Neurodegenerative Disease and
Cancer Comorbidity
Kelly N. H. Nudelman
Alzheimer’s and cancer connection
• Diseases of aging
• Cognitive side-effects of cancer therapies
• Cancer inversely associated with
neurodegenerative diseases – epidemiology
• Many biological connections posited
• Drug repurposing
Hallmarks of cancer: overlap with Alzheimer’s disease
Rosenberger et al., 2015
“Protein kinase activity decreases with higher Braak stages of
Alzheimer’s disease pathology”
Demetrius and Simon, 2012
“An inverse-Warburg effect and the
origin of Alzheimer’s disease”
LeBlanc, 2005
“The role of apoptotic pathways in
Alzheimer’s disease
neurodegeneration and cell death”
Zekanowski and Wojda, 2009
“Aneuploidy, chromosomal
missegregation, and cell cycle
reentry in Alzheimer’s disease”
Blalock et al., 2004
“Incipient Alzheimer’s disease: microarray correlation
analyses reveal major transcriptional and tumor
suppressor responses”
Guillot-Sestier and Town, 2013
“Innate immunity in Alzheimer’s
disease: a complex affair”
Forero et al., 2016
“Meta-analysis of telomere length
in Alzheimer’s disease”
Verdile et al., 2015
“Inflammation and oxidative stress: the
molecular connectivity between insulin
resistance, obesity, and Alzheimer’s
disease”
Desai et al., 2009
“Evidence of angiogenic vessels in Alzheimer’s disease”
Xiang et al., 2016
“CHRNA7 inhibits cell invasion and metastasis of LoVo human
colorectal cancer cells through PI3K/Akt signaling”
Pathways in cancer and Alzheimer’s
disease
Blue lines/boxes = pathways and interactions identified in AD research; orange lines =
interactions found in cancer research; green boxes = investigated in both diseases
Holohan et al., 2013
Ibanez et al., 2014
“Molecular evidence for the inverse comorbidity between central nervous
system disorders and cancers detected by transcriptomic meta-analysis”
Heat map indicates significant
differences in gene expression
comparing diseases.
Most significant effects for cancer
upregulated / Alzheimer’s disease
downregulated (p<1e-77)
Scz = schizophrenia
AD = Alzheimer’s disease
PD = Parkinson’s disease
CRC = colorectal cancer
PC = prostate cancer
LC = lung cancer
Ibanez et al., 2014
“Molecular evidence for the inverse comorbidity between central nervous
system disorders and cancers detected by transcriptomic meta-analysis”
CNS up, cancer down:
• Environmental
information
processing
• Organismal systems
CNS down, cancer up:
• Metabolism
• Genetic information
processing
• Cellular processing
Ibanez et al., 2014. “Molecular evidence for the inverse comorbidity between
central nervous system disorders and cancers detected by transcriptomic
meta-analysis”
Adapted from Table 1
• 372 GWAS identified 1,775
susceptibility SNPs to 105
unique diseases
• used SNPs to create
genomic map of disease
susceptibility
• 92% of 200 kb bins devoid
of disease-associated SNPs
• 10 bins significantly
enriched for multiple
diseases.
– 2 most significant
(p<0.0001) include MHC
locus and INK4/ARF
Ohtani et al., 2004
“The p16INK4a-RB pathway:
molecular link between cellular
senescence and tumor
suppression
MicroRNA pathways in cancer and AD
Holohan et al., 2013
Inverse association
ADNI Cohort
ROS/MAP Cohort
TGen Cohort
Manuscript in preparation
Cancer-related later age of AD onset
ADNI cohort
Nudelman et al., 2014
Cancer-related later age of AD onset
ROS/MAP Cohort
TGen Cohort
Manuscript in preparation
Cancer-related lower gray matter density
Cancer survivors had
lower baseline gray
matter density (GMD)
across AD diagnostic
groups (P<0.01)
At a more stringent
threshold (P<0.001), the
effect was still observed
in the right superior
frontal gyrus (circled in
blue)
P<0.01 uncorrected, cluster threshold P<0.1
Nudelman et al., 2014
Cancer-associated Neuropathology
ROS/MAP: neuropathology
associated with cancer history
*P=0.025
P=0.942
P=0.426
Looked within AD diagnosis groups
to see if there were any cancerassociated differences in plaque
and tangle pathology
• Neuritic plaques were not
associated with cancer
(p=0.159)
• Neurofibrillary tangles were
significantly associated with
cancer (p=0.018)
Manuscript in preparation
Cancer-associated Neuropathology
• ROS/MAP: All three brain regions show a significant or
trending association for cancer history with tangles
within the AD group.
*P=0.041
P=0.091
*P=0.013
P=0.471
*P=0.019
P=0.546
Manuscript in preparation
Cancer-associated Neuropathology
TGen: neuropathology
associated with cancer history
P=0.14
P=0.17
Looked within AD and CN to see if
there were any cancer-associated
differences in plaque and tangle
pathology
• Neuritic plaques were not
associated with cancer
(p=0.270)
• Neurofibrillary tangles were
significantly associated with
cancer (p=0.041)
Manuscript in preparation
Alzheimer’s – Cancer: Tau Connection
Downregulation
of cMyc protooncogene
Abnormal tau
hyperphosphorylation
Heterochromatin
relaxation (linked to
neuronal death)
Future Directions: Drug Repurposing
Malik et al., 2015
• CD33 SNPs are associated with differential
exon splicing in brain tissue and in AML
• rs12459419T allele decreases full-length CD33
expression dose-dependently and decreases
AD odds ratio
• CD33 antibodies such as lintuzumab (safe but
ineffective for AML) may be repurposed for AD
treatment
Conclusions & Future Directions
• Systems biology framework highlights numerous
potentially overlapping pathways/networks in AD
and cancer
• Cancer appears to delay age of AD onset via a
reduction in pathology
– May be expanded to other neurodegenerative
diseases
• Future directions should focus on biological
mechanisms driving this relationship
– Potential to repurpose drugs towards more effective
AD treatments
Future Directions
• Multi-omics data analysis
• microRNA network association with cancer
and AD
– Biomarker effort in AD could benefit from
investigating disease heterogeneity
Acknowledgements
Center for Neuroimaging:
• Andrew Saykin
• Brenna McDonald
• Li Shen
• Kwangsik Nho
• Shannon Risacher
• Sungeun Kim
• Jingwen Yan
• Kacie Deters
• Emrin Horgusluoglu
• Joey Contreras
• John West
IU Collaborators:
• Debomoy Lahiri
• Tatiana Foroud
• Bruce Lamb
TGen:
• Kendall Van Keuren-Jensen
Rush Alzheimer’s Disease Center
Accelerating Alzheimer’s Research
and Drug Development (AMP-AD)
Funding:
NIA, NCI, NLM, Alzheimer’s
Association