Alzheimer’s disease (AD) is characterized by progressive cognitive decline and genetic influences on cognition are well-established. Investigating single nucleotide polymorphisms (SNPs) associated with cognitive function across dementia progression stages may identify early genetic markers of cognitive decline. The Alzheimer's Disease Neuroimaging Initiative (ADNI), which categorized participants as cognitively normal, mild cognitive impairment, or dementia, provide a valuable resource for such studies. We therefore conducted genome-wide association study (GWAS) on ADAS scores in ADNI participants, to identify SNPs associated with cognitive performance, serving as early markers of dementia progression. Genotyped data from three ADNI phases were downloaded and merged. Quality control retained common SNPs with a variant call rate >0.98, sample call rate >0.95, Hardy-Weinberg Equilibrium p -value >10 -6 , and minor allele frequency (MAF) ≥0.01. Individuals were included if their genetic sex matched reported sex and they had no up-to-third-degree relationships with other participants. Genotype imputation was performed using the Michigan Imputation Server. Functional annotation was performed using ANNOVAR. Separate GWAS of ADAS11 and ADAS13 were performed using linear regression in PLINK2, adjusting for age, sex, years of education, and the first ten principal components. Genetic loci were determined based on index SNPs ( p -value <10 -6 ) with more than one nominally associated SNPs ( p -value <10 -4 ) in linkage disequilibrium (r 2 ≥0.02) within 250kb using PLINK clump function. A total of 1,236 participants and 8,416,387 common autosomal SNPs were included in the analyses. Thirteen genetic loci were identified as associated with ADAS11, and six with ADAS13, five of which were shared (Figure 1A and 1B). Four index SNPs reached the genome-wide significant threshold ( p -value <5×10 -8 ), including the strongest signal at the APOE locus, primarily driven by dementia, and three novel but less frequent SNPs (MAF <0.05) located on chromosomes 3, 8 and 13. The chromosome 3 locus is near the SUCLG2 gene, previously reported having an SNP linked to cerebrospinal fluid Aβ 1–42 levels in AD patients. Novel genetic loci identified in ADNI provide insights into the genetic basis of cognitive performance, warranting further research on whether well-established A/T/N imaging or fluid biomarkers mediate their effects on cognitive and diagnostic outcomes.

Alzheimer’s disease (AD) is a progressive neurological disorder with an unclear cause, and its amyloid and tau hypotheses need deeper investigation to understand their link to genetic variants and AD outcomes. To bridge this gap, we conduct a mediation analysis using the genotyping, amyloid and tau imaging, and cognitive data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) to delineate specific mediation pathways from genetic variants such as single nucleotide polymorphisms (SNPs), to regional amyloid/tau protein aggregation in the brain, and to cognitive outcomes. ADNI provides genotyped data and harmonized phenotypes. We further imputed, harmonized, annotated the genotyping data. Post-quality control and subject matching resulted in 1,051 individuals for amyloid and 525 for tau imaging measurements. We first conducted genome-wide association study (GWAS) on 5,302,064 variants to prioritize SNPs significantly associated with cognitive scores. Subsequently, we employed a mediation model to explore how regional amyloid and tau imaging measures mediate the genetic effects on cognitive scores. Specifically, we used prioritized SNPs from GWAS as exposure, two cognitive scores (ADAS-Cog13 and MMSE) as outcomes, and amyloid and tau imaging measures from 68 cortical regions as mediators. Additionally, we contrasted results from GWAS-identified SNPs with five candidate AD SNPs. We assessed amyloid and tau aggregation in 68 cortical brain regions as mediators for SNP effects on cognitive scores; see Figure 1 for top findings. After Bonferroni correction, we found 9,551, 34,402, 5,636, and 193,002 mediation relationships for SNP-amyloid-ADAS13, SNP-amyloid-MMSE, SNP-tau-ADAS13, and SNP-tau-MMSE respectively. Tau aggregation demonstrated a broader impact on AD across cortical regions compared to amyloid. Although 4 of the candidate AD SNPs showed no signal, one of them, rs429358, demonstrated strong amyloid and tau mediated genetic effects on cognitive outcomes. Our results also showed that amyloid and tau hypotheses have different regional mediation patterns (Figure 2). For example, bankstss region only influences the tau pathway, while caudal anterior cingulate only affects the amyloid pathway. Our genome-wide mediation analysis has identified top cortical regions and SNPs associated with amyloid- and tau-mediated cognitive declines in AD. These results yield new insights into AD etiology linking genetic determinants, cellular hallmarks, and phenotypic outcomes.

Alzheimer's disease (AD) is the most common cause of dementia, with global case numbers projected to reach 153 million in 2050 1 . AD is highly heritable, with twin-based heritability estimates of 60-80% 2 . While 1,200 causal loci are predicted to exist for AD 3 , approximately 80 have been associated with AD in two recent studies 4,5 , suggesting that many loci remain to be discovered 6 . Here, we analyzed data from 183,620 AD cases and 2.6 million controls from diverse ancestries, identifying 118 loci in a multi-ancestry analysis and 9 additional loci in ancestry-specific analyses, 48 of which are new. We identified new AD risk genes, prioritized potential drug targets, and identified microglia and, for the first time, several neuronal cell types enriched for AD-associated genetic risk. Moreover, we improved polygenic prediction and estimated a single-nucleotide polymorphism (SNP) heritability of 19%. Together, our findings offer insights into the genetic architecture and potential pathobiology of AD, as well as specific targets for future drug development research.

INTRODUCTION Individuals with Alzheimer's disease (AD) commonly experience neuropsychiatric symptoms of psychosis (AD+P) and/or affective disturbance (depression, anxiety, and/or irritability, AD+A). This study's goal was to identify the genetic architecture of AD+P and AD+A, as well as their genetically correlated phenotypes. METHOD SGenome-wide association meta-analysis of 9988 AD participants from six source studies with participants characterized for AD+P AD+A, and a joint phenotype (AD+A+P). RESULTS AD+P and AD+A were genetically correlated. However, AD+P and AD+A diverged in their genetic correlations with psychiatric phenotypes in individuals without AD. AD+P was negatively genetically correlated with bipolar disorder and positively with depressive symptoms. AD+A was positively correlated with anxiety disorder and more strongly correlated than AD+P with depressive symptoms. AD+P and AD+A+P had significant estimated heritability, whereas AD+A did not. Examination of the loci most strongly associated with the three phenotypes revealed overlapping and unique associations. DISCUSSION AD+P, AD+A, and AD+A+P have both shared and divergent genetic associations pointing to the importance of incorporating genetic insights into future treatment development.

Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

Determining the genetic architecture of Alzheimer's disease (AD) pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we performed a genome-wide association study of cortical tau quantified by positron emission tomography in 3,136 participants from 12 independent studies. The CYP1B1-RMDN2 locus was associated with tau deposition. The most significant signal was at rs2113389, which explained 4.3% of the variation in cortical tau, while APOE4 rs429358 accounted for 3.6%. rs2113389 was associated with higher tau and faster cognitive decline. Additive effects, but no interactions, were observed between rs2113389 and diagnosis, APOE4 , and Aβ positivity. CYP1B1 expression was upregulated in AD. rs2113389 was associated with higher CYP1B1 expression and methylation levels. Mouse model studies provided additional functional evidence for a relationship between CYP1B1 and tau deposition but not Aβ. These results may provide insight into the genetic basis of cerebral tau and novel pathways for therapeutic development in AD.

Alzheimer’s disease (AD) patients carrying T-allele in the single nucleotide polymorphism rs744373 show higher levels of misfolded tau protein levels, as well as faster accumulation of neurofibrillary tangles (Franzmeier-2019; Franzmeier-2022), in addition to established risk gene apolipoprotein E (APOE4). Here we conduct pathway analysis to understand the direct and indirect effects, mediated through amyloid levels, of the rs6733839 T-allele and APOE e4-allele on tau. Amyloid-positive (florbetapir PET) placebo-arm patients with a clinical diagnosis of AD dementia from four clinical trials (NCT01900665, NCT02791191, NCT02245737, NCT02016560, Table.1) underwent baseline (N = 547) and follow-up (N = 230) flortaucipir PET scans. Tau burden was assessed using standardized uptake value ratio (SUVr) in AD-specific region (MUBADA; Devous-2018) with respect to cerebellum-crus. We tested direct and indirect effects of BIN1 (rs6733839) and APOE4 on baseline SUVr and change-from baseline (CFB) in tau-PET mediated by baseline florbetapir signal. Unstandardized indirect effects were computed for each of 1,000 bootstrapped samples, and the 95% confidence interval was computed by determining the indirect effects at the 2.5th and 97.5th percentiles. BIN1 and age showed significant association with the baseline tau-PET level (BIN1: ßeta = 0.05, P = 0.05; Age: ßeta = -0.03, P<0.001), whereas APOE4 association with the baseline tau-PET levels was not statistically significant (ßeta = 0.006, P = 0.81). The bootstrapped unstandardized indirect effect of BIN1, age, and APOE4 mediated via baseline amyloid levels was insignificant (BIN1: ßeta = 0.0002, P = 0.92; Age: ßeta = 3.82e −05 , P = 0.74; APOE4: ßeta = -0.0003, P = 0.86). When evaluated on longitudinal tau measures, the direct effect of APOE4 on CFB in tau-PET SUVr was significant (ßeta = 0.02; P = 0.01). The direct and indirect effects (mediated via baseline amyloid levels) of BIN1 (Direct: ßeta = -0.007, P = 0.215; Indirect: ßeta = -0.0007, P = 0.58) and Age (Direct: ßeta = -0.0009, P = 0.26; Indirect: ßeta = 0.0001, P = 0.32) were insignificant. BIN1 showed significant association with the baseline tau-PET level whereas APOE-e4 allele directly affected longitudinal tau buildup independent of amyloid levels. These observations require additional validation using larger datasets and further optimization of the applied methodology is warranted.

The Bridging Integrator I (BIN1) is a significant genetic risk gene, second only to the established risk gene apolipoprotein E (APOE4), for late-onset Alzheimer’s disease (LOAD, AD) (Carrasquillo, 2011). BIN1 rs744733 risk allele was shown to affect tau pathology and cognitive decline (Franzmeier, 2021). In this study, we compared BIN1 risk allele rs6733839 with APOE4 on interdependency among AD risk factors and biomarkers by applying Bayesian Network (BN) modeling (Scutari, 2017) to data from Lilly AD clinical trials. Data from A05C (n = 142, NCT01565382), A05E (n = 217, NCT02016560), and untreated arms of AZES (n = 206, NCT02245737), LLCF (n = 229, NCT02791191), and LZAX (n = 194, NCT01900665) trial participants were used for the analysis (table 1). We constructed graphs representing the dependencies among the variables, including demographics, genetic risk genes, brain amyloid and tau measured by 18F-Florbetapir or 18F-Flortaucipir positron emission tomography (PET) imaging quantified globally and regionally as a standardized uptake value ratio. Longitudinal tau changes from baseline were computed for a sub cohort (n = 234). Conditional Gaussian Bayesian Network (CGBN) was used to model discrete (gender, genotype) and continuous (age, PET quantifications) variables. Directed Acyclic Graphs (DAG) structure was learned using constraint-based Incremental Association (iamb) algorithm and score-based Hill-Climbing (hc) algorithm with one-sided type I error rate at 10%. The connection strength was estimated by bootstrap resampling and computing the probability of any variable influencing another variable. Model parameters were estimated using the maximum likelihood estimation method. The result shows that age influences baseline amyloid (Strength s = 1.0) and parietal tau (s = 0.83). APOE4 influences baseline amyloid (s = 0.75) and tau at four lopes with strength ranging from 0.84 to 0.31 in the order of frontal, parietal, occipital, and temporal lobes. BIN1 influences baseline tau at the parietal lobe (s = 0.42) and other lobes with strength below 0.3. We have not observed consistent dependency between variables and change in tau, likely due to the small sample size (n = 234). Our study result is consistent with current knowledge of APOE4 influencing amyloid and tau. The finding that BIN1 influences tau supports the observation of BIN1 rs744373, in linkage disequilibrium with rs6733839, in ADNI and BioFINDER studies (Franzmeier, 2021).

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD with psychosis, AD + P). AD + P affects ~50% of individuals with AD, identifies a subgroup with poor outcomes, and is associated with a greater degree of cognitive impairment and depressive symptoms, compared to subjects without psychosis (AD − P). Although the estimated heritability of AD + P is 61%, genetic sources of risk are unknown. We report a genome-wide meta-analysis of 12,317 AD subjects, 5445 AD + P. Results showed common genetic variation accounted for a significant portion of heritability. Two loci, one in ENPP6 (rs9994623, O.R. (95%CI) 1.16 (1.10, 1.22), p = 1.26 × 10 −8 ) and one spanning the 3′-UTR of an alternatively spliced transcript of SUMF1 (rs201109606, O.R. 0.65 (0.56–0.76), p = 3.24 × 10 −8 ), had genome-wide significant associations with AD + P. Gene-based analysis identified a significant association with APOE , due to the APOE risk haplotype ε4. AD + P demonstrated negative genetic correlations with cognitive and educational attainment and positive genetic correlation with depressive symptoms. We previously observed a negative genetic correlation with schizophrenia; instead, we now found a stronger negative correlation with the related phenotype of bipolar disorder. Analysis of polygenic risk scores supported this genetic correlation and documented a positive genetic correlation with risk variation for AD, beyond the effect of ε4. We also document a small set of SNPs likely to affect risk for AD + P and AD or schizophrenia. These findings provide the first unbiased identification of the association of psychosis in AD with common genetic variation and provide insights into its genetic architecture.

Expansion of CAG trinucleotide repeats in ATXN1 causes spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease that impairs coordination and cognition. While ATXN1 is associated with increased Alzheimer's disease (AD) risk, CAG repeat number in AD patients is not changed. Here, we investigated the consequences of ataxin-1 loss of function and discovered that knockout of Atxn1 reduced CIC-ETV4/5-mediated inhibition of Bace1 transcription, leading to increased BACE1 levels and enhanced amyloidogenic cleavage of APP, selectively in AD-vulnerable brain regions. Elevated BACE1 expression exacerbated Aβ deposition and gliosis in AD mouse models and impaired hippocampal neurogenesis and olfactory axonal targeting. In SCA1 mice, polyglutamine-expanded mutant ataxin-1 led to the increase of BACE1 post-transcriptionally, both in cerebrum and cerebellum, and caused axonal-targeting deficit and neurodegeneration in the hippocampal CA2 region. These findings suggest that loss of ataxin-1 elevates BACE1 expression and Aβ pathology, rendering it a potential contributor to AD risk and pathogenesis.

Expansion of CAG trinucleotide repeats in the Ataxin-1 gene (ATXN1) causes spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease that impairs coordinated movement and cognitive functions. ATXN1 is associated with genetic risk for Alzheimer's disease (AD). Here, we show loss of Ataxin-1 potentiates AD pathogenesis. Specifically, knockout of Atxn1 in mice led to increased expression of β-secretase (BACE1) and elevated BACE1-mediated cleavage of the amyloid precursor protein (APP), selectively in AD-vulnerable brain regions. Ataxin-1 depletion exacerbated Aβ plaque deposition and gliosis in AD mice, and impaired hippocampal neurogenesis and axonal targeting. The SCA1-linked CAG repeat number was normal in AD patients. However, in SCA1 mice, aggregation of mutant Ataxin-1 led to BACE1 up-regulation and axon guidance defects in the hippocampal CA2 region. Together, these findings indicate that loss of Ataxin-1 potentiates Aβ pathology, and BACE1 elevation may represent a shared pathogenic mechanism underlying cognitive deficits in SCA1 and AD.

SOX5 encodes a transcription factor that is expressed in multiple tissues including heart, lung and brain. Mutations in SOX5 have been previously found in patients with amyotrophic lateral sclerosis (ALS) and developmental delay, intellectual disability and dysmorphic features. To characterize the neuronal role of SOX5, we silenced the Drosophila ortholog of SOX5, Sox102F, by RNAi in various neuronal subtypes in Drosophila. Silencing of Sox102F led to misorientated and disorganized michrochaetes, neurons with shorter dendritic arborization (DA) and reduced complexity, diminished larval peristaltic contractions, loss of neuromuscular junction bouton structures, impaired olfactory perception, and severe neurodegeneration in brain. Silencing of SOX5 in human SH-SY5Y neuroblastoma cells resulted in a significant repression of WNT signaling activity and altered expression of WNT-related genes. Genetic association and meta-analyses of the results in several large family-based and case-control late-onset familial Alzheimer's disease (LOAD) samples of SOX5 variants revealed several variants that show significant association with AD disease status. In addition, analysis for rare and highly penetrate functional variants revealed four novel variants/mutations in SOX5, which taken together with functional prediction analysis, suggests a strong role of SOX5 causing AD in the carrier families. Collectively, these findings indicate that SOX5 is a novel candidate gene for LOAD with an important role in neuronal function. The genetic findings warrant further studies to identify and characterize SOX5 variants that confer risk for AD, ALS and intellectual disability.

Introduction TREM2 is a lipid‐sensing activating receptor on microglia known to be important for Alzheimer's disease (AD), but whether it plays a beneficial or detrimental role in disease pathogenesis is controversial. Methods We analyzed AD risk of TREM2 variants in the NIMH AD Genetics Initiative Study and AD Sequencing Project. We compared each variant's risk and functional impact by a reporter assay. Finally, we analyzed expression of TREM2 on human monocytes. Results We provide more evidence for increased AD risk associated with several TREM2 variants, and show that these variants decreased or markedly increased binding to TREM2 ligands. We identify HDL and LDL as novel TREM2 ligands. We also show that TREM2 expression in human monocytes is minimal compared to monocyte‐derived dendritic cells. Discussion Our results suggest that TREM2 signaling helps protect against AD but can cause harm in excess, supporting the idea that proper TREM2 function is important to counteract disease progression.

The genetic basis of Alzheimer's disease (AD) is complex and heterogeneous. Over 200 highly penetrant pathogenic variants in the genes APP , PSEN1 , and PSEN2 cause a subset of early-onset familial AD. On the other hand, susceptibility to late-onset forms of AD (LOAD) is indisputably associated to the ɛ4 allele in the gene APOE , and more recently to variants in more than two-dozen additional genes identified in the large-scale genome-wide association studies (GWAS) and meta-analyses reports. Taken together however, although the heritability in AD is estimated to be as high as 80%, a large proportion of the underlying genetic factors still remain to be elucidated. In this study, we performed a systematic family-based genome-wide association and meta-analysis on close to 15 million imputed variants from three large collections of AD families (~3500 subjects from 1070 families). Using a multivariate phenotype combining affection status and onset age, meta-analysis of the association results revealed three single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with AD risk: rs7609954 in the gene PTPRG (P -value=3.98 × 10 −8 ), rs1347297 in the gene OSBPL6 ( P -value=4.53 × 10 −8 ), and rs1513625 near PDCL3 ( P -value=4.28 × 10 −8 ). In addition, rs72953347 in OSBPL6 ( P -value=6.36 × 10 −7 ) and two SNPs in the gene CDKAL1 showed marginally significant association with LOAD (rs10456232, P -value=4.76 × 10 −7 ; rs62400067, P -value=3.54 × 10 −7 ). In summary, family-based GWAS meta-analysis of imputed SNPs revealed novel genomic variants in (or near) PTPRG, OSBPL6 , and PDCL3 that influence risk for AD with genome-wide significance.

Alzheimer's disease (AD) is a progressive dementia disorder characterized by synaptic degeneration and amyloid-beta (A beta) accumulation in the brain. Through whole-genome sequencing of 1345 individuals from 410 families with late-onset AD (LOAD), we identified three highly penetrant variants in PRKCA, the gene that encodes protein kinase C alpha (PKC alpha), in five of the families. All three variants linked with LOAD displayed increased catalytic activity relative to wild-type PKC alpha as assessed in live-cell imaging experiments using a genetically encoded PKC activity reporter. Deleting PRKCA in mice or adding PKC antagonists to mouse hippocampal slices infected with a virus expressing the Ab precursor CT100 revealed that PKC alpha was required for the reduced synaptic activity caused by A beta. InPRKCA(-/-) neurons expressing CT100, introduction of PKC alpha, but not PKC alpha lacking a PDZ interaction moiety, rescued synaptic depression, suggesting that a scaffolding interaction bringing PKC alpha to the synapse is required for itsmediation of the effects of A beta. Thus, enhanced PKC alpha activity may contribute to AD, possibly bymediating the actions of A beta on synapses. In contrast, reduced PKC alpha activity is implicated in cancer. Hence, these findings reinforce the importance of maintaining a careful balance in the activity of this enzyme.

PKCα variants in some patients with Alzheimer’s disease may mediate the pathological effects of amyloid-β.

BACKGROUND:In family-based association analysis, each family is typically ascertained from a single proband, which renders the effects of ascertainment bias heterogeneous among family members. This is contrary to case-control studies, and may introduce sample or ascertainment bias. Statistical efficiency is affected by ascertainment bias, and careful adjustment can lead to substantial improvements in statistical power. However, genetic association analysis has often been conducted using family-based designs, without addressing the fact that each proband in a family has had a great influence on the probability for each family member to be affected.METHOD:We propose a powerful and efficient statistic for genetic association analysis that considered the heterogeneity of ascertainment bias among family members, under the assumption that both prevalence and heritability of disease are available. With extensive simulation studies, we showed that the proposed method performed better than the existing methods, particularly for diseases with large heritability.RESULTS:We applied the proposed method to the genome-wide association analysis of Alzheimer's disease. Four significant associations with the proposed method were found.CONCLUSION:Our significant findings illustrated the practical importance of this new analysis method.