Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
ReviewNeuroimaging Genetic Risk for Alzheimer’s Disease in Preclinical Individuals: From Candidate Genes to Polygenic Approaches
Section snippets
Neuroimaging of Preclinical AD
A common approach for studying preclinical AD is to use a group at increased risk for AD as a potential preclinical cohort and compare them with a cohort of controls without the risk factor. Increased risk can be defined by the presence of a particular genetic risk variant, such as the apolipoprotein E ε4 (APOEε4) allele; a positive family history of AD; subjective memory impairment; and the presence of an early neuroimaging or cerebrospinal fluid biomarker. Well-validated neuroimaging-based
Neuroimaging and AD Candidate Genes
In 2000, the first study to combine neuroimaging and genetic risk for AD in healthy subjects found that carriers of the APOEε4 allele had higher activation across several cortical regions during a memory task compared with noncarriers (Figure 1A) (23). This approach, examining a selected variant within a single gene and the association of that variant with brain structure and function, is a type of candidate gene study. Candidate gene studies in neuroimaging are common, but they are
Polygenic Risk Scores
Combining multiple genetic risk loci into a single metric or score is an attractive way to modernize the candidate gene approach by using the metric or score as the “candidate” rather than a single gene. Associations between a risk score and, for example, an imaging endophenotype cannot be attributed to a single gene, but these associations may be clinically useful in the effort to characterize preclinical AD better (39). Such metrics are designed on one of two main theoretical bases: first,
Regression Approaches to Polygenic Risk
The use of predictive regression models in clinical biostatistics is common (45). Neuroimaging genetics presents a unique problem with millions of genetic markers (in whole-genome data) that can be used as predictors and many outcome phenotypes of interest. Furthermore, linkage disequilibrium, or the tendency of certain genetic loci to be inherited together, must be considered when using any regression method because many of these models assume that predictors are independent (46). The numerous
Power: Effect Sizes and Variant Frequency
A major challenge in neuroimaging genetics is sufficiently powering studies to detect hypothesized effects. One problem is the low effect size of common genetic associations with disease in human polygenic disorders (57, 58). An exception to this pattern is the APOE locus, where a commonly occurring variant is strongly associated with increased AD risk. APOE accounts for a larger amount of the variance in AD heritability than any single known genetic locus in another human neurobehavioral,
Implications for Clinical Trials
Despite major challenges related to statistical power, polygenic risk modeling, and generalizability, the field of neuroimaging genetics is poised to play a major role in the development of effective treatments for AD. All phase 3 AD treatment trials in humans have had negative outcomes, not meeting end points despite promising data in model organisms and in preceding trial phases (68, 69). This high failure rate may be partly the result of heterogeneity across the study participants enrolled
Conclusions
A neuroimaging genetics approach uses minimally invasive technologies to characterize the earliest pathophysiologic changes in preclinical AD. In the effort to prevent and treat AD, the short-term goal of combining multiple genetic factors, neuroimaging biomarkers, and other measures to estimate AD risk is to preselect clinical trial and research participants. The long-term goal is to provide more detailed prognoses in the clinic during the preclinical phase that can be used to create optimized
Acknowledgments and Disclosures
This work was supported by the National Institute on Aging Grant Nos. 5R01AG013308 (SYB) and 1F31AG047041 (TMH).
We thank Ms. Therese Vasagas for her help preparing the figures included in this manuscript.
The authors report no biomedical financial interests or potential conflicts of interest.
References (82)
- et al.
Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease
Alzheimers Dement
(2011) - et al.
The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease
Alzheimers Dement
(2011) - et al.
APOE-epsilon4 and aging of medial temporal lobe gray matter in healthy adults older than 50 years
Neurobiol Aging
(2014) - et al.
Longitudinal changes in medial temporal cortical thickness in normal subjects with the APOE-4 polymorphism
(2010) - et al.
Resting-state BOLD networks versus task-associated functional MRI for distinguishing Alzheimer’s disease risk groups
Neuroimage
(2009) - et al.
Apolipoprotein E genotype, gender and age modulate connectivity of the hippocampus in healthy adults
Neuroimage
(2014) - et al.
Apolipoprotein E ε4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease
Neurobiol Aging
(2013) - et al.
Resting state functional connectivity in preclinical Alzheimer’s disease
Biol Psychiatry
(2013) - et al.
The evolution of preclinical Alzheimer’s disease: Implications for prevention trials
Neuron
(2014) - et al.
The effects of APOE-ε4 on the BOLD response
Neurobiol Aging
(2012)
The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease
Alzheimers Dement
Psychiatric disorders: Diagnosis to therapy
Cell
Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer’s disease and in response to experimental lesions in rat
Neuron
A combined effect of two Alzheimer’s risk genes on medial temporal activity during executive attention in young adults
Neuropsychologia
Markers of cholesterol transport are associated with amyloid deposition in the brain
Neurobiol Aging
Episodic memory of APOE ε4 carriers is correlated with fractional anisotropy, but not cortical thickness, in the medial temporal lobe
Neuroimage
Identification of gene pathways implicated in Alzheimer’s disease using longitudinal imaging phenotypes with sparse regression
Neuroimage
A large scale multivariate parallel ICA method reveals novel imaging-genetic relationships for Alzheimer’s disease in the ADNI cohort
Neuroimage
GCTA: A tool for genome-wide complex trait analysis
Am J Hum Genet
The utility of data-driven feature selection: re: Chu et al. 2012
Neuroimage
Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade
Lancet Neurol
Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: An observational study
Lancet Neurol
High b-value diffusion imaging of dementia: Application to vascular dementia and alzheimer disease
J Neurol Sci
Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans
Alzheimers Dement
Multilocus genetic profiling to empower drug trials and predict brain atrophy
NeuroImage Clin
The effects of APOE on the functional architecture of the resting brain
Neuroimage
A gene-brain-cognition pathway for the effect of an Alzheimer’s risk gene on working memory in young adults
Neuropsychologia
Clinical and biomarker changes in dominantly inherited Alzheimer’s disease
N Engl J Med
Short-term clinical outcomes for stages of NIA-AA preclinical Alzheimer disease
Neurology
Amyloid and APOE ε4 interact to influence short-term decline in preclinical Alzheimer disease
Neurology
How well do MCI criteria predict progression to severe cognitive impairment and dementia?
Alzheimer Dis Assoc Disord
Apolipoprotein E genotype is associated with temporal and hippocampal atrophy rates in healthy elderly adults: A tensor-based morphometry study
J Alzheimers Dis
Reduced gray matter volume in normal adults with a maternal family history of Alzheimer disease
Neurology
Alzheimer disease family history impacts resting state functional connectivity
Ann Neurol
Effect of APOE ε4 status on intrinsic network connectivity in cognitively normal elderly subjects
Arch Neurol
APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42
J Neurosci
Neuroimaging and APOE genotype: A systematic qualitative review
Dement Geriatr Cogn Disord
APOE-4 genotype and neurophysiological vulnerability to Alzheimer’s and cognitive aging
Annu Rev Clin Psychol
Patterns of brain activation in people at risk for Alzheimer’s disease
N Engl J Med
Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease
Nat Genet
Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease
Nat Genet
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2020, Neurobiology of DiseaseCitation Excerpt :Although in their analysis the individual GWAS SNPs were not significantly associated with CSF levels of Aβ1–42 or tau, together the additive risk conferred by all variants was significantly associated with both Aβ1–42 and tau. Similarly, it has been demonstrated that increased genetic risk for LOAD as defined by a high PRS is associated with several imaging endophenotypes, including decreased cortical thickness in brain regions known to be vulnerable to degeneration in AD, decreased total brain volume, and decreased hippocampal volume (Harrison and Bookheimer, 2016). Across studies, the association of GWAS-derived PRS with endophenotypes remained significant even after removal of APOE, suggesting the contribution of small-effect GWAS loci to AD risk is, in part, mediated by the effect of these variants on specific neuropathologies, including Aβ1–42 and tau levels as well as neurodegeneration.
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