LATE is a term that describes a prevalent condition with impaired memory and thinking in advanced age, often culminating in the dementia clinical syndrome. ^[1] In other words, the symptoms of LATE are similar to those of Alzheimer's disease.  

The acronym LATE stands for Limbic-predominant Age-related TDP-43 Encephalopathy: “ limbic” is related to the brain areas first involved, “age-related” and the name “LATE” itself refer to the onset of disease usually in persons aged 80 or older,  “ TDP-43” indicates the aberrant mis-folded protein (or proteinopathy) deposits in the brain that characterize LATE, and “ encephalopathy” means illness of brain.

At present LATE can only be diagnosed with certainty at autopsy. The terminology used to refer to the brain changes identified in autopsy-confirmed LATE is: LATE neuropathologic change (LATE-NC). The diagnosis of LATE-NC at autopsy requires detection of pathologic TDP-43 protein deposits in the brain, especially in the amygdala and hippocampus.

LATE is a very common condition: autopsy studies around the world indicate that LATE is present in the brains of about one-third of people over 85. ^{[1] [2]} LATE typically affects persons older than 75 years of age (with some exceptions; please see below) and becomes increasingly prevalent every year in advanced old age. ^[1] This is in contrast to Alzheimer's disease pathology, which tends to level off and perhaps decrease in prevalence among persons beyond age 85 years. ^[1] LATE is often comorbid with (i.e., occurs in the same brain as) other pathologic changes that are associated with dementia, such as Alzheimer's disease and cerebrovascular disease(s). ^{[3] [4]}

LATE has a large impact on public health. Clinical-pathologic correlation studies have established that the presence of LATE-NC is associated with impairments in memory and thinking. ^[1] In older persons whose brains lack Alzheimer's disease-type amyloid plaques and neurofibrillary tangles, the presence of LATE-NC at autopsy is associated with a relatively slow cognitive decline (in comparison with Alzheimer's disease), mostly affecting the memory domain. ^[5] However, most people (~75%) beyond age 85 have some Alzheimer's disease-type pathology and in this common scenario the impact of LATE-NC is very important. ^[6] Approximately one-half of persons with Alzheimer's disease pathology also have LATE-NC. ^{[7] [8] [9]} In these persons, the presence of LATE-NC is associated with a swifter disease course and with more severe clinical (memory and thinking) impairment than when only Alzheimer's disease pathology is present. ^{[10] [11] [12] [5]} A common combination of brain pathologies—with Alzheimer's disease pathology, Lewy body pathology, and LATE-NC in the same brain—tends to affect younger individuals (often <75 yrs of age) and, on average, is associated with more aggressive (faster) cognitive deterioration. ^{[4] [13] [10]} With or without co-existing Alzheimer's disease pathology or other brain changes, persons with LATE-NC generally lack the clinical features of frontotemporal dementia (FTD). ^{[14] [15]}

For reasons that are presently unknown, the disease process of LATE-NC preferentially affects medial temporal lobe structures of the brain, particularly the amygdala and hippocampus. ^[16] In a significant proportion of persons with LATE-NC, there is atrophy, cell loss and astrogliosis in the hippocampus, diagnosable at autopsy (and somewhat less specifically via MRI during life) as hippocampal sclerosis. ^[17] Brains with LATE-NC and hippocampal sclerosis are relatively more affected clinically than those with LATE-NC alone. ^[18] The phenomenon of hippocampal sclerosis-linked dementia, as well as the link to TDP-43, were first described by Dr. Dennis Dickson and colleagues, ^{[19] [17]} and this clinical-pathologic entity was subsequently confirmed by many others. ^{[20] [21] [22] [23] [24]} However, brain changes diagnosable as "hippocampal sclerosis" is/are also seen in other diseases (such as epilepsy), and many LATE-NC brains lack full-blown hippocampal sclerosis, so, hippocampal sclerosis is neither a sensitive nor specific feature of LATE-NC. ^[1]

The major known risk factors for LATE-NC are genetic: variations in the TMEM106B, GRN, APOE, ABCC9, KCNMB2, and WWOX genes have been linked to altered risk for LATE-NC (and/or hippocampal sclerosis dementia). ^{[1] [25] [26] [27] [28] [29] [30] [31]}

There currently is no known cure or preventative strategy for LATE-NC.

The deleterious impact(s) of TDP-43 proteinopathy may influence the brain via a number of different mechanisms. In normal brains and other tissues, the TDP-43 protein helps to ensure proper functioning of genes in the cell; the misfolded TDP-43 may thus impair normal gene expression regulation (so in LATE-NC, there is a loss-of-normal-function), and, the aberrant TDP-43 protein in LATE-NC may induce toxic gains of function also. ^{[32] [33]}

TDP-43 proteinopathy (a disease-associated phenomenon discovered by Dr. Manuela Neumann and colleagues at UPENN in the Drs John Trojanowski/Virginia Lee CNDR Lab ^[34]) is also implicated in frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and other diseases. ^{[35] [36] [34]}

References

Further reading

• "Guidelines proposed for newly defined Alzheimer's-like brain disorder". National Institute on Aging. National Institute of Health. 30 April 2019. Retrieved 30 April 2019.