Left-handedness, learning disability, autoimmune disease, and seizure history influence age at onset and phenotypical targeting of Alzheimer’s disease
Authors: Miller Zachary A. , Ossenkoppele Rik , Graff-Radford Neill R. , Allen Isabel E. , Shwe Wendy , Rosenberg Lynne , Olguin Dustin J , Erkkinen Michael G. , Butler P. Monroe , Spina Salvatore , Yokoyama Jennifer S. , Desikan Rahul S. , Scheltens Philip , van der Flier Wiesje , Pijnenburg Yolande , Wolters Emma , Rademakers Rosa , Geschwind Daniel H. , Kramer Joel H. , Rosen Howard J. , Rankin Katherine P. , Grinberg Lea T. , Seeley William W. , Sturm Virginia , Perry David C. , Miller Bruce L. , Rabinovici Gil D. , Gorno-Tempini Maria Luisa 
Published: December 2022

AbstractBackgroundRisk factors associated with sporadic non-amnestic and early-onset Alzheimer’s disease remain underexamined. We investigated a large, clinically heterogeneous Alzheimer’s disease cohort for frequencies of established Alzheimer’s disease risk factors (hypertension, hyperlipidemia, diabetes mellitus,APOE-ɛ4 frequency, and years of education), alongside a suite of novel factors with historical theoretical association (non-right-handedness, learning disability, seizures, and autoimmune disease).MethodsIn this case-control study, we screened the demographic and health histories of 750 consecutive early-onset and 750 late-onset Alzheimer’s disease patients from the University of California San Francisco Memory and Aging Center for the prevalence of conventional risk and novel Alzheimer’s disease factors and compared these results with 8,859 Alzheimer’s disease individuals from the National Alzheimer’s Coordinating Center, Amsterdam University Medical Center, Amsterdam, and Mayo Clinic, Jacksonville.ResultsEarly-onset Alzheimer’s disease was associated with significantly lower frequencies of established risk factors (hypertension, hyperlipidemia, diabetes mellitus, allp<0.001,APOE-ɛ4,p=0.03) and significantly higher frequencies of novel factors (non-right-handedness, learning disability, active seizure, allp<0.001, remote seizure,p=0.002, and autoimmune disease,p=0.007). Logistic regressions predicting EOAD vs. LOAD controlling for sex, education,APOE-ɛ4 status, typical, and novel risk factors, produced findings consistent with the above. Principal component analysis loaded novel factors into two components, non-right-handedness and learning disability versus seizure and autoimmune disease, and the combination of factors from both components resulted in an exponential decrease in age at onset from any single factor alone.APOE-ɛ4 provided no additional contribution to age at onset decreases within the non-amnestic Alzheimer’s disease cohort but shifted the age of onset 3 years earlier within amnestic presentations (p=0.013).ConclusionsWe identified non-right-handedness, learning disability, seizures, and autoimmune disease as novel factors that affect both the age at onset and phenotypical targeting of Alzheimer’s disease. Together these results support a new theoretical framework of neurodegenerative disease susceptibility and that through the collection of detailed developmental and health history, neurodegenerative disease risk in some may be highly predictable, offering new opportunities towards early detection, monitoring, therapeutic intervention, and ultimately disease prevention.