Tau aggregation influences cognition and hippocampal atrophy in the absence of beta-amyloid: a clinico-imaging-pathological study of primary age-related tauopathy (PART)

Abstract

We investigate whether there is any association between the Braak neurofibrillary tangle (NFT) stage and clinical and MRI features in definite primary age related tauopathy (PART). We analysed 52 cases with a Braak NFT tangle stage > 0 and ≤ IV, and a Thal phase of 0 (no beta-amyloid present). Twenty-nine (56%) were female. Median age at death was 88 years (IQR: 82–92 years). Fifteen (29%) were TDP-positive (75% TDP stage I), 16 (31%) had argyrophilic grain disease and three (6%) had alpha-synuclein positive Lewy bodies. TDP-43 inclusion when present were rare and predominantly perivascular. Of the 15 with TDP-43, three showed a moderate number of inclusions and also had hippocampal sclerosis, neuronal intranuclear inclusions and fine neurites of the CA1 region of the hippocampus. Four cases (8%) had an apolipoprotein epsilon 4 (APOE4) allele. There was a significant correlation between age at death and Braak NFT stage (r=0.32, P=0.02). After accounting for age at clinical examination, there were significant associations between Braak NFT stage, and WAIS-R Block Design and Trail Making Tests A and B, with higher Braak stage associated with poorer performances. Thirty of the 52 cases had completed an antemortem volumetric head MRI. Two separate MRI analyses revealed an association between higher Braak NFT stage and grey matter atrophy in the head of the left hippocampus. There were no significant clinical or radiologic associations with TDP-43. Findings from this study demonstrate that aggregated tau distribution is associated with poorer cognitive performance, as well as atrophy, in the absence of beta-amyloid. These findings support the parcellation of definite PART as a useful construct. The relatively low frequencies of APOE4, TDP-43, Lewy bodies, and hippocampal sclerosis, and the rarity and morphology of TDP-43 lesions are noted contrasts to what is typically observed in Alzheimer’s disease of the old.

Fitting TDP-43 into the APOE ε4 and neurodegeneration story

“…However, it is also possible that the relationship between APOE ε4 and TDP-43 is specific to AD. In fact, we did not find any effects of TDP-43 on clinical or neuroimaging outcomes in cognitively normal people with primary age related tauopathy 10 . The findings by Yang and colleagues 7 are also limited to this population and may not necessarily generalize to other populations, particularly since only 34 patients (3%) self-reported their race to be non-white.…”

The impact of amyloid‐beta and tau on prospective cognitive decline in older individuals

“…16,17,[27][28][29] These findings are also consistent with laboratory work suggesting that tau is likely the primary mechanism of Aβrelated neurotoxicity, 30 and previous work using other imaging markers of neurodegeneration, [31][32][33][34] suggesting that Aβ pathology in isolation may be insufficient to drive imminent cognitive decline. 36 There have also been two reports of memory decline, using primarily retrospective cognitive trajectories, associated with Linear mixed models were repeated with Aβ treated as a dichotomous variable, and the effect of tau on memory change (Regional tau × Time) was estimated in Aβand Aβ + groups from these models for entorhinal cortex (EC), hippocampus (Hip), and inferior temporal (IT) cortex. These PART studies have reported somewhat variable findings regarding the relationship to cognition, with one recent study finding no association between episodic memory measures and tau pathology, despite substantial hippocampal atrophy, in the setting of low Aβ pathology.…”

Early Tau Burden Correlates with Higher Rate of Atrophy in Transentorhinal Cortex

“…If this is the case, perhaps a longer timeframe than the current study would be necessary to reveal this relationship. Alternatively, it could be that there is little or no relationship between NFT pathology and neurodegeneration in the absence of cerebral amyloid (but note Josephs et al [18] for evidence of increased antemortem MTL atrophy with increasing Braak stage in postmortem PART cases). Finally, it is also possible that 18 F-AV-1451 binds less avidly to more “immature” tangles that are potentially more predominant in PART [19].…”