Apathy, an early marker of frontotemporal dementia (FTD), progresses significantly in presymptomatic carriers of microtubule-associated protein tau (MAPT), progranulin (GRN), or chromosome 9 open reading frame 72 (C9orf72) mutations, and baseline differences in the symptom predict the severity of prospective cognitive decline, researchers found in a study published in Alzheimer’s & Dementia. Atrophy of the frontal lobe and cingulate gyrus at baseline is associated with the progression of apathy over 2 years.

The researchers studied longitudinal changes in apathy and association with subclinical cognitive decline in 304 presymptomatic gene carriers (54 with mutation in MAPT, 142 in GRN, and 108 in C9orf72) and 296 family members without mutations (noncarrier control group) in the international Genetic FTD Initiative (GENFI). They evaluated the participants’ symptomatic status and cognitive performance at baseline and annually for 2 years with the revised Cambridge Behavioural Inventory (CBI-R; using its motivation subscale to test apathy severity), Digit Span Backwards from the Wechsler Memory Scale-Revised, Trail Making Test B (TMT-B), and the Wechsler Adult Intelligence Scale – Revised (WAIS-R) Digit Symbol Substitution test.

Presymptomatic carriers had higher baseline apathy scores (P =.015). They showed a longitudinal increase in apathy severity over a 2-year period (estimate [est], 0.511; standard error (SE), 0.177; z-value, 2.879; P =.004) that was greater than that seen in noncarriers (est, 0.084; SE, 0.081; z-value, 1.036; P =.300).

The rate of cognitive decline in presymptomatic carriers (est, -0.077; SE, 0.031; z-value, -2.487; P =.013), was greater than that seen in noncarriers (est, 0.002; SE, 0.023; z-value, 0.107; P =.915), was faster when approaching the estimated age of onset, and was predicted by baseline apathy severity. The model on Digit Symbol longitudinal scores, including baseline CBI-R apathy scores as a predictor, showed a significant decline only in presymptomatic carriers (est, -0.064; SE, 0.031; z-value, -2.095; P =.036), with a significant effect of the baseline apathy severity on the rate of cognitive decline (est, -0.038; SE, 0.014; z-value, -2.652; std est, -0.395; P =.008).

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Annual progression of apathy severity was associated with baseline gray matter volumes in the frontal lobe (est, -0.208; SE, 0.100; z, -2.077; std est, -0.348; P =.038) and cingulate cortex (est, -0.139; SE, 0.058; z, -2.085; std est, -0.237; P =.037).

Presymptomatic carriers showed progressive atrophy in the frontal, temporal, and parietal lobes, cingulate cortex, and subcortical central structures while noncarriers had no significant structural changes in those regions.

Limitations of the study include the WAIS-R Digit Symbol test’s possible reflection of generalized cognitive decline rather than executive dysfunction deficits.

“Apathy may also be a modifiable factor in its own right, by pharmacological or nonpharmacological interventions,” the researchers said. “As such, it becomes a potential target not only for symptomatic treatment but also interventions to slow down or delay clinical decline in people at risk of FTD.”


Malpetti M, Jones PS, Tsvetanov KA, et al. Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes. Alzheimer’s & Dementia. Published online December 14, 2020. doi:10.1002/alz.12252