Cognitive Outcomes in Autosomal-Dominant Alzheimer’s Disease: A Comprehensive Review from a Colombian Kindred with the Presenilin-1 E280A Mutation

Article type: Review Article

Authors: Giudicessi, Averi^{a; b} | McDowell, Celina Pluim^{a; b} | Martinez, Jairo E.^{a; b} | Baena, Ana^c | Vila-Castelar, Clara^b | Norton, Daniel^d | Aguirre-Acevedo, Daniel C.^c | Tirado, Victoria^{c; e} | Bocanegra, Yamile^c | Guzman-Velez, Edmarie^a | Lopera, Francisco^c | Cronin-Golomb, Alice^{a; b} | Quiroz, Yakeel T.^{a; b; f; *}

Affiliations: [a] Department of Psychological and Brain Sciences, Boston University, Boston, MA, USA | [b] Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA | [c] Grupo de Neurociencias de Antioquia, Facultad de Medicina, Medellin, Colombia | [d] Gordon College, Department of Psychology, Wenham, MA, USA | [e] Hospital Pablo Tobon Uribe, Medellin, Colombia | [f] Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Correspondence: [*] Correspondence to: Yakeel T. Quiroz, PhD, Associate Professor, Harvard Medical School, Departments of Psychiatry and Neurology, Massachusetts General Hospital, 39 1st Avenue, Suite 101, Charlestown, MA 02129, USA. Tel.: +1 617 643 5944; E-mail: yquiroz@mgh.harvard.edu.

Abstract: Background:The largest identified kindred worldwide with a single mutation causing autosomal-dominant Alzheimer’s disease (ADAD) is a family from Antioquia, Colombia, carrying the Presenilin-1 (PSEN1) E280A (Paisa) mutation. The majority of mutation carriers develop dementia, typically commencing in their late 30 s, with a median onset age of 49 years. Cognitive decline is a hallmark feature. Objective:This review synthesizes the existing literature on neuropsychological assessments in PSEN1 E280A mutation carriers throughout their lifespan. We provide a comprehensive overview of cognitive outcomes in this unique population. Methods:We reviewed and integrated the published research, analyzing studies on neuropsychological assessments in PSEN1 E280A carriers. Our focus was on measures of verbal, semantic, episodic, and spatial memory, and encompassed other cognitive domains such as language, attention, visuospatial memory, and executive functioning. Results:Verbal, semantic, episodic, and spatial memory emerged as the most sensitive indicators of preclinical changes in PSEN1 E280A carriers. Inconsistencies were noted in findings from tests assessing language, attention, visuospatial memory, and executive functioning, suggesting potential limitations in detecting early cognitive changes in PSEN1 mutation carriers. Specific cognitive tasks developed for this population proved effective but underutilized. Conclusions:The review underscores the importance of continued test development tailored to detect early cognitive changes in PSEN1 E280A carriers, potentially enhancing ADAD screening. Furthermore, investigating ADAD mutations in children may identify early changes in AD and enhance our understanding of neuropsychological functioning across the lifespan. This synthesis provides valuable insights for researchers, clinicians, and policymakers engaged in the study and management of ADAD.

Keywords: Alzheimer’s disease, autosomal dominant Alzheimer’s disease, cognitive measures, cognitive outcomes, dementia, early detection, familial AD, preclinical AD

DOI: 10.3233/JAD-240360

Journal: Journal of Alzheimer's Disease, vol. 101, no. 2, pp. 397-415, 2024