Pure LATE-NC: Frequency, clinical impact, and the importance of considering APOE genotype when assessing this and other subtypes of non-Alzheimer’s pathologies

Pure limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (pure LATE-NC) is a term used to describe brains with LATE-NC but lacking intermediate or severe levels of Alzheimer's disease neuropathologic changes (ADNC). Focusing on pure LATE-NC, we analyzed data from the National Alzheimer's Coordinating Center (NACC) Neuropathology Data Set, comprising clinical and pathological information aggregated from 32 NIH-funded Alzheimer's Disease Research Centers (ADRCs). After excluding subjects dying with unusual conditions, n = 1,926 autopsied subjects were included in the analyses. For > 90% of these participants, apolipoprotein E (APOE) allele status was known; 46.5% had at least one APOE 4 allele. In most human populations, only 15-25% of people are APOE ε4 carriers. ADRCs with higher documented AD risk allele (APOE or BIN1) rates had fewer participants lacking ADNC, and correspondingly low rates of pure LATE-NC. Among APOE ε4 non-carries, 5.3% had pure LATE-NC, 37.0% had pure ADNC, and 3.6% had pure neocortical Lewy body pathology. In terms of clinical impact, participants with pure LATE-NC tended to die after having received a diagnosis of dementia: 56% died with dementia among APOE ε4 non-carrier participants, comparable to 61% with pure ADNC. LATE-NC was associated with increased Clinical Dementia Rating Sum of Boxes (CDR-SOB) scores, i.e. worsened global cognitive impairments, in participants with no/low ADNC and no neocortical Lewy body pathology (p = 0.0023). Among pure LATE-NC cases, there was a trend for higher LATE-NC stages to be associated with worse CDR-SOB scores (p = 0.026 for linear trend of LATE-NC stages). Pure LATE-NC was not associated with clinical features of disinhibition or primary progressive aphasia. In summary, LATE-NC with no or low levels of ADNC was less frequent than pure ADNC but was not rare, particularly among individuals who lacked the APOE 4 allele, and in study cohorts with APOE 4 frequencies similar to those in most human populations.