The Alzheimer disease continuum : findings from monogenic Alzheimer disease

Alzheimer disease (AD), with accumulation of typical deposits of amyloid-beta (AB) and phosphorylated tau, starts to develop in the CNS many years before the onset of early clinical symptoms. The perception of AD has evolved and it is in- creasingly recognized as a biological entity, not just a distinct clinical phenotype. It has been proposed that the presence of a deterministic mutation or the pres- ence of pathological levels of biomarkers that are surrogate measures to detect AD neuropathological change (AB plaques and tau neurofibrillary tangles), will de- fine whether an individual is on the AD continuum. Concordantly, the AD contin- uum spans over both asymptomatic and symptomatic phases. Autosomal domi- nant AD (ADAD) is caused by deterministic genetic variants in the APP, PSEN1 and PSEN2 genes. Such mutations elicit early-onset disease, with the first symptoms observed before the age of 65 years. Studies of ADAD families provide a unique and important model for investigation of the natural progression of AD patho- physiology and symptoms. In Sweden, the Familial Alzheimer Disease (FAD) study has been ongoing at Karolinska Institutet since the 1990's. This longitudinal obser- vational study enrolls relatives with 50% risk of developing AD and the research protocol includes sampling of biofluids, brain MRI, electroencephalography and neurocognitive testing. The objective of this thesis was to continue profiling of ADAD and investigate novel clinical, biofluid and genetic biomarkers for AD in or- der to explore preclinical and clinical phases of AD pathophysiology, monitor dis- ease severity and improve the diagnostic work-up.

In Study I, we found that plasma concentrations of glial fibrillary acidic protein (GFAP), tau phosphorylated at position 181 (p-tau181) and neurofilament light chain (NfL) all started to increase in the presymptomatic phase and, thus, are potential biomarkers for monitoring asymptomatic individuals on the AD continuum. Eleva- tions of plasma GFAP concentrations were the earliest to be detected, supporting that this is a sensitive marker in presymptomatic AD.

In Study Il we investigated plasma AB concentrations over the AD continuum by mutation type, due to strong variant-specific effects. In the Swedish double mu- tation (APP p.KM670/671NL), AB peptides were more than 3-fold increased in both presymptomatic and symptomatic mutation carriers compared to non-carrier controls at baseline. Thus, measurement in clinical routine would indirectly confer the risk of disclosing mutation status. Plasma Aß did not correlate to CSF AB levels, nor did longitudinal results suggest any mutation-specific effects on AB42/40 ratio with increasing age. Thus, the results did not support the utility of plasma AB measurement in ADAD.

Study III included analyses of transient global topographies or maps of summated neuronal potentials, i.e microstates, as recorded by electroencephalography (EEG). The EEG microstate methodology was employed for the first time in ADAD, and the results pointed out selective changes associated with either clinical symptoms or mutation status. Albeit exploratory, the findings shed light on the activity of intrinsic global neuronal networks over the AD continuum and may be hypothesis-generating for future work in the field.

Lastly, Study IV reported biomarker results and clinical characteristics from a novel C-terminally located APP (p.I718M) mutation, not previously described, po- tentially causative of both AD and mixed AD-DLB phenotypes.

In summary, this thesis integrated studies of fluid and novel EEG biomarkers over the AD continuum. Also, biomarker profiles and clinical characteristics of a novel APP mutation were systematically described. The findings may be crucial for psy- chosocial support and genetic counselling to specific families, advance the gen- eral understanding of pathogenic variants and, thus, may be of importance for the ADAD community worldwide.

List of scientific papers

I. Johansson C, Thordardottir S, Laffita-Mesa J, Rodriguez-Vieitez E, Zetterberg H, Blennow K, Graff C. Plasma biomarker profiles in autosomal dominant Alzheimer's disease. Brain. 2023 Mar 1;146(3):1132- 1140. https://doi.org/10.1093/brain/awac399

II. Johansson C, Thordardottir S, Laffita-Mesa J, Pannee J, Rodriguez- Vieitez E, Zetterberg H, Blennow K, Graff C. Gene-variant specific effects of plasma amyloid-beta levels in Swedish autosomal dominant Alzheimer disease. Alzheimers Res Ther. 2024;16(1):207. https://doi.org/10.1186/s13195-024-01574-w

III. Johansson C, Koenig T, Smailovic U, Hallstrom V, Jelic V*, Graff C *. Selective association of EEG microstates with clinical symptoms and mutation status in monogenic Alzheimer disease. *Shared last authors. [Submitted]

IV. Johansson C, Rodriguez-Vieitez E, Bluma M, Nennesmo I, Thonberg H, Ullgren A, Jelic V, Zetterberg H, Blennow K, Nordberg A, Graff C. Phenotypic variability in early-onset dementia segregating with the novel APP p.I718M variant. [Submitted]