Nuclear Hypertrophy Distinguishes Resilient Neurons in Asymptomatic Alzheimer’s Disease

Riudavets MA, Iacono D, Resnick SM, O’Brien R, Zonderman AB, Martin LJ, Rudow G, Pletnikova O, Troncoso JC. Resistance to Alzheimer’s pathology is associated with nuclear hypertrophy in neurons. Neurobiol Aging 2007;28(10):1484-1492. doi: 10.1016/j.neurobiolaging.2007.05.005.

Background: Alzheimer’s disease (AD) pathology is sometimes present in individuals who remain cognitively normal, suggesting that certain neuronal characteristics may confer resilience to the disease. Understanding the structural features of neurons that allow resistance to AD-related lesions could help explain why some brains remain cognitively intact despite heavy amyloid and tau pathology.

Hypothesis: This study hypothesized that neurons in cognitively normal individuals with AD pathology (asymptomatic AD) exhibit specific morphometric changes that may reflect adaptive or protective mechanisms against neurodegeneration.

Methods: The authors examined post mortem brains from control, asymptomatic AD, mild cognitive impairment (MCI) and AD-dementia subjects. They analyzed neuronal and nuclear volumes in the anterior cingulate gyrus and hippocampal CA1 using stereological techniques with Stereo Investigator and the Vertical Nucleator and Area-Fraction-Fractionator probes. Measurements were performed on cresyl violet–stained sections, with additional quantification of amyloid-β and phosphorylated tau immunoreactivity.

Results: Compared to controls, asymptomatic AD brains showed no neuronal atrophy in either region. In contrast, neuronal cell body volumes were significantly reduced in MCI and AD. Asymptomatic AD neurons displayed marked nuclear hypertrophy, with significantly larger nuclear volumes than controls, MCI and AD, while cerebellar Purkinje cells showed no group differences. Amyloid and tau burdens were comparable between asymptomatic AD and MCI, but both were higher in AD.

Conclusions: Nuclear hypertrophy in asymptomatic AD neurons may represent an early adaptive response to AD pathology, reflecting enhanced metabolic or compensatory activity that delays neuronal degeneration and preserves cognitive function.