Frontotemporal dementia (FTD), a common form of early-onset dementia, is characterized by prominent changes in behavior and/or language. Diagnosing FTD is frequently challenging due to the insidious onset and nature of symptoms, and early FTD may be mistaken for other dementias or psychiatric disorders. In contrast to Alzheimer’s disease (AD), there are no tests in blood or cerebrospinal fluid (CSF) that can specifically recognize FTD.  

Postmortem brain examination in FTD most commonly shows accumulation of either tau protein (FTD-tau) or TAR DNA-binding protein 43 (FTD-TDP). Currently, we cannot determine during life which of these subtypes is the culprit in an individual with FTD. Since treatments will likely target specific subtypes, a test to identify the subtype and select suitable patients for clinical trials is crucial.

Acetylated tau at lysine residue 174 (acTau174) is a modified form of tau protein found in brains of patients with FTD and AD. Tau acetylation promotes accumulation of tau and neurodegeneration, and in mice, inhibiting tau acetylation ameliorates cognitive decline, making it a promising therapeutic target. We developed a test to measure acTau174 in CSF and found elevated levels in FTD and AD patients, probably reflecting cerebral tau acetylation. We hypothesize that acTau174 increases occur in FTD-tau, but not in FTD-TDP, and measuring CSF acTau174 might help distinguish these subtypes. Furthermore, as tau acetylation occurs early in the disease, acTau174 might help clinicians to diagnose early FTD. Finally, acTau174 could be a target engagement marker in trials aiming to reduce tau acetylation.

In this study, we will extend our CSF acTau174 measurements across a larger group of subjects from independent cohorts, including FTD pathological subtypes, and aim to develop a blood test for acTau174. In parallel, we will investigate the amount and location of acTau174 in brain tissue of FTD  and various other dementias.