Left-handedness, learning disability, autoimmune disease, and seizure history influence age at onset and phenotypical targeting of Alzheimer’s disease

Background Risk 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). Methods In 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. Results Early-onset Alzheimer’s disease was associated with significantly lower frequencies of established risk factors (hypertension, hyperlipidemia, diabetes mellitus, all p <0.001, APOE -ɛ4, p =0.03) and significantly higher frequencies of novel factors (non-right-handedness, learning disability, active seizure, all p <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). Conclusions We 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. ### Competing Interest Statement ZAM reports no relevant disclosures. RO has been an associate editor for Alzheimer's Research & Therapy, since 2018. NGR is partly funded by the David Eisenberg Mayo Clinic Professorship. IEA reports no relevant disclosures. WS reports no relevant disclosures. LR reports no relevant disclosures. DJO reports no relevant disclosures. KE reports no relevant disclosures. AK reports no relevant disclosures. MGE has received consultancy fees from Biogen. PMB is currently employed at Biogen but solely contributed to this work during fellowship at the UCSF Memory and Aging Center. SS reports receiving consulting fees from Acsel Health, Precision Xtract, and Techspert.io. JY reports grants from the National Institute on Aging during the conduct of the study, grants from National Institute on Aging, Rainwater Charitable Foundation, Transposon Therapeutics, Alector, and the US Department of Defense, and other support from the Mary Oakley Foundation and French Foundation outside the submitted work. RSD reports no disclosures. WMVDF is guest editor Alzheimer Research Therapy (series on SCD, 2018-2019); associate editor Alzheimer Research Therapy (2020 -). PS has received consultancy fees (paid to the institution) from AC Immune, Alkermes, Alnylam, Alzheon, Anavex, Biogen, Brainstorm Cell, Cortexyme, Denali, EIP, ImmunoBrain Checkpoint, GemVax, Genentech, Green Valley, Novartis, Novo Nordisk, PeopleBio, Renew LLC, Roche; he is PI of studies with AC Immune, CogRx, FUJI- film/Toyama, IONIS, UCB, Vivoryon; he is a part-time employee of Life Sciences Partners Amsterdam; he serves on the board of the Brain Research Center. YALP reports no relevant disclosures. EEW reports no relevant disclosures. RR reports no relevant disclosures. DHG reports no relevant disclosures. JHK reports no relevant disclosures. HJR reports no relevant disclosures. KPR reports no relevant disclosures. LTG reports no relevant disclosures. WWS reports no relevant disclosures. VES reports no relevant disclosures. DCP reports no relevant disclosures. BLM reports serving on the Cambridge National Institute for Health Research Biomedical Research Centre advisory committee and its subunit, the Biomedical Research Unit in Dementia; serving as a board member for the American Brain Foundation; serving on John Douglas French Alzheimer's Foundation board of directors; serving on the Safely You board of directors; serving as scientific director for the Tau Consortium; serving as medical advisor for and receiving a grant from The Bluefield Project for Frontotemporal Dementia Research; serving as a consultant for Rainwater Charitable Foundation, Stanford Alzheimer's Disease Research Center, Buck Institute SAB, Larry L. Hillblom Foundation, University of Texas Center for Brain Health, University of Washington Alzheimer's Disease Research Center EAB, and Harvard University Alzheimer's Disease Research Center EAB; receiving royalties from Guilford Press, Cambridge University Press, Johns Hopkins Press, and Oxford University Press; serving as editor for Neurocase; serving as section editor for Frontiers in Neurology; and receiving grants P30 AG062422, P01 AG019724, R01 AG057234, and T32 AG023481 from the NIH. GDR reports grants from the National Institutes of Health, Alzheimer's Association, the American College of Radiology, Rainwater Charitable Foundation, Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, Life Molecular Imaging, and Genentech, as well as personal fees from Axon Neurosciences, Genentech, Johnson & Johnson, F. Hoffman-La Roche, and GE Healthcare outside the submitted work for service on scientific advisory boards (Axon Neurosciences, Eisai, Genentech, and F. Hoffman-La Roche) and a data safety monitoring board (Johnson & Johnson). MLGT reports no relevant disclosures. ### Funding Statement This work was supported by National Institutes of Health grants (AG048291, AG053435, AG019724, AG062422, AG045611, AG062588, DC015544, and NS050915). Additional funds include the Hellman Research Scientist Award, the Arking Foundation for Frontotemporal Dementia, and the Jon and Gale Love fund. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committees at the University of California San Francisco, Amsterdam University Medical Center, and Mayo Clinic, Jacksonville as well as all participating National Alzheimer's Coordinating Center sites approved the study of patients' clinical data. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data used in this study are available for review upon formal request. As the institutional procedures in place at the time participants' gave informed consent do not authorize open data sharing, all requests will need to undergo UCSF MAC regulated procedures including the submission of a materials transfer agreement. The requesting party will need to provide their name and affiliation as well as a brief description of their intended use of the data.