IntroductionLate-onset Alzheimer's disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly 1 , and risk is partially driven by genetics 2 . Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS) [3][4][5][6][7][8] . To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 x 10 -7 ) indicating that additional rare variants remain to be identified. Main TextOur previous work identified 19 genome-wide significant common variant signals in addition to APOE 9 , that influence risk for LOAD. These signals, combined with 'subthreshold' common variant associations, account for ~31% of the genetic variance of LOAD 2 , leaving the majority of genetic risk uncharacterized 10 . To search for additional signals, we conducted a GWAS metaanalysis of non-Hispanic Whites (NHW) using a larger sample (17 new, 46 total datasets) from our group, the International Genomics of Alzheimer's Project (IGAP) (composed of four AD consortia: ADGC, CHARGE, EADI, and GERAD). This sample increases our previous discovery sample (Stage 1) by 29% for cases and 13% for controls (N=21,982 cases; 41,944 controls) ( Supplementary Table 1 and 2, and Supplementary Note). To sample both common and rare variants (minor allele frequency MAF ≥ 0.01, and MAF < 0.01, respectively), we imputed the discovery datasets using a 1000 Genomes reference panel consisting of . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a 11 36,648,992 single-nucleotide variants, 1,380,736 insertions/deletions, and 13,805 structural variants. After quality control, 9,456,058 common variants and 2,024,574 rare variants were selected for analysis (a 63% increase from our previous common variant analysis in 2013).Genotype dosages were analyzed within each dataset, and then combined with meta-analysis ( Supplementary Figures 1 and 2 and Supplementary Table 3). The Stage 1 discovery metaanalysis was first followed by Stage 2 using the I-select chip we previously developed in Lambert et al (including 11,632 variants, N=18,845) and finally stage 3A (N=6,998). The final sample was 33,692 clinical AD cases and 56,077 controls.Meta-analysis of Stages 1 and 2 produced 21 associations with P ≤ 5x10 -8 (Table 1 and Figure 1). Of these, 18 were previously reported as genome-wide significant and three of them are signals not initially described in Lambert et al: the rare R47H TREM2 coding va...

IMPORTANCE Intracellular tau protein aggregates are a pathological hallmark of neurodegenerative tauopathies, including Alzheimer disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick disease. Emerging evidence supports a model of cell-to-cell transmission of proteinaceous pathological tau seeds, which leads to recruitment and templated fibrillization of endogenous cellular tau followed by the spread of abnormal tau throughout the brain. These findings lead to the strain hypothesis, which predicts that distinct conformational strains or polymorphs of tau may underlie the clinical and neuropathological heterogeneity and cell-type specificity of tauopathies. In this review, we describe the evidence for propagation of distinct tau strains in cell culture and animal models of AD and mechanistic insights into cell-to-cell transmission of pathological tau. OBSERVATIONS Intracranial injections of synthetic tau-preformed fibrils and human brain-derived pathological tau into nontransgenic wild-type mice and transgenic mouse models of AD expressing β-amyloid and tau-amyloid deposits yield widespread pathological tau aggregates observed in neuroanatomically connected brain regions distant from the site of injection. Furthermore, when human brain–derived pathological tau obtained from distinct tauopathies (ie, brains with AD, PSP, and CBD) were injected into the brains of wild-type mice, they seeded tau pathology and faithfully recapitulated cell-type specific tau inclusions characteristic of each tauopathy in a time-dependent, dose-dependent, and injection site–dependent spread reflective of the connectome of the injection site. CONCLUSIONS AND RELEVANCE These findings provide compelling evidence that misfolded or pathological conformers of tau undergo cell-to-cell spread in a tauopathy strain-specific manner. Importantly, evidence to date supports that pathological tau strains do not behave like infectious agents, despite growing evidence that these tau strains undergo templated propagation and spread linked to the neuroanatomical connectome of the injection site.

Pericytes are unique, multi-functional mural cells localized at the abluminal side of the perivascular space in microvessels. Originally discovered in 19th century, pericytes had drawn less attention until decades ago mainly due to lack of specific markers. Recently, however, a growing body of evidence has revealed that pericytes play various important roles: development and maintenance of blood-brain barrier (BBB), regulation of the neurovascular system (e.g., vascular stability, vessel formation, cerebral blood flow, etc.), trafficking of inflammatory cells, clearance of toxic waste products from the brain, and acquisition of stem cell-like properties. In the neurovascular unit, pericytes perform these functions through coordinated crosstalk with neighboring cells including endothelial, glial, and neuronal cells. Dysfunction of pericytes contribute to a wide variety of diseases that lead to cognitive impairments such as cerebral small vessel disease (SVD), acute stroke, Alzheimer's disease (AD), and other neurological disorders. For instance, in SVDs, pericyte degeneration leads to microvessel instability and demyelination while in stroke, pericyte constriction after ischemia causes a no-reflow phenomenon in brain capillaries. In AD, which shares some common risk factors with vascular dementia, reduction in pericyte coverage and subsequent microvascular impairments are observed in association with white matter attenuation and contribute to impaired cognition. Pericyte loss causes BBB-breakdown, which stagnates amyloid β clearance and the leakage of neurotoxic molecules into the brain parenchyma. In this review, we first summarize the characteristics of brain microvessel pericytes, and their roles in the central nervous system. Then, we focus on how dysfunctional pericytes contribute to the pathogenesis of vascular cognitive impairment including cerebral 'small vessel' and 'large vessel' diseases, as well as AD. Finally, we discuss therapeutic implications for these disorders by targeting pericytes.