1. Columbia University Medical Center
Blood Based Biomarkers of Risk for Alzheimer’s Disease among Adults with
Down syndrome
Nicole Schupf. Ph.D.
Columbia University Medical Center

2. Dementia Risk in Adults with Down Syndrome.
Adults with Down syndrome are at high risk for early onset of Alzheimer’s Disease
Virtually all adults with DS have neuropathological changes consistent with AD, including deposition of Aβ in diffuse and neuritic plaques, by 40 years of age
Most will develop clinical dementia by their late 60s

3. Neuropathological changes: Neuritic Plaques
Neuritic plaques are extracellular lesions composed of degenerating neuronal structures such as axons, dendrites and synaptic terminals which are mixed with amyloid fibrils or surround an amyloid core. The blue-black spot in the center of this silver stained cortical section is the amyloid core of this classical plaque.

4. Neuropathological changes: Neurofibrillary Tangles
These are neurofibrillary tangles in a Tau immuno stained cortical section. Neurofibrillary tangles are composed of paired helical filament within neurons and their processes. Neurofibrillary tangles interfere with the normal action of neurons and their synapses

5. Increased Risk of Dementia in Adults with DS
Attributed, in part, to triplication and overexpression of amyloid precursor protein (APP) on chromosome 21, leading to elevated levels of Aβ peptides.
However:
--There large individual differences in Aβ peptide levels;
There is wide range of dementia onset age and a substantial proportion main their abilities even at older ages despite extensive neuropathology
Our study sought to identify preclinical blood based biomarkers of risk to identify those most likely to develop dementia

6. Cumulative Incidence of Alzheimer's Disease in Adults with DS and the General Population
Age

7. Blood Based Preclinical Biomarkers
Identifying preclinical biomarkers of risk and determining which individuals with DS are at the highest risk:
(a) can provide insights into AD pathogenesis in adults with DS,
(b) are critical to the early identification of MCI and dementia risk, and
(c) can guide the development of effective intervention.
(d) While cerebrospinal fluid (CSF) and positron emission tomography (PET) scan biomarkers are accurate in detecting AD pathology, they are invasive and not cost-effective

8. Proteomic Profiles
Prior work from Dr. O’Bryant’s lab has validated a profile of proteins for detecting MCI and AD in the general population, across cohorts, assay technologies, species and tissue.
Here we examined the utility of our previous profile for predicting the development of MCI and AD among a cohort of adults with DS

9. Classification of clinical status
Dementia classification was made based upon consensus case conferences relying on evidence of stability or decline in cognitive and functional performance profiles over time
Individuals were classified as:
No Dementia: No cognitive or functional decline
Mild Cognitive impairment: indications of cognitive and/or functional declines are present but severity or breadth is insufficient to indicate presence of dementia
Possible Dementia: some signs and symptoms of decline in cognitive and functional status were present, but evidence of progressive decline over an extended period of time is limited
Definite Dementia: based upon substantial decline in cognitive and functional status over time

10. Aging and Dementia in Adults with DS cohort : Participant Characteristics:
non-demented; n=273
Incident dementia; n=83
Incident MCI; n = 101
Mean age at blood draw 51.4 (sd=7.1, 31-78)
Female n=266
Male n=133
Up to 10 years of follow-up

11. Proteomic risk scores for MCI and AD
Proteomics were conducted on banked plasma samples via electrochemiluminescence from a previously generated algorithm. Support vector machine (SVM) analyses were utilized to create proteomic risk scores
We identified high/low cut-points scores for incident MCI and incident AD.
Cox proportional hazards modeling examined the relation of the proteomic cut- scores to onset of MCI and AD, adjusting for age, sex, level of function, race/ethnicity and the APOE E4 allele.

12. Baseline characteristics for Incident MCI
Nondemented
Incident MCI
Age (Mean, S.D)*
48.4 (6.6)
52.8 (6.1)
Sex (n, % female)*
138 (76.2)
48 (47.5)
Level of function (n, % severe /profound)*
56 (30.9)
46 (45.5)
Ethnicity (n, % Non-Hispanic White)
167 (92.3)
90 (8.1)
Any APOE E4 allele (n,%)
31 (17.5)
23 (22.8)
Risk Score Predicted MCI (n,%)*
21 (12.2)
80 (80.2)
* P < .05

13. Cumulative Incidence of MCI
High
Low
HR = 7.09*
*Adjusted for age at blood draw, sex, level of intellectual disability and APOE E4

14. Baseline for incident AD
Baseline characteristics for incident AD
Baseline for incident AD
Characteristic
Nondemented
Incident Dementia
Age (M + S.D.)*
49.8 (6.6)
54.2 (5.6)
Sex (n, %female)*
190 (69.6)
48 (57.8)
Level of function (n, % severe /profound)
107 (39.2)
37 (44.6)
Ethnicity (n, % Non-Hispanic white)
248 (90.8)
77 (92.8)
Any APOE E4 (n,%)
54 (20.1)
21 (25.3)
Risk Score Predicted AD*
27 (9.9)
65 (78.3)
* P < .05

15. Cumulative Incidence of AD by risk score with time since blood draw as the time to event variable.
High
Low
HR=11.29*
*Adjusted for age at blood draw, sex, level of intellectual disability and APOE E4

16. Comparison of general population profile with profile of MCI and AD in adults with DS
Plasma AD Profile in non-Hispanic Whites
Plasma Profile of Incident MCI in Down Syndrome – 8 of top 10 markers overlap
Plasma Profile of Incident AD in Down Syndrome – 7 of top 10 markers overlap

17. Predictors
The top 10 proteins associated with increased risk of MCI included IL6,CRP, l309, slCAM1, IL10, SAA, TPO, PPY, TenacinC, TARC
The top 10 markers associated with increased risk of AD included IL6,CRP, l309, slCAM1, IL10, SAA, TPO, PPY, TenacinC, TARC
It is noteworthy that the profiles were heavily weighted towards inflammatory markers for both MCI-DS and AD

18. Summary and Conclusions
These results support the possibility of blood based profiles having utility in predicting onset of MCI and AD among adults with DS
Inflammatory processes have been linked to the pathogenesis of Alzheimer’s disease and neuropsychiatric symptoms . A number of pro- and anti-inflammatory markers have been related to neuropsychiatric symptoms and functional level in aging and Alzheimer’s disease including TNFα ,IL-1 IL-6 IL-7 IL-10 , IL-15 and IL-18
it is possible that the proinflammatory biomarker profile will identify a specific subset of adults with DS where anti-inflammatory interventions, as a part of multi-modal therapy, may be of particular use
We are extending these analyses and relating them to imaging (MRI, PET), metabolomic and genetic biomarkers in our new study of Biomarkers of Alzheimer's disease in Adults with Down Syndrome (ADDS), which is part of the Alzheimer’s Biomarkers Consortium- Down Syndrome (ABC-DS) funded by the NIA and NICHD

19. Acknowledgements
Co-investigators: , Fan Zhang, Joseph H. Lee, Sharon J. Krinsky- McHale, Deborah Pang, Warren B. Zigman, Wayne Silverman, James Hall and Sid O’Bryant
Supported by grant IIRG from the Alzheimer's Association (Schupf, O’Bryant), by grants P01HD (Silverman) from NICHD, R01AG (Schupf) from NIA, and by NYS through its Office for People with Developmental Disabilities.
We thank the study participants and participating agencies from the tri-state area that made these studies possible