Introduction Late-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly 1 , and risk is partially driven by genetics 2 . Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS) 3–8 . To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci ( IQCK , ACE , ADAM10 , and ADAMTS1 ). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants ( P = 1.32 × 10 −7 ) indicating that additional rare variants remain to be identified.
Background: Frontotemporal dementia (FTD) often presents with varying neuropsychiatric symptoms (NPS), which may differ based on genetic mutations. We hypothesized distinct NPS trajectories in FTD progression among carriers of chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN), and microtubule-associated protein tau (MAPT) mutations. Methods: We analyzed 1662 participants from ALLFTD, including 342 C9orf72, 148 GRN, 168 MAPT mutation carriers, and 1004 noncarriers. We categorized participants into four stages based on CDR plus NACC FTLD global scores: 1) Presymptomatic (consistent CDR=0), 2) Early conversion (CDR increasing from 0 to 0.5), 3) Advanced conversion (CDR increasing from 0.5 to ≥1.0), and 4) Symptomatic (CDR>1.0). The Neuropsychiatric Inventory-Questionnaire (NPI-Q) assessed NPS changes, analyzed using a mixed-effects model, accounting for age and baseline scores. Results: Our results indicated similar NPS trajectories in the presymptomatic stage for all groups. Notably, during early conversion, C9orf72 and GRN carriers exhibited significantly higher NPI-Q score increases than MAPT carriers, primarily in psychosis and hyperactivity domains. In later stages, increases in NPS were similar across groups. Conclusions: This study suggests familial FTD progression, particularly in TDP-43 pathology, may involve more severe NPS like psychosis or hyperactivity, differing from tau pathology or sporadic FTD. Further research is needed to explore these distinct trajectories.
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