UC Davis Alzheimer’s Disease Center The Residual Approach to Measuring Cognitive Reserve in Aging and Dementia Bruce Reed & Dan Mungas University of California, Davis

UC Davis Alzheimer’s Disease Center Acknowledgements Funded in part by Grant R13AG A1 from the National Institute on Aging The views expressed in written conference materials or publications and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government.

UC Davis Alzheimer’s Disease Center “What a waste it is to lose one’s mind, or not to have a mind as being truly wasteful. How true that is.” --Dan Quayle

UC Davis Alzheimer’s Disease Center The prevalence of AD is strongly linked to age From: Nessbaum & Ellis (2003). NEJM, 348: 1356.

UC Davis Alzheimer’s Disease Center Rates of cerebrovascular disease strongly linked to age Incident first infarcts: cases per 100, 000 Leary, et al., 2003 Bryan, et al., 1997

UC Davis Alzheimer’s Disease Center Trajectories of cognitive function in later life  Are heterogeneous  Become more negative, on average, with advancing age Individual 5 year change trajectories Distribution of slopes of change Average slopes for 5 year age blocks data: Wilson, et al. Psych & Aging 2002

UC Davis Alzheimer’s Disease Center Cognitive Decline Cognitive Baseline Brain Pathology A simple model to explain decline Reserve is a construct that attempts to explain variability in the amount or rate of cognitive change following brain insult.

UC Davis Alzheimer’s Disease Center Reserve can be thought of as the difference between a person’s actual level of cognitive performance and the average level of performance that would be expected given the amount of brain pathology present Is it useful to operationally define reserve in this way?

UC Davis Alzheimer’s Disease Center Modeling Reserve Cognitive Decline Cognitive baseline Brain Pathology Reserve

UC Davis Alzheimer’s Disease Center Using a residual to measure reserve Cognitive Decline Cognitive baseline Brain Pathology Reserv e Potential advantages explicitly defined wide range of measurement; likely to be nicely distributed a direct estimate; makes no assumptions about what contributes to reserve determinants of reserve can be tested a dynamic (time-specific) measure; will change as disease progresses hypotheses about how reserve might change can be tested measures of reserve can be domain-specific Not a perfect or pure measure Captures unmeasured systematic variance and sources of random error. Whether or not it is a useful measure of reserve can be empirically tested

UC Davis Alzheimer’s Disease Center Initial Approach Used regression to define a residual term. Used the residual values for each person as variables in subsequent analyses. Initial conceptual model:  Episodic memory = brain pathology + R Episodic Memory measure = composite score derived from list learning data MRI used to estimate brain pathology  Atrophy (total brain volume) R = reserve

UC Davis Alzheimer’s Disease Center Hypothesis: Reserve inversely related to cognitive status (Normal > MCI > demented)

UC Davis Alzheimer’s Disease Center Hypothesis: Reserve inversely related to cognitive status (Normal > MCI > demented) Memory Residuals by Syndrome

UC Davis Alzheimer’s Disease Center Hypothesis: Reserve protects against cognitive decline: Decline is slower in persons with high reserve

UC Davis Alzheimer’s Disease Center Hypothesis: Reserve protects against cognitive decline: Decline is slower in persons with high reserve Rate of Change in Executive Function by Memory Residual

UC Davis Alzheimer’s Disease Center Hypothesis: Reserve influences the likelihood of conversion from MCI to dementia

UC Davis Alzheimer’s Disease Center Hypothesis: Reserve influences the likelihood of conversion from MCI to dementia Rate of Conversion from CDR = 0.5 to CDR ≥ 1.0 by Memory Residual Group

UC Davis Alzheimer’s Disease Center limitations  Because the regression does not incorporate education, the residual (error) term contains the variance associated with education. As education is the most commonly used proxy for reserve this makes it unclear what additional information the residual provides  There are additional MRI measures of brain pathology, not in the model; these effects, too, are in the residual  The regression approach, because it uses results of one model in a second separate model (as if the data were independent) is not optimal

UC Davis Alzheimer’s Disease Center Revised approach New conceptual model: Mem = demographics + MRI pathology + R  Demographics = sex, education, ethnicity)  MRI = total brain matter, hippocampal volume, WMH  residual variance Two stage analytic approach.  1) LVM to create uncorrelated component scores; Mem-D, Mem-B, Mem-R  2) hypothesis testing using these LVs.

UC Davis Alzheimer’s Disease Center

Data 288 subjects. 158 normal, 92 MCI, 38 demented 96 African Americans, 74 Hispanics (32 tested in English, 42 tested in Spanish), and 118 Caucasians. Education M = 12.7 yrs (range 0-25) Age M = 74.7 yrs (range 60-93) Mean evaluations = 3.5; 74% had 3 or more evaluations. N of evaluations truncated at 5.

UC Davis Alzheimer’s Disease Center Mem-D ~ 20% of episodic memory variance Mem-B ditto Mem-R ~ 50% of episodic memory variance

UC Davis Alzheimer’s Disease Center H1: Reserve is associated with global cognitive function: lower reserve -> lower cognitive status.

UC Davis Alzheimer’s Disease Center H1: Reserve is associated with global cognitive function: lower reserve -> lower cognitive status. ComponentOdds Ratio95% CIp Mem-D Mem-B Mem-R

UC Davis Alzheimer’s Disease Center H1: Reserve is associated with global cognitive function: reserve correlates with CDR sum of boxes

UC Davis Alzheimer’s Disease Center H1: Reserve is associated with global cognitive function: reserve correlates with CDR sum of boxes DVMemory Component Standardized Coefficient p CDR SumMem-D-0.09ns Mem-B Mem-R

UC Davis Alzheimer’s Disease Center H2: Mem-R is positively associated with another possible index of reserve, specifically reading ability

UC Davis Alzheimer’s Disease Center H2: Mem-R is positively associated with another possible index of reserve, specifically reading ability DVMemory Component Standardized Coefficient p ReadingMem-D Mem-B0.13ns Mem-R

UC Davis Alzheimer’s Disease Center H3: Reserve modifies the risk of conversion to a worse cognitive syndrome

UC Davis Alzheimer’s Disease Center H3: Reserve modifies the risk of conversion to a worse cognitive syndrome Memory Component Relative Risk Ratio (confidence interval) Mem-D1.58 ( ) Mem-B0.19 ( ) Mem-R0.27 ( )

UC Davis Alzheimer’s Disease Center H4: Higher Reserve is associated with slower decline in executive function

UC Davis Alzheimer’s Disease Center H4: Higher Reserve is associated with slower decline in executive function Memory Component Random Effect ParameterStandard Error p Mem-Dbaseline Mem-Bbaseline Mem-Rbaseline Mem-Dchange ns Mem-Bchange Mem-Rchange

UC Davis Alzheimer’s Disease Center H5: Reserve modifies the effect of brain atrophy on rates of decline in executive function

UC Davis Alzheimer’s Disease Center H5: Reserve modifies the effect of brain atrophy on rates of decline in executive function

UC Davis Alzheimer’s Disease Center Summary Consistent with the reserve hypothesis, a residual-based estimate of reserve: Correlates with an education-related index of reserve: higher reading scores -> higher reserve Correlates with contemporaneous, global, cognitive status; lower reserve -> worse dx and worse global cognition Is associated with rates of decline in executive function: higher reserve is associated with slower decline Reduces the risk of conversion from baseline dx to worsened cognitive status Modifies the impact of brain atrophy on cognitive function: brain pathology has a greater effect on cognitive function in low reserve cases than in high reserve cases.

UC Davis Alzheimer’s Disease Center Mem-R is model- dependent Other measures of pathology could be used  Add’l structural measures  fMRI  Molecular imagining  Other biomarkers, e.g. CSF abeta and tau  These would “purify” and presumably strengthen Mem- R as a measure of reserve Other demographic variables could be added  We used education in order to provide proof of principle  Additional demographic variables might not improve Mem-R

UC Davis Alzheimer’s Disease Center What is Mem-D?  Education (as captured in Mem-D) did not affect change independently of MRI variables  Are there factors that affect baseline cognitive performance but which do not modify rates of change?

UC Davis Alzheimer’s Disease Center

future Goal: to study reserve by Measuring brain pathology with PIB PET and MRI In an exceptionally diverse sample (education range ) Modeling reserve as a residual term And testing an alternative hypotheses on the mechanism of education effects

UC Davis Alzheimer’s Disease Center