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Performance on Test of Semantic Abilities Linked to Early Alzheimer's Disease Brain Pathology

Key findings

  • This study examined how total score and clustering on the Category Fluency (Animals) test differed between 29 nondemented carriers of the presenilin 1 E280A mutation, which causes Alzheimer's disease (AD), and 32 noncarrier family members
  • Total scores (number of animals named in one minute) did not differ significantly between carriers and noncarriers
  • However, relative to noncarriers, carriers showed a stronger association between animal fluency clustering (number of animals named sequentially in a subcategory) and brain levels of amyloid-beta and tau protein
  • Further research may identify which cognitive tests (and subcomponents of those tests) are highly sensitive in identifying good candidates for preventive/therapeutic AD interventions

Now that pharmacologic and nonpharmacologic interventions are being used for early Alzheimer's disease (AD), a key goal is to find biomarkers and cognitive measures that identify patients who are candidates. Prior research suggests semantic networks are disrupted early in the AD process, manifesting as inefficient or poor performance on cognitive tests of semantic fluency, such as tests of category fluency.

The gold-standard semantic fluency test is the Category Fluency (Animals) test, in which participants name as many animals as they can think of in one minute. However, in past research, the total score hasn't proven sensitive enough to differentiate people in the preclinical and earliest clinical stages of AD from healthy adults.

Massachusetts General Hospital researchers recently found that category fluency clustering on that test—naming animals sequentially that are part of a subcategory—is related to AD pathophysiology in the preclinical and early stages of the disease.

Joshua T. Fox-Fuller, a doctoral candidate at Boston University participating in the Multicultural Alzheimer's Prevention Program (MAPP) in the Department of Psychiatry, Yakeel T. Quiroz-Gaviria, PhD, director of MAPP, the Multicultural Assessment and Research Center, and the Familial Dementia Neuroimaging Laboratory in the Department of Psychiatry and Department of Neurology, and colleagues report in the Journal of the International Neuropsychological Society.


Since 2015, Mass General researchers have been collaborating with colleagues in Colombia on COLBOS, a longitudinal study of the largest known extended family with the presenilin1 (PSEN1) E280A mutation, which is linked to familial AD. Carriers are nearly certain to develop AD, usually in their forties.

Study participants live in Antioquia, Colombia, and regularly travel to Boston to undergo PET scanning for amyloid-beta and tau. The current analysis involved 29 nondemented carriers of the PSEN1 E280A mutation (seven had mild cognitive impairment) and 32 noncarrier family members. Both participants and study staff were blinded to individuals' PSEN1 status.

Spanish-speaking neuropsychologists conducted clinical and cognitive testing at the University of Antioquia, including the Category Fluency (Animals) test. Six "clusters" of animals were prespecified: wild land animals, animals that live in the water, animals found on a farm, birds, pets (non-farm), and insects.


Key observations were:

  • Nondemented carriers of the PSEN1 E280A mutation and age- and education-matched noncarrier family members did not differ in the total numbers of animals named or the number of animals named within clusters
  • However, relative to noncarriers, carriers exhibited a stronger negative association between category fluency clustering and levels of amyloid and tau protein
  • Category fluency clustering was more strongly negatively correlated with age—a proxy for disease progression in autosomal dominant AD—in both nondemented mutation carriers and cognitively unimpaired carriers, relative to noncarrier family members

Research Implications

The relationship between amyloid and tau burden and animal fluency clustering in this sample suggests AD pathophysiology has subtle effects on word retrieval and semantic access early on—including in the preclinical stage.

Cognitive tests are faster to administer, less invasive, more accessible, and less expensive than PET and other techniques currently used to assess for early AD. The COLBOS team plans to continue investigating which cognitive tests (and subcomponents of those tests) are highly sensitive in identifying good candidates for preventive and therapeutic AD interventions.

Learn more about research in the Department of Psychiatry

Learn more about the Multicultural Alzheimer's Prevention Program


Researchers at Massachusetts General Hospital have identified some of the earliest brain changes associated with the risk to develop Alzheimer's disease by studying a kindred with the PSEN1 E280A gene mutation.


Massachusetts General Hospital researchers found an MRI measure of locus coeruleus (LC) integrity starts declining about 12 years before symptom onset in autosomal dominant Alzheimer's disease. This and related findings suggest LC integrity is a promising prognostic indicator in the preclinical stage of the disease.