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UBC Theses and Dissertations

Gene discovery in individuals from families indicative of Mendelian forms of late onset Alzheimer disease Greenwood, Talitha


Globally, approximately 35.6 million people live with dementia, with a yearly incident increase of approximately 7.7 million. Factoring in the aging population and increasing life expectancies, current projections predict that by 2050, global prevalence of dementia will reach 155 million. Alzheimer disease (AD) is the most common cause of dementia accounting for 60-80% of cases. AD is a complex and genetically heterogeneous condition. Most cases are the result of multifactorial inheritance with advancing age being the greatest contributor to risk; however, approximately 5% of AD occurs in the context of a dominant family history. Because there is such a strong association between young onset age (before age 60-65) and dominantly inherited AD, it is unclear how often late-onset Alzheimer disease (LOAD) is due to single gene inheritance. We hypothesize that LOAD in multi-incident families is, at times, caused by single gene mutation, in either the 3 genes known to cause early-onset AD (PSEN1, PSEN2 and APP) or genes not previously associated with AD. Family history data from attendees of a referral-based memory disorder clinic were entered into a new comprehensive database which allowed selection of thirteen families suggestive of dominantly inherited LOAD. A targeted gene panel containing the coding region of 177 genes implicated in dementia and other neurodegenerative conditions was used to screen for pathogenic mutations in our candidate families. We identified 97 missense variants and 1 nonsense variant, including mutations in PSEN1 (p.I437V), PSEN2 (p.S130L), DNAJC13 (p.N855S), DCTN1 (p.T147A) and LMNA (p.N459S). Our findings justify offering diagnostic genetic testing to individuals symptomatic for LOAD with family histories suggestive of autosomal dominant inheritance. Currently, such testing is only offered to individuals with early-onset disease. This research also provides a useful framework for ongoing gene discovery in LOAD and other dementias utilizing the family history database and population-based DNA samples available at the University of British Columbia Hospital Clinic for Alzheimer Disease and Related Disorders (UBCH-CARD).

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