Manifestations of Alzheimer’s Disease Genetic Risk in the Blood: A Cross-Sectional Multi-Omic Analysis in Healthy Adults Aged 18-90+

Abstract Background: Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease.Methods: We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants, adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed.Results: We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case-control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable.Conclusions: Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.

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Manifestations of genetic risk for Alzheimer’s Disease in the blood: a cross-sectional multi-omic analysis in healthy adults aged 18-90+

10.1101/2021.03.26.437267 ◽

2021 ◽

Author(s):

Laura Heath ◽

John C. Earls ◽

Andrew T. Magis ◽

Sergey A. Kornilov ◽

Jennifer C. Lovejoy ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Association Study ◽

Genetic Variants ◽

Genetic Risk ◽

Multiple Testing ◽

Large Scale ◽

Genome Wide Association Study ◽

Cross Sectional ◽

Risk Variants

AbstractDeeply phenotyped cohort data can elucidate differences associated with genetic risk for common complex diseases across an age spectrum. Previous work has identified genetic variants associated with Alzheimer’s disease (AD) risk from large-scale genome-wide association study meta-analyses. To explore effects of known AD-risk variants, we performed a phenome-wide association study on ~2000 clinical, proteomic, and metabolic blood-based analytes obtained from 2,831 cognitively normal adult clients of a consumer-based scientific wellness company. Results uncovered statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE). These effects were detectable from early adulthood. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. Sex-stratified GWAS results from an independent AD case-control meta-analysis supported sexspecific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable. These analyses support evidence from previous functional genomics studies in the identification of a causal variant within the PILRA gene. Taken together, this study highlights clues to the earliest effects of AD genetic risk variants in individuals where disease symptoms have not (yet) arisen.

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A Systems Biology Approach for Hypothesizing the Effect of Genetic Variants on Neuroimaging Features in Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-201397 ◽

2021 ◽

Vol 80 (2) ◽

pp. 831-840

Author(s):

Sepehr Golriz Khatami ◽

Daniel Domingo-Fernández ◽

Sarah Mubeen ◽

Charles Tapley Hoyt ◽

Christine Robinson ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Variants ◽

Large Scale ◽

Multiple Scales ◽

Association Studies ◽

Hippocampal Atrophy ◽

Genome Wide Association Studies ◽

Biological Processes ◽

Functional Interpretation

Background: Neuroimaging markers provide quantitative insight into brain structure and function in neurodegenerative diseases, such as Alzheimer’s disease, where we lack mechanistic insights to explain pathophysiology. These mechanisms are often mediated by genes and genetic variations and are often studied through the lens of genome-wide association studies. Linking these two disparate layers (i.e., imaging and genetic variation) through causal relationships between biological entities involved in the disease’s etiology would pave the way to large-scale mechanistic reasoning and interpretation. Objective: We explore how genetic variants may lead to functional alterations of intermediate molecular traits, which can further impact neuroimaging hallmarks over a series of biological processes across multiple scales. Methods: We present an approach in which knowledge pertaining to single nucleotide polymorphisms and imaging readouts is extracted from the literature, encoded in Biological Expression Language, and used in a novel workflow to assist in the functional interpretation of SNPs in a clinical context. Results: We demonstrate our approach in a case scenario which proposes KANSL1 as a candidate gene that accounts for the clinically reported correlation between the incidence of the genetic variants and hippocampal atrophy. We find that the workflow prioritizes multiple mechanisms reported in the literature through which KANSL1 may have an impact on hippocampal atrophy such as through the dysregulation of cell proliferation, synaptic plasticity, and metabolic processes. Conclusion: We have presented an approach that enables pinpointing relevant genetic variants as well as investigating their functional role in biological processes spanning across several, diverse biological scales.

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Interaction of Alzheimer’s Disease-Associated Genetic Risk with Indicators of Socioeconomic Position on Mild Cognitive Impairment in the Heinz Nixdorf Recall Study

Journal of Alzheimer s Disease ◽

10.3233/jad-210244 ◽

2021 ◽

pp. 1-11

Author(s):

Mirjam Frank ◽

Jonas Hensel ◽

Lisa Baak ◽

Sara Schramm ◽

Nico Dragano ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Socioeconomic Position ◽

Genetic Risk ◽

Late Onset ◽

Heinz Nixdorf Recall Study ◽

Low Education ◽

Additive Scale

Background: The apolipoprotein E (APOE) ɛ4 allele is reported to be a strong genetic risk factor for mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Additional genetic loci have been detected that influence the risk for late-onset AD. As socioeconomic position (SEP) is also strongly related to cognitive decline, SEP has been suggested to be a possible modifier of the genetic effect on MCI. Objective: To investigate whether APOE ɛ4 and a genetic sum score of AD-associated risk alleles (GRSAD) interact with SEP indicators to affect MCI in a population-based cohort. Methods: Using data of 3,834 participants of the Heinz Nixdorf Recall Study, APOE ɛ4 and GRSAD by SEP interactions were assessed using logistic regression models, as well as SEP-stratified genetic association analysis. Interaction on additive scale was calculated using the relative excess risk due to interaction (RERI). All analysis were additionally stratified by sex. Results: Indication for interaction on the additive scale was found between APOE ɛ4 and low education on MCI (RERI: 0.52 [95% -confidence interval (CI): 0.01; 1.03]). The strongest genetic effects of the APOE ɛ4 genotype on MCI were observed in groups of low education (Odds ratio (OR): 1.46 [95% -CI: 0.79; 2.63] for≤10 years of education versus OR: 1.00 [95% -CI: 0.43; 2.14] for≥18 years of education). Sex stratified results showed stronger effects in women. No indication for interaction between the GRSAD and SEP indicators on MCI was observed. Conclusion: Results indicate that low education may have an impact on APOE ɛ4 expression on MCI, especially among women.

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ApoE4 attenuates cortical neuronal activity and impairs memory in young apoE4 rats

10.1101/2021.01.14.426651 ◽

2021 ◽

Author(s):

Ilona Har-Paz ◽

Elor Arieli ◽

Anan Moran

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Risk Factor ◽

Neuronal Activity ◽

Genetic Risk ◽

Cortical Neurons ◽

Late Onset ◽

Genetic Risk Factor ◽

Normal Brain ◽

Brain Functions

AbstractThe E4 allele of apolipoprotein E (apoE4) is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). However, apoE4 may cause innate brain abnormalities before the appearance of AD related neuropathology. Understanding these primary dysfunctions is vital for early detection of AD and the development of therapeutic strategies for it. Recently we have shown impaired extra-hippocampal memory in young apoE4 mice – a deficit that was correlated with attenuated structural pre-synaptic plasticity in cortical and subcortical regions. Here we test the hypothesis that these early structural deficits impact learning via changes in basal and stimuli evoked neuronal activity. We recorded extracellular neuronal activity from the gustatory cortex (GC) of three-month-old humanized apoE4 and wildtype rats, before and after conditioned taste aversion (CTA) training. Despite normal sucrose drinking behavior before CTA, young apoE4 rats showed impaired CTA learning, consistent with our previous results in apoE4 mice. This behavioral deficit was correlated with decreased basal and taste-evoked firing rates in both putative excitatory and inhibitory GC neurons. Single neuron and ensemble analyses of taste coding demonstrated that apoE4 neurons could be used to correctly classify tastes, but were unable to undergo plasticity to support learning. Our results suggest that apoE4 impacts brain excitability and plasticity early in life and may act as an initiator for later AD pathologies.Significant statementThe ApoE4 allele is the strongest genetic risk-factor for late-onset Alzheimer’s disease (AD), yet the link between apoE4 and AD is still unclear. Recent molecular and in-vitro studies suggest that apoE4 interferes with normal brain functions decades before the development of its related AD neuropathology. Here we recorded the activity of cortical neurons from young apoE4 rats during extra-hippocampal learning to study early apoE4 neuronal activity abnormalities, and their effects over coding capacities. We show that apoE4 drastically reduces basal and stimuli-evoked cortical activity in both excitatory and inhibitory neurons. The apoE4-induced activity attenuation did not prevent coding of stimuli identity and valence, but impaired capacity to undergo activity changes to support learning. Our findings support the hypothesis that apoE4 interfere with normal neuronal plasticity early in life; a deficit that may lead to late-onset AD development.

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P3-006: Late-onset Alzheimer's disease genetic risk factors in two Canadian cohorts: CSHA and ACCORD

Alzheimer s & Dementia ◽

10.1016/j.jalz.2013.05.1075 ◽

2013 ◽

Vol 9 ◽

pp. P551-P552

Author(s):

Ardeshir Omoumi ◽

Alice Fok ◽

Talitha Greenwood ◽

Dessa Sadovnick ◽

Howard Feldman ◽

...

Keyword(s):

Risk Factors ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Risk ◽

Late Onset ◽

Genetic Risk Factors

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P1-155: ASSOCIATION BETWEEN COMMON GENETIC VARIANTS OF LATE-ONSET ALZHEIMER'S DISEASE AND FAMILY HISTORY OF ALZHEIMER'S DEMENTIA: A PRELIMINARY STUDY

Alzheimer s & Dementia ◽

10.1016/j.jalz.2018.06.159 ◽

2006 ◽

Vol 14 (7S_Part_6) ◽

pp. P336-P336

Author(s):

Min Soo Byun ◽

Jieun Seo ◽

Dahyun Yi ◽

Jun Ho Lee ◽

Younghwa Lee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Family History ◽

Genetic Variants ◽

Late Onset ◽

Alzheimer’S Dementia ◽

Alzheimer's Dementia ◽

Common Genetic Variants ◽

History Of ◽

Preliminary Study

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Association Study of Genetic Variants inCDKN2A/CDKN2BGenes/Loci with Late-Onset Alzheimer's Disease

International Journal of Alzheimer s Disease ◽

10.4061/2011/374631 ◽

2011 ◽

Vol 2011 ◽

pp. 1-4

Author(s):

Andrea Tedde ◽

Irene Piaceri ◽

Silvia Bagnoli ◽

Ersilia Lucenteforte ◽

Uwe Ueberham ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Genetic Variants ◽

Genetic Variant ◽

Case Control Study ◽

Late Onset ◽

Common Genetic Variant ◽

Genome Wide ◽

Control Study

Alzheimer's disease (AD) is the most common form of dementia clinically characterized by progressive impairment of memory and other cognitive functions. Many genetic researches in AD identified one common genetic variant (ε4) in Apolipoprotein E (APOE) gene as a risk factor for the disease. Two independent genome-wide studies demonstrated a new locus on chromosome 9p21.3 implicated in Late-Onset Alzheimer's Disease (LOAD) susceptibility in Caucasians. In the present study, we investigated the role of three SNP's in theCDKN2Agene (rs15515, rs3731246, and rs3731211) and one in theCDKN2Bgene (rs598664) located in 9p21.3 using an association case-control study carried out in a group of Caucasian subjects including 238 LOAD cases and 250 controls. The role ofCDKN2AandCDKN2Bgenetic variants in AD is not confirmed in our LOAD patients, and further studies are needed to elucidate the role of these genes in the susceptibility of AD.

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