Alzheimer's disease and related dementias (ADRD) are complex neurodegenerative disorders of which the genetic basis remains incompletely understood. Hippocampal volume loss is a core hallmark of AD. Hippocampal volume also has a strong heritable component and its genetic underpinnings may help us to understand the complex biological mechanism underlying ADRD. To identify shared genetic risk loci across late-onset ADRD and bilateral hippocampal volumes, we conducted a cross-trait analysis of existing GWAS data on the two traits using the conjunctional false discovery rate (conjFDR) framework. Functional annotation and phenome-wide association studies (PheWAS) were performed on the identified shared loci to characterize their biological relevance. We identified 11 unique lead genetic loci, of which 7 loci showed discordant directional effects (loci associated with increased risk for ADRD and smaller hippocampal volumes). We found that SHARPIN and TNIP1 genes play a role in ADRD by affecting hippocampal volumes. In addition, we observed 9 novel ADRD-hippocampus loci in genes previously implicated in AD (IGIP and ACE) and novel ADRD-genes (KCTD13, HINT1, SH3TC2, FAM53B, TPM1, IL34 and SSH2). PheWAS results show that most shared loci associated with neuroimaging measurements, white blood cell markers, red blood cell markers, and lipids. This study shows a shared genetic basis between ADRD and bilateral hippocampal volumes. By integrating summary statistics for these two traits, we identified both novel and previously reported ADRD-hippocampus loci. Functional analysis highlights the role of immune cells and lipid markers in the shared loci, suggesting a shared neurobiological basis for ADRD and bilateral hippocampal volumes.

BACKGROUND: Alzheimer's disease (AD) prevalence increases with age, yet a small fraction of the population reaches ages > 100 years without cognitive decline. We studied the genetic factors associated with such resilience against AD. METHODS: Genome-wide association studies identified 86 single nucleotide polymorphisms (SNPs) associated with AD risk. We estimated SNP frequency in 2281 AD cases, 3165 age-matched controls, and 346 cognitively healthy centenarians. We calculated a polygenic risk score (PRS) for each individual and investigated the functional properties of SNPs enriched/depleted in centenarians. RESULTS: Cognitively healthy centenarians were enriched with the protective alleles of the SNPs associated with AD risk. The protective effect concentrated on the alleles in/near ANKH, GRN, TMEM106B, SORT1, PLCG2, RIN3, and APOE genes. This translated to >5-fold lower PRS in centenarians compared to AD cases (P = 7.69 × 10⁻⁷¹), and 2-fold lower compared to age-matched controls (P = 5.83 × 10⁻¹⁷). DISCUSSION: Maintaining cognitive health until extreme ages requires complex genetic protection against AD, which concentrates on the genes associated with the endolysosomal and immune systems. Highlights: Cognitively healthy cent enarians are enriched with the protective alleles of genetic variants associated with Alzheimer's disease (AD). The protective effect is concentrated on variants involved in the immune and endolysosomal systems. Combining variants into a polygenic risk score (PRS) translated to > 5-fold lower PRS in centenarians compared to AD cases, and ≈ 2-fold lower compared to middle-aged healthy controls.

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 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.

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.

Background: Hemodynamic balance in the heart-brain axis is increasingly recognized as a crucial factor in maintaining functional and structural integrity of the brain and thereby cognitive functioning. Patients with heart failure (HF), carotid occlusive disease (COD), and vascular cognitive impairment (VCI) present themselves with complaints attributed to specific parts of the heart-brain axis, but hemodynamic changes often go beyond the part of the axis for which they primarily seek medical advice. The Heart-Brain Study hypothesizes that the hemodynamic status of the heart and the brain is an important but underestimated cause of VCI. We investigate this by studying to what extent hemodynamic changes contribute to VCI and what the mechanisms involved are. Here, we provide an overview of the design and protocol. Methods: The Heart-Brain Study is a multicenter cohort study with a follow-up measurement after 2 years among 645 participants (175 VCI, 175 COD, 175 HF, and 120 controls). Enrollment criteria are the following: 1 of the 3 diseases diagnosed according to current guidelines, age ≥50 years, no magnetic resonance contraindications, ability to undergo cognitive testing, and independence in daily life. A core clinical dataset is collected including sociodemographic factors, cardiovascular risk factors, detailed neurologic, cardiac, and medical history, medication, and a physical examination. In addition, we perform standardized neuropsychological testing, cardiac, vascular and brain MRI, and blood sampling. In subsets of participants we assess Alz­heimer biomarkers in cerebrospinal fluid, and assess echocardiography and 24-hour blood pressure monitoring. Follow-up measurements after 2 years include neuropsychological testing, brain MRI, and blood samples for all participants. We use centralized state-of-the-art storage platforms for clinical and imaging data. Imaging data are processed centrally with automated standardized pipelines. Results and Conclusions: The Heart-Brain Study investigates relationships between (cardio-)vascular factors, the hemodynamic status of the heart and the brain, and cognitive impairment. By studying the complete heart-brain axis in patient groups that represent components of this axis, we have the opportunity to assess a combination of clinical and subclinical manifestations of disorders of the heart, vascular system and brain, with hemodynamic status as a possible binding factor.

There is evidence for a beneficial effect of aerobic exercise on cognition, but underlying mechanisms are unclear. In this study, we test the hypothesis that aerobic exercise increases cerebral blood flow (CBF) in patients with vascular cognitive impairment (VCI). This study is a multicenter single-blind randomized controlled trial among 80 patients with VCI. Most important inclusion criteria are a diagnosis of VCI with Mini-Mental State Examination ≥22 and Clinical Dementia Rating ≤0.5. Participants are randomized into an aerobic exercise group or a control group. The aerobic exercise program aims to improve cardiorespiratory fitness and takes 14 weeks, with a frequency of three times a week. Participants are provided with a bicycle ergometer at home. The control group receives two information meetings. Primary outcome measure is change in CBF. We expect this study to provide insight into the potential mechanism by which aerobic exercise improves hemodynamic status.