The Nun Study: Insights from 30 years of aging and dementia research

Abstract

The Nun Study is an iconic longitudinal study of aging and dementia on a cohort of 678 Catholic nuns from the School Sisters of Notre Dame. Participants consented to undergoing annual neuropsychological assessments, allowing researchers access to convent archives and medical records and post mortem brain donation. This study investigated the associations between epidemiological factors, cognitive function, and brain pathology. By examining published literature that reports on or utilizes Nun Study data, we provide an overview of its methodology and key findings, emphasizing its significant contributions to understanding cognitive impairment and related neuropathologies. Seminal findings on early-life factors affecting cognitive health, clinicopathological correlations, and apparent resistance and resilience to neuropathology are discussed. Decades of Nun Study research have made critical contributions to our understanding of Alzheimer's disease and related dementias and highlight continuing objectives for future research. HIGHLIGHTS: The uniform lifestyles of participants minimized potential confounds of the study. Early-life cognitive ability influenced late-life cognitive outcomes. Some participants with AD pathology did not exhibit dementia. Neuropathological comorbidities were common and increased the risk of dementia.

Keywords: Alzheimer's disease; Nun Study; aging; cognitive reserve; dementia; digital pathology; epidemiology; neuropathology.

FIGURE 1

Flowchart of search strategy for identifying relevant Nun Study publications. Databases PubMed and BioRxiv were searched, then article titles and abstracts were screened for relevance to the Nun Study. The full text of each article was screened to confirm eligibility and for extraction of data on Nun Study methodology, cognitive assessments, and neuropathological analyses. Additional relevant studies were identified from the reference lists of reviewed articles for inclusion in this review. Of the 49 articles selected for review, 34 were referenced for neuropathology data, 23 for cognitive and clinical data, and 39 for study design and methodology of ante mortem and post mortem assessments (note: a single article can be cited for multiple categories). Figure created with BioRender.

FIGURE 2

Summary of Nun Study publications selected for review. Nun Study publications are denoted by first author, year of publication, and the first one to four words of the article title. Publications are ordered chronologically by year of publication, and then alphabetically by first author if multiple articles were published in the same year. The information cited from each publication in the current review is indicated by a check mark or by a symbol for specific neuropathology data (green square, AD pathology; red circle, cerebrovascular pathology; yellow triangle, hippocampal sclerosis; blue ring, TDP‐43 pathology; orange star, Lewy body pathology). The leftmost panel exhibits publications for the major diagnostic clinical and neuropathological criteria for AD referenced in this review. Figure created with BioRender. AD, Alzheimer's disease; CERAD, Consortium to Establish a Registry for Alzheimer's Disease; CERAD‐NAB, Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery; MCI, mild cognitive impairment; NFT, neurofibrillary tangle; NIA, National Institute on Aging; AA, Alzheimer's Association.

FIGURE 3

Schematic diagram illustrating methodology of Nun Study. Epidemiological data, such as family history and education, were compiled from participant medical records and archived documents including academic transcripts and autobiographies. Longitudinal assessments of physical and cognitive function were conducted according to standardized criteria. APOE genotype was determined from buccal cell samples from living participants or post mortem brain tissue. Additionally, blood samples were collected from a subset of participants for biochemical measurements. Gross brain examination for infarcts, atrophy, and atherosclerosis, as well as histological examination for AD, vascular, LB, LATE, and HS‐A pathologies were performed by a neuropathologist blinded to cognitive test results. Ongoing investigations utilize digital pathology techniques for comprehensive neuropathological assessment. Figure created with BioRender. AD, Alzheimer's disease; HS‐A, hippocampal sclerosis of aging; LATE, limbic predominant age‐related TDP‐43 encephalopathy; LB, Lewy body.

FIGURE 4

Evolution of staining techniques from Bielschowsky silver stain to immunohistochemistry for detection of neuritic plaques. (A–F) Representative sections from frontal cortex stained with Bielschowsky silver stain. (A–C) From brain autopsy case with moderate burden of neuritic plaques. (D–F) From brain autopsy case with sparse neuritic plaque density score. (G–L) Aβ expression using immunohistochemistry with antibodies against 4G8. (G–I) Frontal cortex from research participant with CERAD‐NP density score of 3 (frequent neuritic plaques). (J–L) From research participant with CERAD‐NP density score of 1 (sparse neuritic plaques). The Bielschowsky stain highlights neuritic plaques and NFTs, while the 4G8 antibody specifically labels Aβ, providing greater specificity. Scale bars represent indicated magnifications. Aβ, amyloid beta; CERAD‐NP, Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque staging; NFT, neurofibrillary tangle.

FIGURE 5

Detection of neurofibrillary tangles using Bielschowsky silver stain and PHF‐1 immunohistochemistry. Representative sections from hippocampus from two brain autopsies with Braak stage V Alzheimer's disease pathology, stained with Bielschowsky silver stain (A and B) and immunohistochemistry using antibodies against PHF‐1 (C and D). Neurofibrillary tangles are demonstrated at higher magnification in images B and C. PHF‐1 specifically targets hyperphosphorylated tau, providing more precise detection of tau pathology compared to the broader Bielschowsky stain. Scale bars represent indicated magnifications.