When Alzheimer's is LATE: Why Does it Matter?

Abstract

Recent therapeutic advances provide heightened motivation for accurate diagnosis of the underlying biologic causes of dementia. This review focuses on the importance of clinical recognition of limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE affects approximately one-quarter of older adults and produces an amnestic syndrome that is commonly mistaken for Alzheimer's disease (AD). Although AD and LATE often co-occur in the same patients, these diseases differ in the protein aggregates driving neuropathology (Aβ amyloid/tau vs TDP-43). This review discusses signs and symptoms, relevant diagnostic testing, and potential treatment implications for LATE that may be helpful for physicians, patients, and families. ANN NEUROL 2023;94:211-222.

Figure 1.. A pie chart depicts the relative contributions of different neuropathologic entities to amnestic (“Alzheimer’s type”) dementia in a large community-based cohort.

These data derive directly from an attributable risk analyses as described in detail in Refs^, . The research volunteers were from two large community-based studies of aging from Rush University (n=1,161 participants were included); mean age at death was 89.7 years. Multi-variable logistic regression models examined associations between the outcome of Alzheimer’s-type (eg. amnestic) dementia with neuropathologic indices. Vascular pathologies included large infarcts, arteriolosclerosis, atherosclerosis in the Circle of Willis, and cerebral amyloid angiopathy.

Figure 2.. Clinical and imaging characteristics of a prototypical “pure” LATE-NC case (#1, age 93 years at death) and a “mixed” AD-NC & LATE-NC case (#2 age 90 years at death).

A) Longitudinal CDR-SOB scores show a more severe rate of decline over the three years prior to death for Case #2 (“mixed” LATE-NC) compared to Case #1 (“pure” LATE-NC). B) T1 MRI coronal image in Case #1 (“pure” LATE-NC) at first diagnosis of MCI, 3 years prior to death and autopsy, demonstrating left greater than right hippocampal atrophy. C) ¹⁸F-Florbetapir PET axial image demonstrating no significant amyloid accumulation (SUVr 1.04) one year prior to death and autopsy for Case #1 (“pure” LATE-NC), compared to D) a prototypic AD case with SUVr 1.73. E) Severe bilateral hippocampal atrophy is seen in a T1 MRI coronal image of Case #2 (“mixed” AD-MC & LATE-NC) one year prior to death and autopsy. The cerebrospinal fluid ptau181/Ab42 ratio was 0.15in Case #2 demonstrating antemortem evidence for Alzheimer’s disease. Cases presented are from the University of Kentucky AD Research Center (UK-ADRC) cohort. Use of the clinical, biofluid, and imaging data presented in this figure was approved by the University of Kentucky IRB.

Figure 3.. Hippocampal sclerosis in aging is associated with LATE-NC and dementia, not with seizure disorders.

During clinical workup, the findings on structural MRI (representative example shown in Panel A) usually show marked anterior middle temporal lobe atrophy, particularly in the amygdala (green arrow) and anterior hippocampus (red arrow). Most HS in aging is a subset of LATE-NC. In community-based cohorts such as those followed at Rush University Medical Center, approximately 1/3^rd of LATE-NC cases show HS at autopsy (see Venn diagram; Panel B). A smaller percentage of individuals show HS without LATE-NC; these are a different disease categories that may include vascular, metabolic, and anoxic changes. The primary data for this chart were derived from Ref. HS is not primarily associated with seizures in older subjects. For example, in 678 subjects from the UK-ADRC cohort (panel C), among those with autopsy proven HS, 8.1% with seizure history, whereas in those lacking HS, 7.1% had seizures. As was shown in a larger multicenter cohort previously, this difference was not statistically significant at P<0.05.

Figure 4.. A stacked-bar chart helps convey the differences of pathologic features seen in different age groups of dementia patients.

Notably, “pure” severe Alzheimer’s disease neuropathologic changes (AD) is predominantly in relatively young individuals, whereas most subjects with dementia with onset in advanced age have LATE-NC, either with or without comorbid severe AD. These data were from the University of Kentucky ADRC autopsy cohort (n=378 dementia subjects), and are in agreement with prior studies in this and other cohorts^{, , , ,} .

Figure 5.. A schematic diagram depicts two different perspectives of how LATE-NC may relate to new anti-Aβ amyloid therapeutic strategies.

In the red text are aspects that may be directly affected by anti-Aβ amyloid biological medications. It is credible but presently unknown whether “downstream” TDP-43 pathology will be affected by those new medicines. In the purple text are pathologic features that may still occur despite AD-oriented medicines; these may require new LATE-NC (TDP-43 and/or HS) tailored therapeutic strategies.