Alzheimer's disease, which is defined pathologically by abundant
amyloid plaques and neurofibrillary tangles concurrent with synaptic and neuronal loss, is the most common underlying cause of
dementia in the elderly. Among the oldest-old, those aged 90 and older, other ageing-related brain pathologies are prevalent in addition to
Alzheimer's disease, including
cerebrovascular disease and
hippocampal sclerosis. Although definite
Alzheimer's disease pathology can distinguish
dementia from normal individuals, the pathologies underlying
cognitive impairment, especially in the oldest-old, remain poorly understood. We therefore conducted studies to determine the relative contributions of
Alzheimer's disease pathology,
cerebrovascular disease,
hippocampal sclerosis and the altered expression of three synaptic
proteins to cognitive status and global cognitive function. Relative immunohistochemistry intensity measures were obtained for
synaptophysin, Synaptic vesicle transporter Sv2 (now known as SV2A) and
Vesicular glutamate transporter 1 in the outer molecular layer of the hippocampal dentate gyrus on the first 157 participants of 'The 90+ Study' who came to autopsy, including participants with
dementia (n = 84), those with
cognitive impairment but no
dementia (n = 37) and those with normal cognition (n = 36). Thal phase, Braak stage,
cerebrovascular disease,
hippocampal sclerosis and Pathological 43-kDa transactive response sequence DNA-
binding protein (TDP-43) were also analysed. All measures were obtained blind to cognitive diagnosis. Global cognition was tested by the Mini-Mental State Examinaton. Logistic regression analysis explored the association between the pathological measures and the odds of being in the different cognitive groups whereas multiple regression analyses explored the association between pathological measures and global cognition scores. No measure clearly distinguished the control and
cognitive impairment groups. Comparing the
cognitive impairment and
dementia groups,
synaptophysin and SV2 were reduced, whereas Braak stage, TDP-43 and
hippocampal sclerosis frequency increased. Thal phase and VGLUT1 did not distinguish the
cognitive impairment and
dementia groups. All measures distinguished the
dementia and control groups and all markers associated with the cognitive test scores. When all markers were analysed simultaneously, a reduction in
synaptophysin, a high Braak stage and the presence of TDP-43 and
hippocampal sclerosis associated with global cognitive function. These findings suggest that tangle pathology,
hippocampal sclerosis, TDP-43 and perforant pathway synaptic loss are the major contributors to
dementia in the oldest-old. Although an increase in plaque pathology and glutamatergic synaptic loss may be early events associated with
cognitive impairment, we conclude that those with
cognitive impairment, but no
dementia, are indistinguishable from cognitively normal subjects based on the measures reported here.