NEURODEVELOPMENTAL DIFFERENCES AND ENVIRONMENTAL INSULTS INVERSELY CORRELATE WITH AGE OF ONSET IN ALZHEIMER’S DISEASE

Surprisingly little is known about the demographics of sporadic early onset Alzheimer's disease (EOAD). To address this shortcoming, we investigated a large EOAD cohort for the prevalence of typical late onset Alzheimer's disease (LOAD) associated risk factors (education, APOE ɛ4 allelic frequency, hypertension, hypercholesterolemia, and diabetes) alongside a suite of novel factors we had previously observed as relevant to pre-senile dementia syndromes (non-right-handedness, learning disability, autoimmune disease, seizure). Method: We screened 750 EOAD and 750 LOAD from the University of California San Francisco Memory and Aging Center for the prevalence of typical Alzheimer's disease (AD) risk and novel factors. To validate our findings, we assessed external cohorts of ∼9,000 AD from the National Alzheimer's Coordinating Centers, VU University Medical Center, Amsterdam, and Mayo Clinic, Jacksonville. Result: EOAD and LOAD were no different in APOE ɛ4 allelic frequency or education. EOAD possessed significantly lower frequencies of hypertension, hypercholesterolemia, and diabetes, and higher frequencies of non-right-handedness, learning disability, seizure, autoimmune disease, as well as non-amnestic AD presentations. All differences between EOAD and LOAD survived separating out non-amnestic AD, further, comparisons between these three cohorts demonstrated lowest APOE ɛ4 and highest autoimmune frequencies in non-amnestic AD. Age at onset displayed inverse relationships with novel factors and maximal differences between novel and typical factors occurred at age 69.2. Novel factors loaded into two principal components, non-right-handedness and learning disability vs. seizure and autoimmune disease. The pattern of overrepresented autoimmune diseases in MAC and validated cohorts were nearly identical (and based on known pathophysiology, implicate Fcγ and IL-12/23 pathways in the pathogenesis of AD). Conclusion: We identified a group of novel factors within AD that predict age of onset, distinguish early onset and non-amnestic AD from LOAD, act independently of and synergistically with APOE ɛ4, and support a data driven approach towards redefining EOAD as a disorder with first symptoms of <70 years of age. The observed neurodevelopmental signatures provide powerful new opportunities for individualized disease prediction (for both age at onset and phenotypic presentation), while the association between selective autoimmunity and seizure support development of innovative strategies for monitoring, prevention, and therapeutic intervention.