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Link to original content: http://pubmed.ncbi.nlm.nih.gov/39285750/
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. 2024 Nov;20(11):7819-7830.
doi: 10.1002/alz.14244. Epub 2024 Sep 17.

Integrating amyloid imaging and genetics for early risk stratification of Alzheimer's disease

Bing He  1 , Ruiming Wu  2 , Neel Sangani  3 , Pradeep Varathan Pugalenthi  1 , Alice Patania  4 , Shannon L Risacher  3 , Kwangsik Nho  3 , Liana G Apostolova  2 , Li Shen  2 , Andrew J Saykin  3 , Jingwen Yan  1 ; Alzheimer's Disease Neuroimaging Initiative
Affiliations

Integrating amyloid imaging and genetics for early risk stratification of Alzheimer's disease

Bing He et al. Alzheimers Dement. 2024 Nov.

Abstract

Introduction: Alzheimer's disease (AD) initiates years prior to symptoms, underscoring the importance of early detection. While amyloid accumulation starts early, individuals with substantial amyloid burden may remain cognitively normal, implying that amyloid alone is not sufficient for early risk assessment.

Methods: Given the genetic susceptibility of AD, a multi-factorial pseudotime approach was proposed to integrate amyloid imaging and genotype data for estimating a risk score. Validation involved association with cognitive decline and survival analysis across risk-stratified groups, focusing on patients with mild cognitive impairment (MCI).

Results: Our risk score outperformed amyloid composite standardized uptake value ratio in correlation with cognitive scores. MCI subjects with lower pseudotime risk score showed substantial delayed onset of AD and slower cognitive decline. Moreover, pseudotime risk score demonstrated strong capability in risk stratification within traditionally defined subgroups such as early MCI, apolipoprotein E (APOE) ε4+ MCI, APOE ε4- MCI, and amyloid+ MCI.

Discussion: Our risk score holds great potential to improve the precision of early risk assessment.

Highlights: Accurate early risk assessment is critical for the success of clinical trials. A new risk score was built from integrating amyloid imaging and genetic data. Our risk score demonstrated improved capability in early risk stratification.

Keywords: Alzheimer's disease; imaging genetics; longitudinal association analysis; pseudotime analysis; survival analysis.

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Conflict of interest statement

Dr. Saykin has received support from Avid Radiopharmaceuticals, a subsidiary of Eli Lilly (in kind contribution of PET tracer precursor) and holds advisory roles with Siemens Medical Solutions USA, Inc., NIH NHLBI, and Eisai. His editorial commitments include serving as editor‐in‐chief for the journal Brain Imaging and Behavior, and he participates in various NIH/NIA advisory committees. Liana G. Apostolova receives funding from NIA U01 AG057195, NIA R01 AG057739, NIA P30 AG010133, Alzheimer Association LEADS GENETICS 19‐639372, and Roche Diagnostics RD005665; research support from AVID Pharmaceuticals and Life Molecular Imaging; does consulting for Biogen, Two Labs, Eli Lilly, NIH, Florida Dept. Health, NIH Biobank; participates on data safety monitoring boards for IQVIA, NIA R01 AG061111, UAB Nathan Schick Center; owns stock in Semiring, Inc. and Cassava Neurosciences; receives honoraria from AAN, MillerMed, ASiM, Health and Hospitality Corporation, Mayo Clinic; and is editor‐in‐chief for Disease Assessment and Disease Monitoring. Bing He, Ruiming Wu, Neel Sangani, Pradeep Varathan Pugalenthi, Alice Patania, Shannon L. Risacher, Kwangsik Nho, Li Shen, Jingwen Yan have nothing to disclose. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
A, Subjects were ordered along a two‐dimensional progression trajectory learned from PHATE, which took the input as the fused similarity network. B, Pseudotime of each subject is estimated as the relative position on the trajectory, ranging from 0 to 1. C, Pseudotime distribution across diagnosis groups for training data. D, Pseudotime distribution across diagnosis groups for testing data. ***: P ≤ 0.001, ****: P ≤ 0.0001. AD, Alzheimer's disease; CN, cognitively normal; EMCI, early mild cognitive impairment; GRM, genetic relationship matrix; LMCI, late mild cognitive impairment
FIGURE 2
FIGURE 2
Spearman correlation with clinical cognitive performance. Memory and executive function on the right end are two composite scores. AD, Alzheimer's disease; ADAS, Alzheimer's Disease Assessment Scale; APOE, apolipoprotein E; GRM, genetic relationship matrix; MMSE, Mini‐Mental State Examination; PRS, polygenic risk score; RAVLT, Rey Auditory Verbal Learning Test
FIGURE 3
FIGURE 3
Differential rate of cognitive decline in MCI training subjects stratified by fused pseudotime (A), diagnostic groups (B), APOE ε4 status (C), and amyloid positivity (D). Significant longitudinal association was only observed for ADAS13 score (top) and composite memory score (bottom). AD, Alzheimer's disease; ADAS, Alzheimer's Disease Assessment Scale; ADNI, Alzheimer's Disease Neuroimaging Initiative; APOE, apolipoprotein E; CN, cognitively normal; EMCI, early mild cognitive impairment; LMCI, late mild cognitive impairment
FIGURE 4
FIGURE 4
Differential progression risk of MCI subjects (Row 1‐2) and CN/EMCI subjects (Row 3‐4). Row 1: MCIs stratified by (A) pseudotime derived from integration of amyloid imaging and candidate SNPs, (B) diagnosis, (C) APOE ε4 status, and (D) amyloid positivity. Row 2: pseudotime can further stratify MCI subjects with differential survival risk within groups like (E) EMCIs, (F) APOE ε4+ MCIs, (G) APOE ε4– MCIs, and (H) amyloid positive MCIs. Row 3: CN/EMCIs stratified by (I) pseudotime derived from integration of amyloid imaging and candidate SNPs, (J) diagnosis, (K) APOE ε4 status, and (L) amyloid positivity. Row 4: differential survival risk across pseudotime groups within (M) EMCIs, (N) APOE ε4+ CN/EMCIs, (O) APOE ε4– CN/EMCIs, and (P) amyloid positive CN/EMCIs. AD, Alzheimer's disease; ADNI, Alzheimer's Disease Neuroimaging Initiative; APOE, apolipoprotein E; CN, cognitively normal; EMCI, early mild cognitive impairment; HR, hazard ratio; LMCI, late mild cognitive impairment; MCI, mild cognitive impairment
FIGURE 5
FIGURE 5
Validation results of longitudinal association and survival analyses on test subjects. A‐D, Rate of decline in composite memory score across MCI subgroups delineated by fused pseudotime, diagnosis, APOE ε4 status, and amyloid positivity. E‐H, Progression risk of MCI subgroups delineated by pseudotime, diagnosis, APOE ε4 status, and amyloid positivity. I‐L, Rate of decline in composite memory score across CN/EMCI subgroups delineated by pseudotime, diagnosis, APOE ε4 status, and amyloid positivity. M‐P, progression risk of CN/EMCI subgroups delineated by pseudotime, diagnosis, APOE ε4 status, and amyloid positivity. AD, Alzheimer's disease; ADNI, Alzheimer's Disease Neuroimaging Initiative; APOE, apolipoprotein E; CN, cognitively normal; EMCI, early mild cognitive impairment; HR, hazard ratio; LMCI, late mild cognitive impairment; MCI, mild cognitive impairment
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