In 2014, Yakeel Quiroz, PhD launched COLBOS (Colombia-Boston), a longitudinal, collaborative study between the Universidad de Antioquia, Colombia, and Massachusetts General Hospital, Boston, allowing investigators to use various techniques, including neuroimaging, to study the largest cohort of individuals with autosomal dominant Alzheimer’s disease (ADAD). In this kindred, those who develop AD have a single mutation in the gene coding for the amyloid precursor protein, presenilin 1 (PSEN-1); carriers of the Presenilin-1 E280A mutation experience early onset of AD, typically in their mid-40s.
Carriers of the PSEN-1 E280A mutation provide a unique opportunity for researchers to study the pathogenesis of Alzheimer’s disease. The hope is that, by studying carriers of the PSEN-1 mutation with preclinical AD, before cognitive changes occur, it may be possible to identify the earliest signs of this disease in the brain and to find biomarkers that could be used to identify individuals at risk for AD. Ideally these biomarkers would also help to identify early signs of AD in those with non-familial forms of AD.
Verbal Fluency as an Early Sign of Alzheimer’s Dementia
In a recent study, Quiroz and her research team from the Multicultural Alzheimer’s Prevention Program (MAPP) investigated whether performance on a test of verbal fluency is associated with markers of AD brain pathology in the preclinical and early stages of AD.
In individuals with Alzheimer’s disease, previous studies have demonstrated that changes in verbal fluency, particularly category fluency, occur relatively early in the course of illness. The category fluency test (animal naming) has been widely used and studied; in this test, subjects are asked to name as many animals as they can in one minute. Total scores on this test — the number of animals named — are lower in those with AD; however, recent research indicates that certain elements of category fluency, such as clustering (naming animals sequentially that belong to a subcategory, such as domestic animals) may be more sensitive in terms of detecting early cognitive changes associated with AD.
In this study, a total of 29 carriers of the Presenilin1 E280A ADAD mutation without dementia and 32 non-carrier family members completed the category fluency test (Animals) and the Mini-Mental State Examination (MMSE). The participants also underwent positron emission tomography (PET) scans to evaluate accumulation of amyloid-beta in the neocortex and tau in the medial temporal lobe regions.
Total scores on the category fluency test did not differ between carriers and non-carriers. However, carriers showed a stronger association between animal fluency clustering and AD brain pathology visualized with PET (neocortical amyloid and entorhinal tau) compared to non-carriers.
What’s Next?
The relationship between amyloid and tau accumulation in the brain and category fluency clustering in this sample suggests that changes in the brain AD pathophysiology have subtle effects on word retrieval and semantic access early on in the course of the illness, even before other measures of cognitive functioning are affected.
While PET and other techniques may be used to identify changes in the brain prior to the onset of cognitive changes in individuals with AD, tests of verbal fluency are easier to administer, more accessible, less invasive, and less expensive. The COLBOS team will continue to investigate which cognitive tests are the most sensitive in identifying individuals with preclinical AD with the goal of identifying those who may be good candidates for preventative and therapeutic interventions.
Other researchers involved in this project include Defne Yucebas, Joshua Fox-Fuller, Alex Badillo Cabrera, Ana Baena, Celina Pluim McDowell, Paula Aduen, Clara Vila-Castelar, Yamile Bocanegra, Victoria Tirado, Justin S Sanchez, Alice Cronin-Golomb, and Francisco Lopera.
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Yucebas D, Fox-Fuller JT, Badillo Cabrera A, Baena A, Pluim McDowell C, Aduen P, Vila-Castelar C, Bocanegra Y, Tirado V, Sanchez JS, Cronin-Golomb A, Lopera F, Quiroz YT. Associations of category fluency clustering performance with in vivo brain pathology in autosomal dominant Alzheimer’s disease. J Int Neuropsychol Soc. 2023 Apr 26:1-7.
COLBOS Study Reveals Mysteries of Alzheimer’s Disease (NIH Record)
Yakell Quiroz, PhD is the Director of the MGH Familial Dementia Neuroimaging Lab and the Multicultural Alzheimer’s Prevention Program (MAPP) and is an Associate Professor in the Departments of Psychiatry and Neurology at Harvard Medical School. Her research focuses on the study of the neural underpinnings of memory dysfunction in the preclinical stages of Alzheimer’s disease (AD). By applying her efforts to the world’s largest family with a single, early onset AD-causing mutation (E280A in PSEN1), her research has provided evidence of brain abnormalities in individuals at genetic risk for AD decades before their clinical onset.
