. 62%, p = 0.002). Among TDP-43-positive cases, TDP-43 type α inclusions were absent in resilient to ADNC participants and were dominant in matched nonresilient cases (65%, p = 0.03). TDP-43 and TDP-43 types appear to be one of the key pathological determinants of loss of cognitive resilience to ADNC and hence are important in the understanding of the clinical expression of ADNC.

Magnetic resonance spectroscopy (MRS) characteristics of dementia with Lewy bodies (DLB) Alzheimer's disease (AD) and cognitively normal controls were compared. DLB (n = 34), AD (n = 35), and cognitively normal controls (n = 148) participated in a MRS study from frontal, posterior cingulate, and occipital voxels. We investigated DLB patients with preserved hippocampal volumes to determine the MRS changes in DLB with low probability of overlapping AD pathology. DLB patients were characterized by decreased N-acetylaspartate/creatine (NAA/Cr) in the occipital voxel. AD patients were characterized by lower NAA/Cr in the frontal and posterior cingulate voxels. Normal NAA/Cr levels in the frontal voxel differentiated DLB patients with preserved hippocampal volumes from AD patients. DLB and AD patients had elevated choline/creatine, and myo-Inositol/creatine in the posterior cingulate. MRS abnormalities associated with loss of neuronal integrity localized to the occipital lobes in DLB, and the posterior cingulate gyri and frontal lobes in AD. This pattern of MRS abnormalities may have a role in differential diagnosis of DLB and in distinguishing DLB patients with overlapping AD pathology.

We aimed to assess associations between clinical, imaging, pathologic, and genetic features and frontal lobe asymmetry in behavioral variant frontotemporal dementia (bvFTD). Volumes of the left and right dorsolateral, medial, and orbital frontal lobes were measured in 80 bvFTD subjects and subjects were classified into 3 groups according to the degree of asymmetry (asymmetric left, asymmetric right, symmetric) using cluster analysis. The majority of subjects were symmetric (65%), with 20% asymmetric left and 15% asymmetric right. There were no clinical differences across groups, although there was a trend for greater behavioral dyscontrol in right asymmetric compared with left asymmetric subjects. More widespread atrophy involving the parietal lobe was observed in the symmetric group. Genetic features differed across groups with symmetric frontal lobes associated with C9ORF72 and tau mutations, while asymmetric frontal lobes were associated with progranulin mutations. These findings therefore suggest that neuroanatomical patterns of frontal lobe atrophy in bvFTD are influenced by specific gene mutations.

Pattern of diffusion tensor MRI (DTI) alterations were investigated in pathologically-staged Alzheimer's disease (AD) patients (n = 46). Patients with antemortem DTI studies and a range of AD pathology at autopsy were included. Patients with a high neurofibrillary tangle (NFT) stage (Braak IV-VI) had significantly elevated mean diffusivity (MD) in the crus of fornix and ventral cingulum tracts, precuneus, and entorhinal white matter on voxel-based analysis after adjusting for age and time from MRI to death (p < 0.001). Higher MD and lower fractional anisotropy in the ventral cingulum tract, entorhinal, and precuneus white matter was associated with higher Braak NFT stage and clinical disease severity. There were no MD and fractional anisotropy differences among the low (none and sparse) and high (moderate and frequent) β-amyloid neuritic plaque groups. The NFT pathology of AD is associated with DTI alterations involving the medial temporal limbic connections and medial parietal white matter. This pattern of diffusion abnormalities is also associated with clinical disease severity.

Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes in mean diffusivity (MD) and fractional anisotropy were analyzed. Asymptomatic MAPT mutation carriers had higher MD in entorhinal WM, which propagated to the limbic tracts and frontotemporal projections in the symptomatic stage compared with noncarriers. Reduced fractional anisotropy and increased MD in the entorhinal WM were associated with the proximity to estimated and actual age of symptom onset. The annualized change of entorhinal MD on serial DTI was accelerated in MAPT mutation carriers compared with noncarriers. Entorhinal WM diffusion abnormalities precede the symptom onset and track with disease progression in MAPT mutation carriers. Our cross-sectional and longitudinal data showed a potential clinical utility for DTI to track neurodegenerative disease progression for MAPT mutation carriers in clinical trials.