Toggle Main Menu Toggle Search

Open Access padlockePrints

Novel presenilin 1 mutation with profound neurofibrillary pathology in an indigenous Southern African family with early-onset Alzheimer's disease

Lookup NU author(s): Dr Roger Low, Dr Harpal Rao, Dr Christopher Morris, Professor Raj Kalaria


Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


Genetically determined Alzheimer's disease (AD) is virtually unknown in Africa. We report clinicopathological findings and a presenilin 1 (PS1) mutation associated with early-onset AD in a large Xhosa family from Southern Africa. Twelve individuals spanning four generations were affected, four of whom underwent clinical and psychometric evaluation. Their phenotype was characterized by memory impairment beginning in the early part of the fifth decade, with progressive dementing illness lasting 6-7 years that did not appear to be modified by the presence of an apolipoprotein E (APOE)-epsilon4 allele. Initial linkage-based analysis using known DNA markers suggested allele cosegregation with a locus on chromosome 14. Direct sequencing of the PS1 gene disclosed a novel I143M (ATT to ATG at nucleotide 677) mutation that lies in a cluster in the second transmembrane domain of the protein. Examination of the proband's brain at autopsy revealed severe AD pathology characterized by neuronal loss, abundant beta amyloid (Abeta) neuritic plaques (Abeta42) and neurofibrillary degeneration extending into the brainstem. The phenotype of the I143M mutation was clearly associated with a high degree of neurofibrillary change compared with early-onset sporadic AD cases. Although sporadic cases of AD do exist in African populations, our study confirms the existence of early-onset familial AD among indigenous Southern Africans.

Publication metadata

Author(s): Heckmann JM, Low WC, de Villiers C, Rutherfoord S, Vorster A, Rao H, Morris CM, Ramesar RS, Kalaria RN

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2004

Volume: 127

Issue: 1

Pages: 133-142

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press


DOI: 10.1093/brain/awh009


Altmetrics provided by Altmetric