OBJECTIVE: Neuroimaging and other biomarker assays suggest that the pathological 
processes of Alzheimer's disease (AD) begin years prior to clinical dementia 
onset. However, some 30 to 50% of older individuals who harbor AD pathology do 
not become symptomatic in their lifetime. It is hypothesized that such 
individuals exhibit cognitive resilience that protects against AD dementia. We 
hypothesized that in cases with AD pathology, structural changes in dendritic 
spines would distinguish individuals who had or did not have clinical dementia.
METHODS: We compared dendritic spines within layer II and III pyramidal neuron 
dendrites in Brodmann area 46 dorsolateral prefrontal cortex using the Golgi-Cox 
technique in 12 age-matched pathology-free controls, 8 controls with AD 
pathology (CAD), and 21 AD cases. We used highly optimized methods to trace 
impregnated dendrites from bright-field microscopy images that enabled accurate 
3-dimensional digital reconstruction of dendritic structure for morphologic 
analyses.
RESULTS: Spine density was similar among control and CAD cases but was reduced 
significantly in AD. Thin and mushroom spines were reduced significantly in AD 
compared to CAD brains, whereas stubby spine density was decreased significantly 
in CAD and AD compared to controls. Increased spine extent distinguished CAD 
cases from controls and AD. Linear regression analysis of all cases indicated 
that spine density was not associated with neuritic plaque score but did display 
negative correlation with Braak staging.
INTERPRETATION: These observations provide cellular evidence to support the 
hypothesis that dendritic spine plasticity is a mechanism of cognitive 
resilience that protects older individuals with AD pathology from developing 
dementia. Ann Neurol 2017;82:602-614.