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We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer’s dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

INTRODUCTIONAlzheimer’s disease (AD) is heterogeneous, both clinically and neuropathologically. We investigated whether polygenic risk scores (PRSs) integrated with transcriptome profiles from AD brains can explain AD clinical heterogeneity.METHODSWe conducted co-expression analysis and identified gene-sets (modules) which were preserved in three AD transcriptome datasets and associated with AD-related neuropathological traits for neuritic plaques (NPs) or neurofibrillary tangles (NFTs). We computed the module-based PRS (mbPRS) for each module and tested associations for mbPRSs with cognitive test scores, cognitively-defined AD subgroups, and brain imaging data.RESULTSOf the modules significantly associated with NPs and/or NFTs, the mbPRSs from two modules (M6 and M9) showed distinct associations with language and visuospatial functioning as well as their matching AD-subgroups and brain atrophy at specific regions.DISCUSSIONOur findings demonstrate that polygenic profiling based on co-expressed gene-sets can explain heterogeneity in AD patients, enabling to genetically-informed patient stratification and precision medicine in AD.

Background and ObjectivesCerebrovascular disease (CBVD) is frequently comorbid with autopsy-confirmed Alzheimer disease (AD), but its contribution to the clinical presentation of AD remains unclear. We leveraged the National Alzheimer's Coordinating Center (NACC) uniform and neuropathology datasets to compare the cognitive and functional trajectories of AD+/CBVD+ and AD+/CBVD− brain donors.MethodsThe sample included NACC brain donors with autopsy-confirmed AD (Braak stage ≥3,Consortium to Establish a Registry for Alzheimer's Diseasescore ≥2) and complete Uniform Data Set (UDS) evaluations between 2005 and 2019, with the most recent UDS evaluation within 2 years of autopsy. CBVD was defined as moderate to severe arteriosclerosis or atherosclerosis. We used propensity score weighting to isolate the effects of comorbid AD and CBVD. This method improved the balance of covariates between the AD+/CBVD+ and AD+/CBVD− groups. Longitudinal mixed-effects models were assessed with robust bayesian estimation. UDS neuropsychological test and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) scores were primary outcomes.ResultsOf 2,423 brain donors, 1,476 were classified as AD+/CBVD+. Compared with AD+/CVBD− donors, the AD+/CBVD+ group had accelerated decline (i.e., group × time effects) on measures of processing speed (β = −0.93, 95% CI −1.35, −0.51, Bayes factor [BF] 130.75), working memory (β = 0.05, 95% CI 0.02, 0.07, BF 3.59), verbal fluency (β = 0.10, 95% CI 0.04, 0.15, BF 1.28), naming (β = 0.09, 95% CI 0.03, 0.16, BF = 0.69), and CDR-SB (β = −0.08, 95% CI −0.12, −0.05, BF 18.11). Effects ranged from weak (BFs DiscussionIn brain donors with autopsy-confirmed AD, comorbid CBVD was associated with an accelerated functional and cognitive decline, particularly on neuropsychological tests of attention, psychomotor speed, and working memory. CBVD magnified effects of AD neuropathology on semantic-related neuropsychological tasks. Findings support a prominent additive and more subtle synergistic effect for comorbid CBVD neuropathology in AD.

To examine the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), we performed repeat sizing of ten genetic loci previously implicated in neurodegenerative diseases. We examined whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range: 40 to 64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent cohort, and identified five (0.14%) out of 3,674 FTD/ALS patients harboring pathogenic HTT CAG expansions. Postmortem evaluations of two patients revealed huntingtin-positive, as well as TDP43- and ubiquitin-positive aggregates, predominantly in the frontal cortex, without neostriatal atrophy. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes, and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Objectives: To determine and compare the accuracy of the Boston criteria for the diagnosis of cerebral amyloid angiopathy (CAA) applied to: 1) a large hospital-based cohort; 2) a cohort of community-dwelling individuals. Methods: Among patients seen at a single academic medical center and participants enrolled in the Framingham Heart Study (FHS) we identified all individuals having had brain MRI (including hemosiderin-specific sequences) and pathological assessment of CAA at age ≥55. CAA was defined as Vonsattel degree ≥2, except in non-autopsy studies, where any vascular amloyid deposition was considered diagnostic of CAA. We excluded cases with: 1) non-lobar ICH; 2) alternative clinical diagnosis for the lobar hemorrhage/es; 3) CAA-negative studies based on small brain biopsy samples (greater diameter 1 strictly lobar hemorrhage) in both cohorts. Results: The study included 143 cases: 96 from the hospital cohort (mean age at time of MRI 74.1±8.2 years, 47.9% women, 47.9% autopsy studies, 54.2% cases with any lobar microbleed, 44.8% with any lobar ICH) and 47 from FHS (mean age at time of MRI 83.4±10.9 years, 48.9% women, 100% autopsy studies, 17% cases with any lobar microbleed, no lobar ICH cases). Hospital cohort: CAA prevalence was 72.6%. Specificity/sensitivity of “possible CAA” and “probable CAA” were 78.2%/33.3% and 92%/57.7%. Community cohort: CAA prevalence was 47%. Specificity/sensitivity of “probable CAA” were 88%/3%. Discussion: Specificity of detection of multiple lobar hemorrhages on MRI (“probable CAA”) for moderate-severe CAA is similarly high in both hospital and community cohorts. This increases the opportunity to identify individuals with CAA for observational studies and emerging anti-amyloid therapeutic trials. In view of its poor sensitivity, “probable CAA” diagnosis represents an inadequate screening tool for exclusion of CAA in both populations.