Cognitive reserve, presynaptic proteins and dementia in the elderly

Abstract

Differences in cognitive reserve may contribute to the wide range of likelihood of dementia in people with similar amounts of age-related neuropathology. The amounts and interactions of presynaptic proteins could be molecular components of cognitive reserve, contributing resistance to the expression of pathology as cognitive impairment. We carried out a prospective study with yearly assessments of N = 253 participants without dementia at study entry. Six distinct presynaptic proteins, and the protein-protein interaction between synaptosomal-associated protein 25 (SNAP-25) and syntaxin, were measured in post-mortem brains. We assessed the contributions of Alzheimer's disease (AD) pathology, cerebral infarcts and presynaptic proteins to odds of dementia, level of cognitive function and cortical atrophy. Clinical dementia was present in N = 97 (38.3%), a pathologic diagnosis of AD in N = 142 (56.1%) and cerebral infarcts in N = 77 (30.4%). After accounting for AD pathology and infarcts, greater amounts of vesicle-associated membrane protein, complexins I and II and the SNAP-25/syntaxin interaction were associated with lower odds of dementia (odds ratio = 0.36-0.68, P < 0.001 to P = 0.03) and better cognitive function (P < 0.001 to P = 0.03). Greater cortical atrophy, a putative dementia biomarker, was not associated with AD pathology, but was associated with lower complexin-II (P = 0.01) and lower SNAP-25/syntaxin interaction (P < 0.001). In conclusion, greater amounts of specific presynaptic proteins and distinct protein-protein interactions may be structural or functional components of cognitive reserve that reduce the risk of dementia with aging.

Figure 1

Variability and overlap in Alzheimer's disease (AD) pathology within and between dementia and no-dementia subgroups. The ends of the boxes depict the 25th and 75th percentiles in each group, and the line across the middle is the median. The whiskers represent 1.5 times the interquartile range.

Figure 2

Probability of dementia illustrated for a female, age 88 years and with 14 years of education, representative of the sample. Percentiles of presynaptic proteins vesicle-associated membrane protein (VAMP), complexin-I, complexin-II and the synaptosomal-associated protein 25 (SNAP-25)/syntaxin interaction are shown as colored lines (green: 90th percentile, limited by the amount of available data, red: 50th percentile, blue: 10th percentile). Probability of dementia increases as Alzheimer's disease (AD) pathology increases, but may vary considerably depending on the levels of presynaptic proteins and protein–protein interactions.

Figure 3

Global cognitive function (z-score, controlled for age, sex and education) illustrated for study participants in relation to levels of presynaptic proteins, protein–protein interactions and severity of Alzheimer's disease (AD) pathology. For the full sample, as well as subsamples free of infarcts, or with infarcts present, both levels of presynaptic proteins and AD pathology contributed to global cognitive function. SNAP-25, synaptosomal-associated protein 25; VAMP, vesicle-associated membrane protein.

Figure 4

Relationships of cortical atrophy and pathological or synaptic variables. Cases of dementia are shown in red, and nondemented in blue. After controlling for age, sex and education, complexin-II levels and the synaptosomal-associated protein 25 (SNAP-25)/syntaxin interaction were associated with the extent of cortical atrophy. In contrast, Alzheimer's disease (AD) pathology did not predict cortical atrophy. VAMP, vesicle-associated membrane protein.