Pattern and mechanisms of atrophy progression in individuals with a family history of Alzheimer's disease: a comparative study

Alzheimer's disease (AD) includes a long period of presymptomatic brain changes. Different risk factors are associated with AD development, including having a family history of AD (FHAD). The Braak scheme suggests that tau pathology, in synergy with amyloid-beta (Aβ), spreads along structural connections in AD, eventually leading to atrophy. Studying the pathways in which atrophy spreads early on, as well as the factors underpinning this pathway, is crucial for improving diagnostic accuracy and early interventions. However, the pattern of atrophy progression in people with a FHAD and the biological factors associated with this progression remain unclear. Here we used structural MRI from three databases (ADNI, PREVENT-AD and Montreal Adult Lifespan Study) to map the atrophy progression in FHAD and AD and assess the constraining effects of structural connectivity on atrophy progression. Cross-sectional and longitudinal data up to 4 years were used to perform atrophy progression analysis in FHAD and AD compared to controls. Positron emission tomography (PET) radiotracers were also used to quantify the distribution of tau and Aβ proteins at baseline. We first derived cortical atrophy progression maps using deformation-based morphometry from 153 FHAD, 156 AD, and 116 controls with similar age, education, and sex at baseline. We next examined the spatial relationship between atrophy progression and spatial patterns of tau and Aβ deposition, structural connectivity, and neurotransmitter receptor and transporter distributions. Our results show that there were similar patterns of atrophy progression in FHAD and AD, notably in the cingulate, temporal and parietal cortices, with more widespread and severe atrophy in AD. Both tau and Aβ pathology tended to accumulate in regions that were structurally connected in FHAD and AD. The pattern of atrophy and its progression also aligned with existing structural connectivity in FHAD. In AD, our findings suggest that atrophy progression results from propagating pathology that occurred much earlier, on an intact connectome. Moreover, a relationship was found between the serotonin 5-HT6 receptors spatial distribution and atrophy progression in AD, supporting an important role of these receptors in neurodegeneration. The current study demonstrates that regions showing atrophy progression in FHAD and AD present with specific connectivity and cellular characteristics, uncovering certain of the mechanisms involved in preclinical and clinical neurodegeneration. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by grants from the Michael J Fox Foundation for Parkinson's Research, the Alzheimer's Association, the Weston Brain Institute, the Canadian Institutes of Health Research and the Healthy Brains for Healthy Lives (HBHL) initiative of McGill University. FM receive a scholarship from the Fonds de Recherche du Quebec - Sante (FRSQ). Data used in the preparation of this article were obtained from the PRe-symptomatic EValuation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) program data release 7.0. PREVENT-AD was launched in 2011 as a $13.5 million, 7-year public-private partnership using funds provided by McGill University, the Fonds de Recherche du Quebec - Sante (FRQ-S), an unrestricted research grant from Pfizer Canada, the Levesque Foundation, the Douglas Hospital Research Centre and Foundation, the Government of Canada, the Canada Fund for Innovation, the Canadian Institutes of Health Research, the Alzheimer Society of Canada, and the Alzheimer Association. Private sector contributions are facilitated by the Development Office of the McGill University Faculty of Medicine and by the Douglas Hospital Research Centre Foundation (http://www.douglas.qc.ca/). Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. ### 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: The ethics commitee of the Faculty of Medicine and Health Sciences in McGill University (Montreal, Canada) gave ethical approval for this work (IRBs:A08-M33-16B, A08-M34-16B, A05-B16-11B, A05-M54-11B, A05-M55-11B). 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes T1w-MRI and PET data used in this article were from the internal PREVENT-AD database (release 6.0) and ADNI dataset (available at https://adni.loni.usc.edu/data-samples/access-data/). The DWI data are available online at https://openpreventad.loris.ca (PREVENT-AD) and at https://adni.loni.usc.edu/data-samples/access-data/ (ADNI). All other datasets and software used are available from the sources cited in the Methods. The brain atrophy progression and PET maps, as well as the structural connectivity matrices for the FHAD and AD groups, are available upon reasonable request to the authors.