Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer's disease

Abstract

Abnormally phosphorylated tau accumulates as neurofibrillary tangles and neuropil threads in older persons with and without Alzheimer's disease. The relationship between neurofibrillary tangles and neuropil threads and how they relate to cognitive function is unknown. This study investigated the relationship between phosphorylated tau lesions and cognitive function in 31 persons participating in the Religious Orders Study, a prospective, longitudinal clinicopathological study of aging and Alzheimer's disease. All subjects underwent detailed neuropsychological performance testing within a year of death and evidenced a spectrum of cognitive performance ranging from normal abilities to mild dementia. Measures of neurofibrillary tangle density and phosphorylated tau immunoreactive structures (predominantly neuropil threads) in the entorhinal and perirhinal cortices by quantitative image analysis were significantly correlated (r = 0.5). In multiple linear regression analyses controlling for age, sex, and education, parahippocampal neurofibrillary tangles and neuropil threads were significantly lower in persons without cognitive impairment compared to those with mild cognitive impairment and/or Alzheimer's disease. Further, neurofibrillary tangles were significantly correlated to measures of episodic memory but not other cognitive abilities; neuropil tangles were not significantly related to memory or other cognitive functions. These data indicate that phosphorylated tau pathology in the ventromedial temporal lobe develop prior to the onset of clinical dementia and their presence is associated with cognitive impairment, particularly impairment of episodic memory.

Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses

“…Postmortem scores on AD-related pathologic indices for Braak staging, hippocampal NFTs, and diffuse and neuritic senile plaques were determined as described (47). The MMSE and NFT values were selected as our primary markers for quantifying AD progression because of the Braak scale's limited range and because our NFT results correlated more closely with the MMSE (r ϭ 0.45) than did our plaque values (r ϭ 0.19), consistent with prior findings (33)(34)(35)48). Further, the evidence that soluble rather than deposited A␤ may be more relevant to cognitive impairment is mounting (2,5,7).…”

“…Based primarily on MMSE criteria (35,46), subjects were categorized initially into four groups, termed ''Control'' (MMSE Ͼ25), ''Incipient AD'' (MMSE 20-26), ''Moderate AD'' (MMSE [14][15][16][17][18][19], and ''Severe AD'' (MMSE Ͻ14) ( Table 1). Several borderline cases (e.g., MMSE ϭ 26) were assigned based on NFT, amyloid plaque, and Braak stage data.…”

“…One is the vast extent and complexity of the disease, which affects numerous molecules, cells, and systems and impedes attempts to determine which alterations are specifically associated with early pathology. Another is that clinically normal subjects may exhibit considerable AD pathology, blurring criteria for distinguishing subjects with normal aging, mild cognitive impairment, or incipient AD (33)(34)(35).…”

The role of cerebral amyloid accumulation in common forms of Alzheimer disease

“…Outside the cell, the amyloid β (Aβ) peptide aggregates into clumps called oligomers, which accumulate and form deposits called amyloid plaques. Based on studies of a syndrome known as mild cognitive impairment (MCI) (a possible prodrome to dementia), the development of detectable entorhinal NFTs is considered to be the histological correlate of MCI and, many believe, the harbinger of incipient AD (1). Still, levels of cortical synaptic markers correlate with cognitive status at time of death better than do either plaque load or tangle load (2), which is consistent with the concept that neurotransmission failure is the proximate cause of cognitive decline.…”

Characterization of Japanese-American men with a single neocortical AD lesion type

“…In a triple transgenic mouse model, intraneuronal accumulation of Aβ was shown to be associated with deficits in synaptic plasticity before AD lesions developed. [33] Conversely, other autopsy studies [11,26,38] reported NFT to be the dominant lesion in AD and mild cognitive impairment.…”