Limbic-Predominant Age-Related TDP-43 Encephalopathy

Limbic predominant age related TDP-43 encephalopathy (LATE) is a neurodegenerative disease with deposition of TDP-43 protein in the amygdala, hippocampus and middle frontal gyrus, causing an amnestic dementia that resembles Alzheimer disease. It usually affects people over 80.

It is present at autopsy in a substantial proportion of people over 80, often alongside Alzheimer pathology, which worsens cognitive decline.

Pathophysiology. Misfolded, phosphorylated TDP-43 accumulates in neurons, with neuronal loss and hippocampal sclerosis in many cases. Genetic associations include TMEM106B, GRN and APOE. Vascular disease, Alzheimer and Lewy pathologies often coexist.

Slowly progressive memory loss with relatively preserved other domains, later onset and slower decline than Alzheimer disease. Functional loss is typically mild to moderate over years. Behavioural change is less prominent.

Definite diagnosis needs neuropathology. Clinically, suspect it in a very old person with amnestic dementia, disproportionate hippocampal atrophy on MRI, medial temporal hypometabolism on fluorodeoxyglucose PET and negative amyloid and tau biomarkers. Specific biomarkers are not yet available. Exclude reversible causes.

Differential diagnosis.

• Alzheimer disease and primary age related tauopathy.
• Hippocampal sclerosis of ageing and vascular cognitive impairment.
• Frontotemporal dementia and depression.

No specific treatment. Cholinesterase inhibitors and memantine may be tried for symptoms but benefit is unproven. Control cardiovascular risk factors, treat hearing loss and depression, encourage activity and social engagement, and plan for support and capacity decisions.

Monitoring. Cognition, function and carer strain every 6 to 12 months.