Genetic Analysis of an Amyloid PET‐Negative Autopsy‐Confirmed Alzheimer's Pedigree

• DOI: 10.1002/alz.093931
• Publication Date: 2025-01-09T10:18:43Z
• Authors: Lia Talozzi; Andrés Peña‐Tauber; Tanner D. Jensen; Edward N. Wilson; Christina B. Young; Ilaria Stewart; Inma Cobos; Kristen Vallejo; Marco M Hefti; Yann Le Guen; Kennedy Williams; Hillary Vossler; John Gorzynski; Katrin I. Andreasson; Elizabeth Mormino; Euan Ashley; Michael D Greicius
• Keywords: Amyloid (mycology)

Abstract Background Alzheimer's disease (AD) is the most common form of dementia. Neuropathologically, AD stands out as a mixed proteinopathy. Beta‐amyloid and tau biomarkers can now add in‐vivo support to diagnosis. Rarely, patient with confirmed at autopsy may have negative amyloid PET. Here we describe pedigree in whom index case was PET‐negative. We performed genetic sequencing two affected siblings identify set candidate single nucleotide variants (SNVs) structural (SVs) associated rare healthy older controls from several large databases. Method long‐read (LRS) comprehensively evaluate both SNVs SVs. The case, an APOE3/E4 male, developed memory trouble 68 that progressed probable 72. Notably (Figure 1) his amyloid‐PET scan, which be high technical quality, negative. His PET scan positive plasma Abeta42/40 expected range for Stanford patients. family history extensive suggestive autosomal dominant pattern late‐onset 2). patient's sister diagnosed 62. filtered their shared heterozygous keeping those minor allele frequency < 0.01 gnomAD were not present any ADSP (HC) over 70y.o. (N=19771;62.1%females;81±6.4y.o). Shared SVs kept candidates if they seen LRS HC (N=95;59%females;72±1.5y.o.) Result Neuropathological analysis revealed met A3B3C3 criteria had cerebral angiopathy. Among mutations on genes expressed brain (Table 1), novel missense ADNP (Activity‐Dependent‐Neuroprotector‐Homeobox), 267bp deletion TET1 (Tet‐Methylcytosine‐Dioxygenase) identified. 3426bp insertion ATP8A2 (ATPase‐Phospholipid‐Transporting‐8A2) longest, found. Additionally, duplication (∼20Kbp) inversion (∼160Kbp) observed. Conclusion This study highlights unusual emphasizes potential utility identifying causal In future work plan perform additional stains understand why amyloid‐negative. are also assessing members improve our ability mutation.