Neurology: Relationship between cerebrospinal fluid GAP-43 and cognitive decline and dementia progression in amyloid-positive individuals

The accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs), as well as synaptic loss and neurodegenerative diseases, are fundamental features
of the pathophysiology of Alzheimer's disease (AD).
Tau and Aβ aggregation are known to have a subtle effect on synaptic integrity, while synaptic loss and/or synaptic degeneration are thought to be more closely related
to cognitive decline than other pathological markers of AD.

Recently, a study published in Neurology tested the horizontal and longitudinal correlation
between the presynaptic growth-associated protein 43 (GAP-43) protein and the pathophysiological biomarker of Alzheimer's disease (AD).

 In this retrospective study, GAP-43 was measured in participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort using an internal ELISA method and compared levels
cross-sectionally and longitudinally between groups.
Linear regression models tested associations
between AD biomarkers (Aβ and tau pathology, neurodegenerative diseases, and cognition) adjusted for age, sex, and diagnosis.
The linear mixed-effects model (LME) assesses how baseline GAP-43 predicts brain hypometabolism, atrophy, and cognitive decline
over time.
The Cox proportional hazards regression model tested how GAP-43 levels and Aβ status at baseline increased the risk
of progression to AD dementia over time.

This study included 786 participants from the ADNI cohort, further classified as unimpaired cognitive function (CU) Aβ-negative (nCU-= 197); CU Aβ positive (nCU = 55), mild cognitive impairment (MCI), Aβ negative (nMCI-= 228), MCI Aβ-positive (nMCI = 193), and AD dementia Aβ-positive (nAD = 113).

Compared with Aβ-negative patients, Aβ-positive patients have elevated CSF GAP-43 levels, independent of
cognitive status.
In Aβpositive participants, high baseline GAP-43 levels led to more severe decreased brain metabolism (P=0.
01), more severe brain atrophy (P=8.
8×10-27), and worse MMSE scores (P=0.
03) over time compared
to those with low GAP-43 levels.

Similarly, Aβ-positive participants with a high baseline GAP-43 had the highest risk of transitioning to AD dementia (hazard ratio [HR = 8.
56, 95% CI, 4.
94-14.
80, P = 1.
5x10-14]).

。 Although significantly associated with Aβ pathology (η2Aβ PET = 0.
09, PAβ PET < 0.
001), CSF tTau and P-Tau had a greater effect on GAP43 than Aβ PET (η2pTau-181 = 0.
53, P pTau-181 < 0.
001; η2tTau = 0.
59, P tTau < 0.
001).

This study provides class III evidence that high baseline levels of cerebrospinal fluid GAP-43 are associated with progression in Aβ-positive individuals with more aggressive neurodegenerative processes, faster rates of cognitive decline, and an increased
risk of transforming into dementia.

Sources:

Öhrfelt A, Benedet AL, Ashton NJ, et al.
Association of CSF GAP-43 With the Rate of Cognitive Decline and Progression to Dementia in Amyloid-Positive Individuals [published online ahead of print, 2022 Oct 3].
Neurology.
2022; 10.
1212/WNL.
0000000000201417.
doi:10.
1212/WNL.
0000000000201417