Relationship of cognitive reserve and cerebrospinal

fluid biomarkers to the emergence of clinical symptoms

in preclinical Alzheimers disease
Authors:

Anja Soldan
Corinne Pettigrew
Shanshan Li

Article:
Journal Name- Neurobiology of
Aging

Mei- Cheng Wang

Abhay Moghekar
Ola A. Selnes

Date- December 2013

Volume- 34

Marilyn Albert
Richard OBrien
The BIOCARD research team
Presentation by: Erika Abrantes

Pages- 2,827- 2,834

Purpose: Was to recruit and follow a cohort of

cognitively normal individuals who were primarily in
middle age at baseline. These people were followed over
time where levels of specific biomarkers were measured
(B- amyloid and phosphorylated tau), these markers
were found in the cerebrospinal fluid. Also examined was
if cognitive reserve does anything to lessen or increase
risk of Alzheimer's. This helped show how people go
from being cognitively normal to developing Alzheimer's
Disease.

Review of Literature:
- Jack et al., 2013
C.R. Jack Jr., D.S. Knopman, W.J. Jagust, R.C. Petersen, M.W. Weiner, P.S. Aisen, L.M. Shaw, P. Vemuri, H.J. Wiste,

S.D. Weigand, T.G. Lesnick, V.S. Pankratz, M.C. Donohue, J.Q. Trojanowski
Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers
Lancet Neurol., 12 (2013), pp. 207216

-Sperling et al., 2011

R.A. Sperling, P.S. Aisen, L.A. Beckett, D.A. Bennett, S. Craft, A.M. Fagan, T. Iwatsubo, C.R. Jack Jr., J. Kaye, T.J.
Montine, D.C. Park, E.M. Reiman, C.C. Rowe, E. Siemers, Y. Stern, K. Yaffe, M.C. Carrillo, B. Thies, M. MorrisonBogorad, M.V. Wagster, C.H. Phelps

Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on AgingAlzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease
Alzheimers Dement., 7 (2011), pp. 280292

- Bennett et al., 2006

D.A. Bennett, J.A. Schneider, Z. Arvanitakis, J.F. Kelly, N.T. Aggarwal, R.C. Shah, R.S. Wilson
Neuropathology of older persons without cognitive impairment from two community-based studies
Neurology, 66 (2006), pp. 18371844

- Hulette et al., 1998

C.M. Hulette, K.A. Welsh-Bohmer, M.G. Murray, A.M. Saunders, D.C. Mash, L.M. McIntyre
Neuropathological and neuropsychological changes in normal aging: evidence for preclinical Alzheimer disease in
cognitively normal individuals
J. Neuropathol. Exp. Neurol., 57 (1998), pp. 11681174

- Knopman et al., 2003

D.S. Knopman, J.E. Parisi, A. Salviati, M. Floriach-Robert, B.F. Boeve, R.J. Ivnik, G.E. Smith, D.W. Dickson, K.A. Johnson,
L.E. Petersen, W.C. McDonald, H. Braak, R.C. Petersen
Neuropathology of cognitively normal elderly
J Neuropathol. Exp. Neurol., 62 (2003), pp. 10871095

- De Meyer et al., 2010

G. De Meyer, F. Shapiro, H. Vanderstichele, E. Vanmechelen, S. Engelborghs, P.P. De Deyn, E. Coart, O. Hansson, L. Minthon, H.
Zetterberg, K. Blennow, L. Shaw, J.Q. Trojanowski
Diagnosis-independent Alzheimer disease biomarker signature in cognitively normal elderly people

Arch. Neurol., 67 (2010), pp. 949956

- Morris et al., 2010

J.C. Morris, C.M. Roe, C. Xiong, A.M. Fagan, A.M. Goate, D.M. Holtzman, M.A. Mintun
APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging
Ann. Neurol., 67 (2010), pp. 122131

-Reiman et al., 2009

E.M. Reiman, K. Chen, X. Liu, D. Bandy, M. Yu, W. Lee, N. Ayutyanont, J. Keppler, S.A. Reeder, J.B. Langbaum, G.E.

Alexander, W.E. Klunk, C.A. Mathis, J.C. Price, H.J. Aizenstein, S.T. DeKosky, R.J. Caselli
Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease
Proc. Natl. Acad. Sci. U.S.A, 106 (2009), pp. 68206825

-Rowe et al., 2010

C.C. Rowe, K.A. Ellis, M. Rimajova, P. Bourgeat, K.E. Pike, G. Jones, J. Fripp, H. Tochon-Danguy, L. Morandeau, G. O'Keefe, R.
Price, P. Raniga, P. Robins, O. Acosta, N. Lenzo, C. Szoeke, O. Salvado, R. Head, R. Martins, C.L. Masters, D. Ames, V.L.
Villemagne
Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging
Neurobiol. Aging, 31 (2010), pp. 12751283

-Stern, 2009

Y. Stern

Elaborating a hypothetical concept: comments on the special series on cognitive reserve

J. Int. Neuropsychol. Soc., 17 (2009), pp. 639642

-Fitzpatrick et al., 2004

A.L. Fitzpatrick, L.H. Kuller, D.G. Ives, O.L. Lopez, W. Jagust, J.C. Breitner, B. Jones, C. Lyketsos, C. Dulberg
Incidence and prevalence of dementia in the Cardiovascular Health Study

J. Am. Geriatr. Soc., 52 (2004), pp. 195204

-Stern et al., 1994

Y. Stern, B. Gurland, T.K. Tatemichi, M.X. Tang, D. Wilder, R. Mayeux

Influence of education and occupation on the incidence of Alzheimer's disease

JAMA, 271 (1994), pp. 10041010

-Manly et al., 2005

J.J. Manly, N. Schupf, M.X. Tang, Y. Stern
Cognitive decline and literacy among ethnically diverse elders
J. Geriatr. Psychiatry Neurol., 18 (2005), pp. 213217

-Andel et al., 2005

R. Andel, M. Crowe, N.L. Pedersen, J. Mortimer, E. Crimmins, B. Johansson, M. Gatz
Complexity of work and risk of Alzheimer's disease: a population-based study of Swedish twins

-Scarmeas et al., 2001

N. Scarmeas, G. Levy, M.X. Tang, J. Manly, Y. Stern
Influence of leisure activity on the incidence of Alzheimer's disease
Neurology, 57 (2001), pp. 22362242

-Wilson et al., 2002

R.S. Wilson, C.F. Mendes De Leon, L.L. Barnes, J.A. Schneider, J.L. Bienias, D.A. Evans, D.A. Bennett
Participation in cognitively stimulating activities and risk of incident Alzheimer disease
JAMA, 287 (2002), pp. 742748

-Bennett et al., 2003

D.A. Bennett, R.S. Wilson, J.A. Schneider, D.A. Evans, C.F. Mendes de Leon, S.E. Arnold, L.L. Barnes, J.L. Bienias
Education modifies the relation of AD pathology to level of cognitive function in older persons
Neurology, 60 (2003), pp. 19091915

-Bennett et al., 2005

D.A. Bennett, J.A. Schneider, R.S. Wilson, J.L. Bienias, S.E. Arnold

Education modifies the association of amyloid but not tangles with cognitive function
Neurology, 65 (2005), pp. 953955

-Rentz et al., 2010

D.M. Rentz, J.J. Locascio, J.A. Becker, E.K. Moran, E. Eng, R.L. Buckner, R.A. Sperling, K.A. Johnson
Cognition, reserve, and amyloid deposition in normal aging
Ann. Neurol., 67 (2010), pp. 353364

-Roe et al., 2008a

C.M. Roe, M.A. Mintun, G. D'Angelo, C. Xiong, E.A. Grant, J.C. Morris
Alzheimer disease and cognitive reserve: variation of education effect with carbon 11-labeled Pittsburgh Compound B uptake
Arch. Neurol., 65 (2008), pp. 14671471

-Roe et al., 2008b

C.M. Roe, C. Xiong, J.P. Miller, N.J. Cairns, J.C. Morris
Interaction of neuritic plaques and education predicts dementia
Alzheimer Dis. Assoc. Disord., 22 (2008), pp. 188193

-Vemuri et al., 2011

P. Vemuri, S.D. Weigand, S.A. Przybelski, D.S. Knopman, G.E. Smith, J.Q. Trojanowski, L.M. Shaw, C.S. Decarli, O.
Carmichael, M.A. Bernstein, P.S. Aisen, M. Weiner, R.C. Petersen, C.R. Jack Jr.

Cognitive reserve and Alzheimer's disease biomarkers are independent determinants of cognition
Brain, 134 (2011), pp. 14791492

-Roe et al., 2011a

C.M. Roe, A.M. Fagan, E.A. Grant, D.S. Marcus, T.L. Benzinger, M.A. Mintun, D.M. Holtzman, J.C. Morris
Cerebrospinal fluid biomarkers, education, brain volume, and future cognition
Arch. Neurol., 68 (2011), pp. 11451151

-Yaffe et al., 2011

K. Yaffe, A. Weston, N.R. Graff-Radford, S. Satterfield, E.M. Simonsick, S.G. Younkin, L.H. Younkin, L. Kuller, H.N. Ayonayon, J.
Ding, T.B. Harris
Association of plasma beta-amyloid level and cognitive reserve with subsequent cognitive decline
JAMA, 305 (2011), pp. 261266

-Manly et al., 2003

J.J. Manly, P. Touradji, M.X. Tang, Y. Stern
Literacy and memory decline among ethnically diverse elders

J. Clin. Exp. Neuropsychol., 25 (2003), pp. 680690

-Manly et al., 2005

J.J. Manly, N. Schupf, M.X. Tang, Y. Stern
Cognitive decline and literacy among ethnically diverse elders
J. Geriatr. Psychiatry Neurol., 18 (2005), pp. 213217

-Sole-Padulles et al., 2011

C. Sole-Padulles, A. Llado, D. Bartres-Faz, J. Fortea, R. Sanchez-Valle, B. Bosch, A. Antonell, J.L. Molinuevo, L. Rami
Association between cerebrospinal fluid tau and brain atrophy is not related to clinical severity in the Alzheimer's disease
continuum
Psychiatry Res., 192 (2011), pp. 140146

Vocabulary:
Cognitive Reserve (CR)- Describes the minds resistance to damage of the brain.
Pathology- The science that studies the causes and effects of diseases.
Preclinical Alzheimer's Disease- People are forgetting things, and acting different, it is the stages
before it kicks in.
Mild Cognitive impairment (MCI)- a brain function syndrome involving the onset and evolution of
cognitive impairments beyond those expected based on the age and education of the individual, but
which are not significant enough to interfere with their daily activities
Cerebrospinal fluid (CSF)- A clear colorless bodily fluid found in the Spine + Brain.
Tau Protein- Proteins that stabilize molecules.
Amyloid- a starchlike protein that is deposited in the liver, kidneys, spleen, or other tissues in certain
diseases.
Cohort studies- Group that you are compared to.
Biomarkers- Reliable predictors + indicators of the disease process.
Baseline- A minimum or starting point, used for comparison.

Hypotheses or Problem Statement:

- To examine whether CR (Cognitive Reserve) modifies
the relationship between the rates of change of CSF
(Cerebrospinal Fluid) biomarkers over time and
increases the risk of developing clinical symptoms of
Alzheimer's Disease.

Methodology:

2.1- Study Design

o Designed to recruit and follow a cohort of cognitively normal
individuals who were primarily middle age at baseline.
o Three quarters of the participants had a first degree relative with a
history of dementia.
o Overreaching goal was to identify variables among cognitively normal
individuals, that could predict the subsequent development of mild to
moderate symptoms of AD (Alzheimer's Disease).

 2.2- Selection of Participants

Total of 349 individuals were enrolled in study.
Participants were enrolled over time, starting 1995 and ending 2005.

Participants were recruited via printing advertisements, articles in

local or national media, informational lectures, or word of mouth.
All participants completed a comprehensive evaluation at the clinical
center of NIH.
Evaluation consisted of a physical and neurologic examination, an
electrocardiogram, standard laboratory studies, and
neuropsychological testing.
CSF was obtained from 307 participants.
239 of the 307 participants provided the baseline CSF.

2.3- CSF assessments

o Calibration curves were produced for each biomarker.
o Each participant had all samples analyzed on the same plate.
o This protocol used the xMAP- based AlzBio3 kit run on the Bioplex
200 system.
i. contains monoclonal antibodies specific for AB1- 42, t-tau, and ptau.

2.4- Clinical and cognitive assessment.

o The annual cognitive assessment consisted of a neuropsychological
exam covering all major cognitive domains.
o A clinical assessment was completed annually.

o Clinical Evaluation included

i. physical and neurologic examination
ii. record of medication use
iii. behavioral and mood assessments
iv. family history of dementia
v. history of symptom onset
vi. A clinical dementia rating

2.5- CR composite score

o Created a CR composite score based on 3 measures that were thought
to reflect CR.
i. baseline scores on the National Adult Reading Test.
i. baseline scores on the Wechsler Adult Intelligence Scale- Revised
vocabulary subtest.
i. years of education.

 2.6- Consensus diagnoses

The age at which the clinical symptoms began was estimated (many
instances, the estimated age of onset clinical symptoms preceded the
date of diagnosis).
Each participant received a consensus diagnoses that was handled in
the same manner.
i. clinical data pertaining to the medical, neurologic, and psychiatric
status of the participant were examined.

i. reports of changes in cognition by the participant were examined.

i. decline in cognitive performance, based on review of longitudinal
testing from multiple domains, was established.

2.7- Statistical methods

1. tested whether there was an association between baseline
CR and CSF biomarker values.
a. CSF biomarker was the dependent variable.
a. CR composite score, age at baseline, and gender were independent
variables.
2. examined if baseline CR was predictive of the rate of change in
CSF biomarkers over time to determine if CR influences rate of
biomarker accumulation.
a. Rate of change was calculated as the difference in CSF measurements
between the last follow- up and the baseline visits, divided by the
corresponding difference in time.
b. Rate of change in the CSF value is the dependent variable.
a. CR composite score, baseline CSF value, age at baseline, and sex as
independent variable.

 2.7.2- Baseline CR and baseline CSF biomarkers in relation to time to onset of

clinical symptoms.
Data from 2 groups were included (based on diagnosis at their last visit).
i. Participants who remained cognitively normal (n= 186).
i. Participants who received a diagnosis of mild cognitive impairment or
dementia (n= 53).
Set of Cox regression analyses were performed for each CSF biomarker.
i. Cox regression analyses were performed for participants with CSF
biomarker values at or greater than the median.
Goal of these comparisons was to determine the difference in the association
between the CR and the risk of progression for participants with high levels
compared with those with low levels of CSF biomarkers.

 2.7.3- Baseline CR and longitudinal CSF biomarkers in relation to time to onset

of clinical symptoms
i. A previous analyses demonstrated a differential rate of change in the
ratios of CSF t-tau/ AB- 42 and CSF p- tau/ AB1-42 in cognitively
normal participants who later developed clinical symptoms of and
subsequent MCI.
Second Cox regression analyses was conducted...
i. To determine whether the time dependent rate of change in these
ratios, in combination with CR, was associated with the time to onset of
clinical symptoms.
i. Outcome variable was age of onset Alzheimer's.
i. Predictors were
Baseline CSF values,
Time- dependant rate of change in CSF values,
CR composite score

HR indicates the change in risk of progression per unit change in

the predictor.
CSF values were converted to z- scores, so that it would be
possible to compare the HRs for each predictor with each other.

Results:

3.1. - Association of baseline CR and baseline CSF biomarker values.

o Analyses showed that after controlling age at baseline and gender, that there
were no associations between the baseline CR composite score and CSF
values for any of the 5 biomarkers.
3.2. - Association of baseline CR and longitudinal rate of change of CSF
biomarker values.
o Revealed no associations between the baseline CR composite score and the
rate of change in CSF values.

3.3. - Baseline CR and CSF in relation to time to onset of clinical symptoms.

o CR was a significant predictor of the time to onset of clinical symptoms in all
models.
Each SD increase in CR was associated with around a 50% decrease in the
risk of progression from normal cognition to onset of clinical symptoms for
each of the 5 biomarkers.

3.4. Baseline CR and longitudinal change in CSF in relation to time to onset of

clinical symptoms.

Time dependent rate of change in p-tau/AB1-42 and baseline CR independently

predicted the time to onset of clinical symptoms.
Greater increases in p-tau/AB1-42 being associated with a greater
risk of developing clinical symptoms.
Higher CR with a smaller risk of symptom onset.
No interaction between CR and the time- dependent rate of change
in p-tau/AB1-42.

o Rate of increase in t-tau/AB1-42 ratio was associated with a greater risk of

progressing to clinical symptom onset.
o Interaction between CR and the rate of change in the t-atu/AB1-42 ratio was
not significant.

Discussion
The data showed that participants with higher levels of CR had a significantly
lower risk of progressing from normal cognition to onset of clinical symptoms.
o had same level of AD pathology measured using each of the 5 CSF
biomarkers.
The average age of the cohort was 56.9 years at baseline.
o Cognitively normal individuals with higher CR are able to tolerate higher
levels of AD pathology.
o Individuals with high CR have lower levels of CSF AB42-1 compared with
those with low CR.
The higher levels of CSF biomarkers had a stronger relationship between the
people with higher CR and the development of clinical symptoms of Alzheimer's.
o Participants were highly educated and primarily Caucasian, so the results do
not generalize the US population.

Conclusion
No the hypothesis was not supported, their data showed that baseline levels
of Cognitive Reserve were not associated with those of CSF biomarkers or
the rate of change in their biomarkers overtime.

Suggests Cognitive Reserve does not directly influence the aggregation of

tau and amyloid pathology, but instead serves to modify the effect of that
pathology on the expression of clinical symptoms.
Higher CR reduces risk of symptom onset regardless of baseline and
amyloid levels.
o reduces the risk of symptom onset even less if baseline levels of tau are
high.