Cognitive and functional performance and plasma biomarkers of early Alzheimer's disease in Down syndrome.

INTRODUCTION: People with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials. METHODS: This large cross-sectional cohort study investigated the associations between plasma biomarkers of amyloid beta (Aß)42/40, total tau, and neurofilament light chain (NfL) and cognitive (episodic memory, visual-motor integration, and visuospatial abilities) and functional (adaptive behavior) impairments in 260 adults with DS without dementia (aged 25-81 years). RESULTS: In general linear models lower plasma Aß42/40 was related to lower visuospatial ability, higher total tau was related to lower episodic memory, and higher NfL was related to lower visuospatial ability and lower episodic memory. DISCUSSION: Plasma biomarkers may have utility in tracking AD pathology associated with early stages of cognitive decline in adults with DS, although associations were modest. Highlights: Plasma Alzheimer's disease (AD) biomarkers correlate with cognition prior to dementia in Down syndrome.Lower plasma amyloid beta 42/40 was related to lower visuospatial abilities.Higher plasma total tau and neurofilament light chain were associated with lower cognitive performance.Plasma biomarkers show potential for tracking early stages of AD symptomology.

Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer's disease: a cross-sectional study.

BACKGROUND: In people with genetic forms of Alzheimer's disease, such as in Down syndrome and autosomal-dominant Alzheimer's disease, pathological changes specific to Alzheimer's disease (ie, accumulation of amyloid and tau) occur in the brain at a young age, when comorbidities related to ageing are not present. Studies including these cohorts could, therefore, improve our understanding of the early pathogenesis of Alzheimer's disease and be useful when designing preventive interventions targeted at disease pathology or when planning clinical trials. We compared the magnitude, spatial extent, and temporal ordering of tau spread in people with Down syndrome and autosomal-dominant Alzheimer's disease. METHODS: In this cross-sectional observational study, we included participants (aged ≥25 years) from two cohort studies. First, we collected data from the Dominantly Inherited Alzheimer's Network studies (DIAN-OBS and DIAN-TU), which include carriers of autosomal-dominant Alzheimer's disease genetic mutations and non-carrier familial controls recruited in Australia, Europe, and the USA between 2008 and 2022. Second, we collected data from the Alzheimer Biomarkers Consortium-Down Syndrome study, which includes people with Down syndrome and sibling controls recruited from the UK and USA between 2015 and 2021. Controls from the two studies were combined into a single group of familial controls. All participants had completed structural MRI and tau PET (18F-flortaucipir) imaging. We applied Gaussian mixture modelling to identify regions of high tau PET burden and regions with the earliest changes in tau binding for each cohort separately. We estimated regional tau PET burden as a function of cortical amyloid burden for both cohorts. Finally, we compared the temporal pattern of tau PET burden relative to that of amyloid. FINDINGS: We included 137 people with Down syndrome (mean age 38·5 years [SD 8·2], 74 [54%] male, and 63 [46%] female), 49 individuals with autosomal-dominant Alzheimer's disease (mean age 43·9 years [11·2], 22 [45%] male, and 27 [55%] female), and 85 familial controls, pooled from across both studies (mean age 41·5 years [12·1], 28 [33%] male, and 57 [67%] female), who satisfied the PET quality-control procedure for tau-PET imaging processing. 134 (98%) people with Down syndrome, 44 (90%) with autosomal-dominant Alzheimer's disease, and 77 (91%) controls also completed an amyloid PET scan within 3 years of tau PET imaging. Spatially, tau PET burden was observed most frequently in subcortical and medial temporal regions in people with Down syndrome, and within the medial temporal lobe in people with autosomal-dominant Alzheimer's disease. Across the brain, people with Down syndrome had greater concentrations of tau for a given level of amyloid compared with people with autosomal-dominant Alzheimer's disease. Temporally, increases in tau were more strongly associated with increases in amyloid for people with Down syndrome compared with autosomal-dominant Alzheimer's disease. INTERPRETATION: Although the general progression of amyloid followed by tau is similar for people Down syndrome and people with autosomal-dominant Alzheimer's disease, we found subtle differences in the spatial distribution, timing, and magnitude of the tau burden between these two cohorts. These differences might have important implications; differences in the temporal pattern of tau accumulation might influence the timing of drug administration in clinical trials, whereas differences in the spatial pattern and magnitude of tau burden might affect disease progression. FUNDING: None.

Prodromal Alzheimer's disease can affect activities of daily living for adults with Down syndrome.

INTRODUCTION: Alzheimer's disease (AD) affecting adults with Down syndrome (DS-AD), like late-onset AD (LOAD) in the neurotypical population, has preclinical, prodromal, and more advanced stages. Only tasks placing high demands on cognition are expected to be affected during the prodromal stage, with activities of daily living (ADLs) typically being spared. However, cognitive demands of ADLs could be high for adults with DS and may be affected during prodromal DS-AD. METHODS: Cognitively stable cases that subsequently developed prodromal DS-AD were identified within a set of archived data from a previous longitudinal study. Measures of ADLs and multiple cognitive domains were examined over time. RESULTS: Clear declines in ADLs accompanied cognitive declines with prodromal DS-AD while stability in all measures was verified during preclinical DS-AD. DISCUSSION: Operationally defining prodromal DS-AD is essential to disease staging in this high-risk population and for informing treatment options and timing as new disease-modifying drugs become available. Highlights: Cognitive and functional stability were demonstrated prior to the onset of prodromal DS-AD.ADL declines accompanied cognitive declines as adults with DS transitioned to prodromal AD.Declines in ADLs should be a defining feature of prodromal AD for adults with DS.Better characterization of prodromal DS-AD can improve AD diagnosis and disease staging.Improvements in DS-AD diagnosis and staging could also inform the timing of interventions.

Individualized estimated years from onset of Alzheimer's disease- related decline for adults with Down syndrome.

Introduction: Adults with Down syndrome (DS) are at increased risk for Alzheimer's disease (AD) and vary in their age of transition from AD preclinical to prodromal or more advanced clinical stages. An empirically based method is needed to determine individual "estimated years from symptom onset (EYO)," the same construct used in studies of autosomal dominant AD . Methods: Archived data from a previous study of > 600 adults with DS were examined using survival analysis methods. Age-specific prevalence of prodromal AD or dementia, cumulative risk, and EYOs were determined. Results: Individualized EYOs for adults with DS ranging in age from 30 to 70+ were determined, dependent upon chronological age and clinical status. Discussion: EYOs can be a useful tool for studies focused on biomarker changes during AD progression in this and other populations at risk, studies that should contribute to improved methods for diagnosis, prediction of risk, and identification of promising treatment targets. HIGHLIGHTS: Years from Alzheimer's disease (AD) onset (EYO) was estimated for adults with Down syndrome (DS).EYOs were informed by AD clinical status and age, ranging from 30 to > 70 years.Influences of biological sex and apolipoprotein E genotype on EYOs were examined.EYOs have advantages for predicting risk of AD-related dementia compared to age.EYOs can be extremely informative in studies of preclinical AD progression.

A modified Cued Recall Test for detecting prodromal AD in adults with Down syndrome.

Introduction: The development of valid methods to diagnose prodromal Alzheimer's disease (AD) in adults with Down syndrome (DS) is one of the many goals of the Alzheimer's Biomarkers Consortium-Down Syndrome (ABC-DS). Methods: The diagnostic utility of a modified Cued Recall Test (mCRT) was evaluated in 332 adults with DS ranging from 25 to 81 years of age. Total recall was selected a priori, as the primary indicator of performance. Multiple regression and receiver-operating characteristic (ROC) analyses were used to compare diagnostic groups. Results: Performance on the mCRT, as indicated by the total recall score, was highly sensitive to differences between diagnostic groups. ROC areas under the curve (AUCs) ranging from 0.843 to 0.955, were observed. Discussion: The mCRT has strong empirical support for its use in clinical settings, as a valuable tool in studies targeting biomarkers of AD, and as a potential outcome measure in clinical trials targeting AD in this high-risk population.

Correction: Hom et al. Cognitive Function during the Prodromal Stage of Alzheimer's Disease in Down Syndrome: Comparing Models. BrainSci. 2021, 11, 1220.

We would like to submit the following correction to our recently published paper [...].

Adults with Down syndrome in randomized clinical trials targeting prevention of Alzheimer's disease.

INTRODUCTION: Adults with Down syndrome, the largest population genetically predisposed to high risk for Alzheimer's disease (AD), are ideally suited participants for clinical trials targeting prevention. Critically important considerations for the design of such trials include appropriate selection of participants, outcome measures, and duration of follow-up. METHODS: Archived data for 12 measures of performance over a 3-year period were analyzed for 185 adults with Down syndrome 36 years of age and older with presumptive preclinical AD. RESULTS: Declines over 3 years were not observed prior to 46 years of age. However, declines were observed at older ages, increasing monotonically for groups aged 46-49, 50-55, and >55, as did incidence of prodromal AD and dementia. DISCUSSION: Significant decline over a 2- to 3-year period for a prospective placebo group of adults with Down syndrome enrolled in clinical prevention trials can only be expected when inclusion is limited to adults older than 45 years of age.

Cognitive Function during the Prodromal Stage of Alzheimer's Disease in Down Syndrome: Comparing Models.

Accurate identification of the prodromal stage of Alzheimer's disease (AD), known as mild cognitive impairment (MCI), in adults with Down syndrome (MCI-DS) has been challenging because there are no established diagnostic criteria that can be applied for people with lifelong intellectual disabilities (ID). As such, the sequence of cognitive decline in adults with DS has been difficult to ascertain, and it is possible that domain constructs characterizing cognitive function in neurotypical adults do not generalize to this high-risk population. The present study examined associations among multiple measures of cognitive function in adults with DS, either prior to or during the prodromal stage of AD to determine, through multiple statistical techniques, the measures that reflected the same underlying domains of processing. Participants included 144 adults with DS 40-82 years of age, all enrolled in a larger, multidisciplinary study examining biomarkers of AD in adults with DS. All participants had mild or moderate lifelong intellectual disabilities. Overall AD-related clinical status was rated for each individual during a personalized consensus conference that considered performance as well as health status, with 103 participants considered cognitively stable (CS) and 41 to have MCI-DS. Analyses of 17 variables derived from 10 tests of cognition indicated that performance reflected three underlying factors: language/executive function, memory, and visuomotor. All three domain composite scores significantly predicted MCI-DS status. Based upon path modeling, the language/executive function composite score was the most affected by prodromal AD. However, based upon structural equation modeling, tests assessing the latent construct of memory were the most impacted, followed by those assessing visuomotor, and then those assessing language/executive function. Our study provides clear evidence that cognitive functioning in older adults with DS can be characterized at the cognitive domain level, but the statistical methods selected and the inclusion or exclusion of certain covariates may lead to different conclusions. Best practice requires investigators to understand the internal structure of their variables and to provide evidence that their variables assess their intended constructs.

The Association between Sex and Risk of Alzheimer's Disease in Adults with Down Syndrome.

BACKGROUND: Sex differences in the risk of Alzheimer's Disease (AD) in adults with Down Syndrome (DS) have not been extensively investigated, and existing studies have found conflicting results. This study examined the effect of sex on the risk of AD in adults with DS, adjusted for covariates. METHODS: Adults with DS were assessed longitudinally for the development of AD. Competing risk survival analyses were used to determine the effect of sex alone and after adjustment for APOE-ε4 status, ethnicity, and level of intellectual disability (ID). RESULTS: Sex differences were significant only in adults over 60 years of age, where men with DS were 6.32 (95% CI: 2.11-18.96, p < 0.001) times more likely to develop AD compared with age-matched women with DS. CONCLUSIONS: There is an age-associated effect of sex on the risk of AD, with men over 60 years old having six times the risk of AD compared with age-matched women, independent of APOE-ε4 status, ethnicity, and level of ID.

Evaluation of the National Task Group-Early Detection Screen for Dementia: Sensitivity to 'mild cognitive impairment' in adults with Down syndrome.

BACKGROUND: The accuracy of the National Task Group-Early Detection Screen for Dementia (NTG-EDSD) was evaluated in a sample of 185 adults with Down syndrome (DS), emphasizing 'mild cognitive impairment (MCI-DS)'. METHOD: Knowledgeable informants were interviewed with the NTG-EDSD, and findings were compared to an independent dementia status rating based on consensus review of detailed assessments of cognition, functional abilities and health status (including physician examination). RESULTS: Results indicated that sections of the NTG-EDSD were sensitive to MCI-DS, with one or more concerns within the 'Memory' or 'Language and Communication' domains being most informative. CONCLUSIONS: The NTG-EDSD is a useful tool for evaluating dementia status, including MCI-DS. However, estimates of sensitivity and specificity, even for detecting frank dementia, indicated that NTG-EDSD findings need to be supplemented by additional sources of relevant information to achieve an acceptable level of diagnostic/screening accuracy.

Plasma Total-Tau and Neurofilament Light Chain as Diagnostic Biomarkers of Alzheimer's Disease Dementia and Mild Cognitive Impairment in Adults with Down Syndrome.

BACKGROUND: The need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD); however, the application of such biomarkers has been limited among the DS population. OBJECTIVE: This study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults. METHODS: Plasma samples were analyzed from n = 305 (n = 225 cognitively stable (CS); n = 44 MCI-DS; n = 36 DS-AD) participants enrolled in the Alzheimer's Biomarker Consortium -Down Syndrome. RESULTS: In distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS. CONCLUSION: Advanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs.

Alzheimer-related altered white matter microstructural integrity in Down syndrome: A model for sporadic AD?

INTRODUCTION: Virtually all adults with Down syndrome (DS) develop Alzheimer's disease (AD)-associated neuropathology by the age of 40, with risk for dementia increasing from the early 50s. White matter (WM) pathology has been reported in sporadic AD, including early demyelination, microglial activation, loss of oligodendrocytes and reactive astrocytes but has not been extensively studied in the at-risk DS population. METHODS: Fifty-six adults with DS (35 cognitively stable adults, 11 with mild cognitive impairment, 10 with dementia) underwent diffusion-weighted magnetic resonance imaging (MRI), amyloid imaging, and had assessments of cognition and functional abilities using tasks appropriate for persons with intellectual disability. RESULTS: Early changes in late-myelinating and relative sparing of early-myelinating pathways, consistent with the retrogenesis model proposed for sporadic AD, were associated with AD-related cognitive deficits and with regional amyloid deposition. DISCUSSION: Our findings suggest that quantification of WM changes in DS could provide a promising and clinically relevant biomarker for AD clinical onset and progression.

The AT(N) framework for Alzheimer's disease in adults with Down syndrome.

The National Institute on Aging in conjunction with the Alzheimer's Association (NIA-AA) recently proposed a biological framework for defining the Alzheimer's disease (AD) continuum. This new framework is based upon the key AD biomarkers (amyloid, tau, neurodegeneration, AT[N]) instead of clinical symptoms and represents the latest understanding that the pathological processes underlying AD begin decades before the manifestation of symptoms. By using these same biomarkers, individuals with Down syndrome (DS), who are genetically predisposed to developing AD, can also be placed more precisely along the AD continuum. The A/T(N) framework is therefore thought to provide an objective manner by which to select and enrich samples for clinical trials. This new framework is highly flexible and allows the addition of newly confirmed AD biomarkers into the existing AT(N) groups. As biomarkers for other pathological processes are validated, they can also be added to the AT(N) classification scheme, which will allow for better characterization and staging of AD in DS. These biological classifications can then be merged with clinical staging for an examination of factors that impact the biological and clinical progression of the disease. Here, we leverage previously published guidelines for the AT(N) framework to generate such a plan for AD among adults with DS.

Language skills as a predictor of cognitive decline in adults with Down syndrome.

INTRODUCTION: Adults with Down syndrome (DS) are at high risk for early onset Alzheimer's disease (AD), characterized by a progressive decline in multiple cognitive domains including language, which can impact social interactions, behavior, and quality of life. This cross-sectional study examined the relationship between language skills and dementia. METHODS: A total of 168 adults with DS (mean age = 51.4 years) received neuropsychological assessments, including Vineland Communication Domain, McCarthy Verbal Fluency, and Boston Naming Test, and were categorized in one of three clinical groups: cognitively stable (CS, 57.8%); mild cognitive impairment (MCI-DS, 22.6%); and probable/definite dementia (AD-DS, 19.6%). Logistic regression was used to determine how well language measures predict group status. RESULTS: Vineland Communication, particularly receptive language, was a significant predictor of MCI-DS. Semantic verbal fluency was the strongest predictor of AD-DS. DISCUSSION: Assessment of language skills can aid in the identification of dementia in adults with DS. Clinically, indications of emerging language problems should warrant further evaluation and monitoring.

Proteomic profiles for Alzheimer's disease and mild cognitive impairment among adults with Down syndrome spanning serum and plasma: An Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study.

INTRODUCTION: Previously generated serum and plasma proteomic profiles were examined among adults with Down syndrome (DS) to determine whether these profiles could discriminate those with mild cognitive impairment (MCI-DS) and Alzheimer's disease (DS-AD) from those cognitively stable (CS). METHODS: Data were analyzed on n = 305 (n = 225 CS; n = 44 MCI-DS; n = 36 DS-AD) enrolled in the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS). RESULTS: Distinguishing MCI-DS from CS, the serum profile produced an area under the curve (AUC) = 0.95 (sensitivity [SN] = 0.91; specificity [SP] = 0.99) and an AUC = 0.98 (SN = 0.96; SP = 0.97) for plasma when using an optimized cut-off score. Distinguishing DS-AD from CS, the serum profile produced an AUC = 0.93 (SN = 0.81; SP = 0.99) and an AUC = 0.95 (SN = 0.86; SP = 1.0) for plasma when using an optimized cut-off score. AUC remained unchanged to slightly improved when age and sex were included. Eotaxin3, interleukin (IL)-10, C-reactive protein, IL-18, serum amyloid A , and FABP3 correlated fractions at r2 > = 0.90. DISCUSSION: Proteomic profiles showed excellent detection accuracy for MCI-DS and DS-AD.

Promising outcome measures of early Alzheimer's dementia in adults with Down syndrome.

INTRODUCTION: Adults with Down syndrome (DS) are at high risk for developing Alzheimer's disease (AD) and its associated dementia, warranting the development of strategies to improve early detection when prevention is possible. METHODS: Using a broad battery of neuropsychological assessments, informant interviews, and clinical record review, we evaluated the psychometrics of measures in a large sample of 561 adults with DS. We tracked longitudinal stability or decline in functioning in a subsample of 269 participants over a period of 3 years, all initially without indications of clinically significant aging-related decline. RESULTS: Results identified an array of objective measures that demonstrated sensitivity in distinguishing individuals with incident "mild cognitive impairment" (MCI-DS) as well as subsequent declines occurring with incident dementia. DISCUSSION: Several instruments showed clear promise for use as outcome measures for future clinical trials and for informing diagnosis of individuals suspected of experiencing early signs and symptoms of a progressive dementia process.

Proteomic profiles of incident mild cognitive impairment and Alzheimer's disease among adults with Down syndrome.

INTRODUCTION: We sought to determine if proteomic profiles could predict risk for incident mild cognitive impairment (MCI) and Alzheimer's disease (AD) among adults with Down syndrome (DS). METHODS: In a cohort of 398 adults with DS, a total of n = 186 participants were determined to be non-demented and without MCI or AD at baseline and throughout follow-up; n = 103 had incident MCI and n = 81 had incident AD. Proteomics were conducted on banked plasma samples from a previously generated algorithm. RESULTS: The proteomic profile was highly accurate in predicting incident MCI (area under the curve [AUC] = 0.92) and incident AD (AUC = 0.88). For MCI risk, the support vector machine (SVM)-based high/low cut-point yielded an adjusted hazard ratio (HR) = 6.46 (P < .001). For AD risk, the SVM-based high/low cut-point score yielded an adjusted HR = 8.4 (P < .001). DISCUSSION: The current results provide support for our blood-based proteomic profile for predicting risk for MCI and AD among adults with DS.

Proteomic profiles of prevalent mild cognitive impairment and Alzheimer's disease among adults with Down syndrome.

INTRODUCTION: We sought to determine if a proteomic profile approach developed to detect Alzheimer's disease (AD) in the general population would apply to adults with Down syndrome (DS). METHODS: Plasma samples were obtained from 398 members of a community-based cohort of adults with DS. A total of n = 186 participants were determined to be non-demented and without mild cognitive impairment (MCI) at baseline and throughout follow-up; n = 50 had prevalent MCI; n = 42 had prevalent AD. RESULTS: The proteomic profile yielded an area under the curve (AUC) of 0.92, sensitivity (SN) = 0.80, and specificity (SP) = 0.98 detecting prevalent MCI. For detecting prevalent AD, the proteomic profile yielded an AUC of 0.89, SN = 0.81, and SP = 0.97. The overall profile closely resembled our previously published profile of AD in the general population. DISCUSSION: These data provide evidence of the applicability of our blood-based algorithm for detecting MCI/AD among adults with DS.

Longitudinal telomere shortening and early Alzheimer's disease progression in adults with down syndrome.

Telomere shortening was shown to parallel Alzheimer's disease (AD) associated dementia. By using a dual PNA Probe system we have developed a practical method for comparing telomere length in T-lymphocyte interphases from individuals with Down syndrome (DS) with and without "mild cognitive impairment" (MCI-DS) and demonstrated that telomere length can serve as a valid biomarker for the onset of MCI-DS in this high-risk population. To verify progressive cognitive decline we have now examined sequential changes in telomere length in 10 adults with DS (N = 4 Female, N = 6 Male) developing MCI-DS. Cases were selected blind to telomere length from a sample of adults with DS previously enrolled in a prospective longitudinal study at 18-month intervals with clinical and telomere assessments: (1) MCI-DS group data were collected approximately three years prior to development of MCI-DS; (2) 18 months later; (3) when MCI-DS was first observed. These telomere measures were compared to those from another 10 adults with DS matched by sex and approximate age but without indications of MCI-DS (Controls). PNA (peptide nucleic acid) probes for telomeres together with a chromosome two centromere probe were used. Findings indicated telomere shortening over time for both Cases and Controls. Group differences emerged by 18-months prior to recognition of MCI-DS onset and completely non-overlapping distributions of telomere measures were observed by the time of MCI-DS onset. This study adds to accumulating evidence of the value of telomere length, as an early biomarker of AD progression in adults with Down syndrome.

Candidate gene analysis for Alzheimer's disease in adults with Down syndrome.

Individuals with Down syndrome (DS) overexpress many genes on chromosome 21 due to trisomy and have high risk of dementia due to the Alzheimer's disease (AD) neuropathology. However, there is a wide range of phenotypic differences (e.g., age at onset of AD, amyloid ß levels) among adults with DS, suggesting the importance of factors that modify risk within this particularly vulnerable population, including genotypic variability. Previous genetic studies in the general population have identified multiple genes that are associated with AD. This study examined the contribution of polymorphisms in these genes to the risk of AD in adults with DS ranging from 30 to 78 years of age at study entry (N = 320). We used multiple logistic regressions to estimate the likelihood of AD using single-nucleotide polymorphisms (SNPs) in candidate genes, adjusting for age, sex, race/ethnicity, level of intellectual disability and APOE genotype. This study identified multiple SNPs in APP and CST3 that were associated with AD at a gene-wise level empirical p-value of 0.05, with odds ratios in the range of 1.5-2. SNPs in MARK4 were marginally associated with AD. CST3 and MARK4 may contribute to our understanding of potential mechanisms where CST3 may contribute to the amyloid pathway by inhibiting plaque formation, and MARK4 may contribute to the regulation of the transition between stable and dynamic microtubules.