Complex Regulation of Protocadherin Epigenetics on Aging-Related Brain Health

Poster No:


Submission Type:

Abstract Submission 


Vanessa Schmithorst1, Daryaneh Badaly2, Julia Wallace3, Vince Lee1, Cecilia Lo4, Ashok Panigrahy3


1UPMC Children's Hospital, Pittsburgh, PA, 2Child Mind Institute, New York, NY, 3UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, 4University of Pittsburgh, Pittsburgh, PA

First Author:

Vanessa Schmithorst, Ph.D.  
UPMC Children's Hospital
Pittsburgh, PA


Daryaneh Badaly  
Child Mind Institute
New York, NY
Julia Wallace  
UPMC Children's Hospital of Pittsburgh
Pittsburgh, PA
Vince Lee  
UPMC Children's Hospital
Pittsburgh, PA
Cecilia Lo  
University of Pittsburgh
Pittsburgh, PA
Ashok Panigrahy  
UPMC Children's Hospital of Pittsburgh
Pittsburgh, PA


The clustered protocadherin (PCDH) gene clusters comprising three distinct gene families (α, β and γ) encode homotypic cell adhesion proteins regulating synaptic connectivity via specification of neuronal identity with combinatorial expression of genes in the three clusters (Yagi, 2008; Flaherty & Maniatis, 2020; Jia & Wu, 2020). Epigenetic alterations are a hallmark of aging; we investigate the impact of DNA methylation in the PCDH clusters on brain volume and neurocognitive outcomes.


We acquired subject data (N = 1936) from the Framingham Heart Study (FHS) Offspring Cohort, which was formed in 1971 to include children of participants consented into the original study. MR brain imaging outcomes were acquired using 1.0/1.5T scanners, and volumes were quantified from T2-weighted double spin-echo coronal sequences. Neuropsychological measures included: measures of language/verbal reasoning, verbal/visual memory, executive functions, and visuospatial skills.

DNA methylation levels were quantified using the Infinium HumanMethylation450 BeadChip platform from Illumina. For the current study, we investigated total, PCDHA, PCDHB, and PCDHG methylation.

To examine the relationship between age, methylation, brain volumes and neurocognitive outcomes, we performed the following analyses. The outcomes (dependent variables) were either brain volumes or cognitive performance. The best model for each outcome was found using the following procedure. Models were tested for each methylation value: 1) Completely excluded from the model; 2) Main effect only; 3) Main effect and interaction (with the independent variable); 4) Main effect and quadratic term; 5) Main effect, interaction, and quadratic term. As there are 5 options for each of four methylation values, a total of 5^4 = 625 linear regression models were tested. The best model was selected using the Aikake's Information Criterion (AIC).


For each brain region and type (gray/white matter) except frontal gray, an increase in PCDHA methylation resulted in a retardation of age-related volume loss in both white and gray matter (Figure 1). An increase in PCDHB methylation resulted in a retardation of age-related volume loss in frontal gray matter. However, an increase in PCDHG methylation resulted in an acceleration of age-related volume loss in parietal white matter and temporal white matter.

An increase in PCDHA methylation (Figure 2) also results in age-related preservation of acquired verbal skill as measured by Word Reading on the Wide Range Achievement Test (WRAT), while an increase in PCDHB methylation results in a retardation in age-related cognitive decline for the similarities test (SIM; verbal reasoning). However, an increase in PCDHG methylation results in an acceleration of age-related cognitive decline for the WRAT and the SIM tests.
Supporting Image: Figure1Aging.PNG
   ·Figure 1. An increase in PCDHA methylation resulted in a retardation of age-related volume loss in both white matter and gray matter of multiple lobes.
Supporting Image: Figure2Aging.PNG
   ·Figure 2. An increase in PCDHA/PCDHB methylation or a decrease in PCDHG methylation results in age-related retardation of cognitive loss as measured by the WRAT/SIM.


Our results show that normal aging processes affecting the brain and cognition are regulated by epigenetic configurations, particularly at PCDH loci. Unlike the characteristic pattern often seen for Alzheimer's, in which memory impairments are often an initial and core feature, we showed that PCDH methylation affects a set of cognitive skills unrelated to memory. We hypothesize that these results reflect optimal conditions for synaptogenesis during aging, specifically synaptic specificity, which differ from optimal conditions during neurodevelopment. Synaptogenesis during normal aging is a likely mechanism for maintaining cognitive function in the presence of synaptic loss and efficiency, as well as retarding the process of synaptic loss. Synaptogenesis likely enables aging individuals to retain more language ability in a manner similar to second language acquisition, as distinct from executive function and memory, involving a refinement process and increased specialization.

Higher Cognitive Functions:

Executive Function, Cognitive Control and Decision Making
Higher Cognitive Functions Other 2


Language Acquisition

Learning and Memory:

Working Memory

Lifespan Development:

Aging 1



1|2Indicates the priority used for review

Provide references using author date format

Flaherty, E. & Maniatis, T. The role of clustered protocadherins in neurodevelopment and neuropsychiatric diseases. Current Opinion in Genetics & Development 65, 144-150 (2020).
Jia, Z. & Wu, Q. Clustered protocadherins emerge as novel susceptibility loci for mental disorders. Frontiers in Neuroscience, 1191 (2020).
Yagi, T. Clustered protocadherin family. Development, growth & differentiation 50, S131-S140 (2008).