Primary Age-Related Tauopathy

Prevalence, Pathology, Genetics, and Definition

Primary age-related tauopathy (PART) is a new name for the tangles which frequently occur in the hippocampus—particularly the anterior hippocampus—without the amyloid plaques that define Alzheimer’s disease ( Fig. 5.1 ). Older names for PART include “tangle-predominant senile dementia,” “tangle-only dementia,” “preferential development of NFT [neurofibrillary tangles] without senile plaques,” and “senile dementia of the neurofibrillary tangle type.” Although some contend that PART is simply part of Alzheimer’s disease ( ), the consensus in the field is that it is a different disorder ( ).

The tangles in PART are similar to those seen in Alzheimer’s disease, containing both 3-repeat and 4-repeat tau isoforms. They display a typical paired helical filament morphology. The grading system of PART is from the Braak tangle staging system, although PART-type pathology is generally only seen in Braak stages I through IV (entorhinal to limbic regions) and not stages V and VI (neocortical regions) ( ).

The majority of individuals with PART are older. In one study, whereas individuals without PART or other neuropathologies died at approximately age 81, those with stage I died age about age 82, those with stages II or III died at about age 88, and those with stage IV died about age 92 ( ). Another study found the average age at death in individuals with PART to be 88 years ( ). Studies of centenarians whose brains come to autopsy show that virtually 100% of those without Alzheimer’s amyloid plaques still have neurofibrillary tangles (i.e., PART) in their hippocampus ( ). Because PART appears to be inevitable with aging, some speculated that it may be one of the causes of the so-called normal “age-associated memory impairment.” It may also be a common cause of MCI in individuals in their 80s, as well as subjective cognitive decline and mild dementia.

One reason that the consensus is that PART is separate from Alzheimer’s disease, is that their genetics are different. There has been no observed association between PART and common genetic risk factors for Alzheimer’s disease, such as apolipoprotein E status. One study found an association between PART and the microtubule-associated protein tau (MAPT) H ₁ haplotype, which has also been associated with another tauopathy, progressive supranuclear palsy (see Chapter 12 ) ( ).

Clinical Features, History, and Pattern of Impairment on Cognitive Tests

There are no published clinical diagnostic criteria for PART. One study showed that before their death, about one-third of individuals with PART were given an MCI diagnosis (67% amnestic MCI, 33% nonamnestic) and two-thirds were given a dementia diagnosis, with Alzheimer’s being the most common suspected etiology, 57% for those with MCI and 52% for those with dementia. The authors noted that these rates of a clinical diagnosis of Alzheimer’s were considerably lower than those individuals with MCI and dementia and Alzheimer’s pathology age autopsy (69% and 86%, respectively), suggesting that clinicians were aware that many of patients with PART didn’t look quite like Alzheimer’s disease ( ).

Another study using subjects from the Mayo Clinic Alzheimer’s Disease Research Center and the Mayo Clinic Study of Aging found that their 52 subjects with PART showed very few cognitive deficits ( ). These individuals, who were an average of 87 years old when evaluated, had an average MMSE score of 28 (normal), and only showed deficits on the Trailmaking Test Part B and Wechsler Adult Intelligence Scale (WAIS) block design. Other neuropsychological tests and scales were within normal limits including Wechsler Memory Scale-Revised (WMS-R) logical memory delayed recall, Boston Naming Test, controlled oral word association test, auditory verbal learning test (AVLT) delayed recall, and the Unified Parkinson’s Disease Rating Scale (UPDRS) (Trailmaking Test Part A results were borderline). These researchers also found a correlation between the Braak stage of these patients and focal atrophy in the left anterior—but not posterior—hippocampus. They suggested that this lack of involvement of the posterior hippocampus was important as it is this latter region that has been associated with episodic memory dysfunction ( ).

Another study correlated MMSE score with PART Braak stage. They found that for Braak stages 0 (no pathology), I, II, III, and IV, average MMSE scores were 28.0, 28.4, 26.5, 25.1, and 24.3, respectively ( ).

Without biomarkers to identify individuals with PART before death, we can only extrapolate from cross-sectional autopsy data like these to infer the course and prognosis of this disease. Nonetheless, when we combine the results of these three studies, the fact that virtually 100% of centenarians develop PART, and the fact that part of the definition of PART is that it only affects Braak stages I through IV (entorhinal to limbic regions) and not stages V and VI (neocortical regions), we can draw some conclusions.

These data suggest that PART is a mild neurodegenerative disease. It is likely a common cause of the cognitive deficits seen “normal aging,” as well as subjective cognitive decline, mild cognitive impairment, and mild dementia. One would not expect individuals who only have PART pathology to reach the moderate to severe stages of dementia. The cognitive deficits are expected to be difficulty with executive function, particularly on timed test involving set shifting and visuospatial function. Although patients and families may complain of “memory” problems, the expectation is that those with pure PART pathology would either perform normally on tests of episodic memory, or they would show a so-called “frontal pattern of memory deficits,” with impairment of encoding and delayed recall but intact recognition for those items encoded.