Differential brain atrophy and neurogenetic profiles in cognitively-defined Alzheimer's disease subgroups
Michel J Grothe,
Anna Catharina van Loenhoud,
Shannon L. Risacher,
Andrew J Saykin,
Christine L Mac Donald,
Emily H. Trittschuh,
Yolande A.L. Pijnenburg,
Wiesje M. van der Flier,
Paul K Crane,
Posted 04 Aug 2020
bioRxiv DOI: 10.1101/2020.08.04.235762
Posted 04 Aug 2020
Elucidating mechanisms underlying the clinical heterogeneity observed among individuals with Alzheimer's disease (AD) is key to facilitate personalized treatments. We categorized 679 individuals with AD into subgroups based on a relative impairment in one cognitive domain (i.e. AD-Memory, AD-Executive-Functioning, AD-Language and AD-Visuospatial-Functioning). We compared atrophy patterns derived from MRI and identified patterns that closely matched the respective cognitive profiles, i.e. medial temporal lobe atrophy in AD-Memory, fronto-parietal in AD-Executive-Functioning, asymmetric left-temporal in AD-Language, and posterior in AD-Visuospatial-Functioning. We then determined spatial correlations between subgroup-specific atrophy and a transcriptomic atlas of gene expression, which revealed both shared (e.g. mitochondrial respiration and synaptic function/plasticity) and subgroup-specific (e.g. cell-cycle for AD-Memory, protein metabolism in AD-Language, and modification of gene expression in AD-Visuospatial-Functioning) biological pathways associated with each subgroup's atrophy patterns. We conclude that cognitive heterogeneity in AD is related to neuroanatomical differences, and specific biological pathways may be involved in their emergence. ### Competing Interest Statement Philip Scheltens has received consultancy/speaker fees (paid to the institution) from Biogen, People Bio, Roche (Diagnostics), Novartis Cardiology. He is PI of studies with Vivoryon, EIP Pharma, IONIS, CogRx, AC Immune and Toyama. Research programs of Wiesje van der Flier have been funded by ZonMW, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, CardioVascular Onderzoek Nederland, Health~Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Pasman stichting, Biogen MA Inc, Boehringer Ingelheim, Life-MI, AVID, Roche BV, Janssen Stellar, Combinostics. Wiesje van der Flier has performed contract research for Biogen MA Inc and Boehringer Ingelheim. Wiesje van der Flier has been an invited speaker at Boehringer Ingelheim and Biogen MA Inc. All funding is paid to her institution. Frederik Barkhof has been consulting for Biogen, Merck, Bayer, Novartis, Roche and IXICO. Rupert Lanzenberger received travel grants and/or conference speaker honoraria within the last three years from Bruker BioSpin MR, Heel, and support from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of BM Health GmbH since 2019. The other authors report no disclosures.
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