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We recently showed that early ALS patients and presymptomatic carriers of ALS\u2010associated gene mutations display altered sleep macroarchitecture, characterised by increased wakefulness and decreased non\u2010REM sleep, together with altered microarchitecture, particularly reduced slow oscillations and sleep spindles. Here we aimed at determining whether sleep alterations are progressive in premanifest carriers of ALS\u2010associated gene mutations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This longitudinal observational cohort study included presymptomatic first\u2010degree relatives of ALS patients carrying pathogenic gene mutations (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200918) and noncarrier family members (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u20093). Sleep macroarchitecture and sleep microarchitecture were assessed using standardised polysomnography and electroencephalographic analyses at baseline and in a follow\u2010up examination after 2.3\u2009\u00b1\u20091.5\u2009years.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In all carriers, sleep alterations were more severe at follow\u2010up compared to the initial examination, for both macro\u2010 and microarchitecture. The progression of sleep alterations was seemingly independent of proximity to motor onset, whether evaluated by increased neurofilament levels or phenoconversion during the study period.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Sleep macro\u2010 and microarchitectural abnormalities progressively worsen during the premanifest phase of ALS. These findings suggest that polysomnography\u2010derived sleep measures and their neurochemical correlates may serve as sensitive, noninvasive surrogate biomarkers of disease progression in clinically silent ALS. This could support disease prevention, for example, by the antisense oligonucleotide tofersen in patients carrying SOD1 mutations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/ene.70755","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T11:54:13Z","timestamp":1789991653000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic\n                    <scp>ALS<\/scp>\n                    \u2014Progressive Sleep Defects Precede the Onset of Clinical Disease"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2953-7157","authenticated-orcid":false,"given":"Christina","family":"Lang","sequence":"first","affiliation":[{"name":"Department of Neurology University Hospital of Ulm  Ulm Germany"},{"name":"Deutsches Zentrum f\u00fcr Neurodegenerative Erkrankungen (DZNE)  Ulm 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