Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer’s disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and longevity is expected. We explored this interplay by studying the prevalence of AD-associated single-nucleotide-polymorphisms (SNPs) in cognitively healthy centenarians, and replicated findings in a parental-longevity GWAS. We found that 28/38 SNPs that increased AD-risk also associated with lower odds of longevity. For each SNP, we express the imbalance between AD- and longevity-risk as an effect-size distribution. Based on these distributions, we grouped the SNPs in three groups: 17 SNPs increased AD-risk more than they decreased longevity-risk, and were enriched for β-amyloid metabolism and immune signaling; 11 variants reported a larger longevity-effect compared to their AD-effect, were enriched for endocytosis/immune-signaling, and were previously associated with other age-related diseases. Unexpectedly, 10 variants associated with an increased risk of AD and higher odds of longevity. Altogether, we show that different AD-associated SNPs have different effects on longevity, including SNPs that may confer general neuro-protective functions against AD and other age-related diseases.

BACKGROUND: Dementia in families can be caused by one genetic variant. Identifying these so-called monogenic causes of dementia is important, because it explains the origin of dementia in families and raises the possibility of predictive testing for relatives. Still, we do not know how frequent these monogenic causes are, due to strict selection criteria for DNA testing based on age at onset and a positive family history. We aimed to identify the mutation frequency of monogenetic dementia by screening a large, unselected cohort of patients from a memory clinic specialized in early onset dementia. METHOD: Between 1-1-2010 and 1-7-2012, 1,138 patients visited the Alzheimer Center Amsterdam and all patients underwent the same diagnostic trajectory (van der Flier et al 2018). Of these, 1,093 (96%) consented to research and donated blood. An additional 73 patients (7%) were excluded because suboptimal DNA quality. Whole exome sequencing and C9orf72-repeat length analysis was performed in the remaining 1,020 patients (90% of all patients). All variants in 54 dementia related genes were analysed and classified. C9orf72 repeat length >30 repeat units was considered pathogenic. Variants classified as likely pathogenic and pathogenic were considered a monogenic cause of dementia. RESULT: The average age at presentation was 62(±6SD) years and 419(41%) were female. We found a monogenic cause of dementia in 34 (3.4%) patients. The most frequently occurring (likely) pathogenic variants were found in the genes C9orf72, PSEN1, NOTCH3 and MAPT. These genes explained 65% of the (likely) pathogenic variants. The clinical characteristics of the patients screened positive; 50% were diagnosed with dementia and 50% had a first degree relative with dementia; and 40% had an age at presentation of <60 years and 44% was between 60 to 70 years, the remainder was older. Surprisingly, only 47% of the patients with a (likely) pathogenic variant fulfilled our current criteria (based on diagnosis, age and familial history) for offering diagnostic genetic testing (21% of patients). CONCLUSION: In our large unselected cohort of patients from a memory clinic specialized in early onset dementia, the majority of the patients with a monogenetic predisposition for dementia did not fulfill our current criteria for genetic testing.

Dysfunction of the endolysosomal-autophagy network is emerging as an important pathogenic process in Alzheimer's disease. Mutations in the sorting receptor-encoding gene SORL1 cause autosomal-dominant Alzheimer's disease, and SORL1 variants increase risk for late-onset AD. To understand the contribution of SORL1 mutations to AD pathogenesis, we analyze the effects of a SORL1 truncating mutation on SORL1 protein levels and endolysosome function in human neurons. We find that truncating mutation results in SORL1 haploinsufficiency and enlarged endosomes in human neurons. Analysis of isogenic SORL1 wild-type, heterozygous, and homozygous null neurons demonstrates that, whereas SORL1 haploinsufficiency results in endosome dysfunction, complete loss of SORL1 leads to additional defects in lysosome function and autophagy. Neuronal endolysosomal dysfunction caused by loss of SORL1 is relieved by extracellular antisense oligonucleotide-mediated reduction of APP protein, demonstrating that PSEN1, APP, and SORL1 act in a common pathway regulating the endolysosome system, which becomes dysfunctional in AD.

BACKGROUND: Several collaborative genome-wide-association studies (GWAS) have characterized the genetic landscape of Alzheimer's disease (AD), which now counts >70 single-nucleotide polymorphisms (SNPs) associated with AD-risk. METHOD: We linked these SNPs to their affected biological pathways, and combined the effect of multiple SNPs into pathway-specific polygenic-risk-scores (PRS). Using a genetically homogeneous dataset of 2,458 AD-patients (age=70.2±10.4), 3,848 healthy controls (age=61.1±14.8), 343 cognitively healthy centenarians (age=101.1±1.8) and 705 individuals with mild-cognitive-impairment (MCI, age=69.1±8.9), we studied the association between pathway-PRS and AD-risk, MCI-to-AD conversion, and resilience against AD. RESULT: With an integrative strategy, we linked 72 AD-associated SNPs to 5 clusters of biological pathways: beta-amyloid cluster, immune cluster, vascular cluster, endocytosis cluster and a trafficking cluster (Figure 1). A PRS comprising all 72 SNPs (excluding APOE-SNPs) was significantly associated with AD-risk (OR=1.53, p<2e-16), progression of MCI to AD dementia (OR=1.45, p=5.5e-4), and, albeit in the opposite direction, resilience against AD in healthy centenarians (OR=0.82, p=6.4e-4) (Figure 2, Figure 3). At the pathway level, all pathway-PRS significantly associated with increased AD-risk while specifically the vascular-, endocytosis- and trafficking-PRS associated with resilience against AD (p<0.05) (Figure 4). Interestingly, the beta-amyloid-, endocytosis and trafficking-PRSs were significantly associated with MCI-to-AD progression (p<0.05), with a higher-PRS leading up to 1.5-year shorter conversion time. CONCLUSION: Our results add on the efficacy of pathway-specific PRSs to identify individuals at highest or the lowest risk for the development of AD. Further, our results suggest that specific biological pathways are more important at different stages of the disease or in fact, associate with the escape of disease. AD diagnostic procedures may benefit from the identification of individual, pathway-specific vulnerabilities. In the future, pathway-specific PRSs may contribute to the selection of patients who may benefit most from pathway-specific treatment strategies.

Background: Dementia with Lewy bodies (DLB) is a complex, progressive neurodegenerative disease with considerable phenotypic, pathological, and genetic heterogeneity. Objective: We tested if genetic variants in part explain the heterogeneity in DLB. Methods: We tested the effects of variants previously associated with DLB (near APOE, GBA, and SNCA) and polygenic risk scores for Alzheimer's disease (AD-PRS) and Parkinson's disease (PD-PRS). We studied 190 probable DLB patients from the Alzheimer's dementia cohort and compared them to 2,552 control subjects. The p-tau/Aβ1-42 ratio in cerebrospinal fluid was used as in vivo proxy to separate DLB cases into DLB with concomitant AD pathology (DLB-AD) or DLB without AD (DLB-pure). We studied the clinical measures age, Mini-Mental State Examination (MMSE), and the presence of core symptoms at diagnosis and disease duration. Results: We found that all studied genetic factors significantly associated with DLB risk (all-DLB). Second, we stratified the DLB patients by the presence of concomitant AD pathology and found that APOE ϵ4 and the AD-PRS associated specifically with DLB-AD, but less with DLB-pure. In addition, the GBA p.E365K variant showed strong associated with DLB-pure and less with DLB-AD. Last, we studied the clinical measures and found that APOE ϵ4 associated with reduced MMSE, higher odds to have fluctuations and a shorter disease duration. In addition, the GBA p.E365K variant reduced the age at onset by 5.7 years, but the other variants and the PRS did not associate with clinical features. Conclusion: These finding increase our understanding of the pathological and clinical heterogeneity in DLB.

Developing Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N = 1895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N = 293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p < 0.05). The pathway that contributed most to the overall modulation of AD-risk was β-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintained cognitive functioning until extreme ages. Our work suggests that a favorable immune response and a maintained endocytosis pathway might be involved in general neuro-protection, which highlight the need to investigate these pathways, next to β-amyloid metabolism.