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Advanced Neurology Limbic-predominant TDP-43 encephalopathy

Recently, a new anatomopathological entity age, especially among individuals over 80 years old.
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characterized by the deposition of the protein TDP-43 Its prevalence in this age group ranges from 20 – 40%,
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has been described, especially among the elderly (those although some cases have been described in individuals
over 80 years old), which clinically may resemble the as young as their 70s. Therefore, it represents a relevant
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typical clinical syndrome of AD. Specifically, it has been etiology of cognitive decline, providing an alternative to
established that limbic-predominant age-related TDP- the 40 – 60% of cases accounted for by AD, cerebrovascular
43 encephalopathy (LATE) can manifest with cognitive pathology, and Lewy body disease (LBD). 8-10
impairment characterized by a clear predominance of Furthermore, copathology involving LATE-NC with
episodic memory impairment. Therefore, it is evident AD, LBD, and cerebrovascular pathology is common,
3,4
that LATE should be included in the differential diagnosis potentially impacting the clinical and even biological
of AD, especially among the elderly. It is estimated that course of these conditions. 4,11,12 Specifically, LATE-NC
up to 20% of older individuals diagnosed with AD based copathology is present in up to 55% of AD cases, with the
on clinical criteria (progressive amnesic predominant likelihood of copathology detection increasing alongside
cognitive impairment) and solely supported by both the clinical and anatomopathological progression of
structural neuroimaging (without core amyloid, tau, and AD. Notably, there appear to be no differences in the
8,13
neurodegeneration [AT{N}] biomarkers in cerebrospinal prevalence of pure LATE-NC or LATE-NC associated
fluid [CSF] or positron emission tomography [PET] scans) with other copathologies based on race (whites vs. African
may actually have LATE. 5 Americans) or sex. 14
This is particularly important at present as we begin to
have anti-amyloid therapies with the potential to modify 3. Risk factors
the clinical course of AD. To reduce the risk of diagnostic There is increasing evidence regarding modifiable risk
errors, it is essential to perform biological diagnosis using factors, including cardiovascular factors (hypertension,
core AD biomarkers in every patient with mild cognitive diabetes, and hypercholesterolemia), that can impact the
impairment (MCI), including those presenting with development of various forms of cognitive impairment,
typical clinical syndrome (predominantly amnestic MCI). including AD. However, this association with a higher
9,15
The efficacy of these biomarkers remains high up to the risk of LATE-NC has not been demonstrated for any of the
age of 80 – 85 years. In cases where a syndromic diagnosis cardiovascular risk factors studied to date. Surprisingly, there
of memory-predominant MCI is made, and there is is a relationship between increased central nervous system
negativity for AT(N) biomarkers in CSF or PET, along with atherosclerosis and a higher frequency of LATE-NC, as
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advanced age and a gradually progressive clinical course, well as with capillary-specific amyloid angiopathy; however,
consideration should be given to a possible diagnosis of this relationship does not extend to the severity of amyloid
LATE. However, diagnosing LATE remains challenging angiopathy. 16,17 Conversely, there is no relationship between
as it currently relies on post-mortem examination using systemic autoimmune diseases and an increased risk of
anatomopathological criteria (LATE-NC). At present, there LATE-NC, unlike hippocampal sclerosis (HS), which often
are no diagnostic criteria applicable in clinical practice, occurs concomitantly with LATE-NC. 15
nor are there biochemical or neuroimaging biomarkers Recently, the relationship between LATE-NC and a
enabling precise diagnosis of LATE during an individual’s personal history of estrogen exposure has also been studied
lifetime. Moreover, this complexity is compounded by (information about the menstrual cycle, pregnancies,
the fact that the copathology of LATE-NC with AD is age of menopause, exposure to hormone replacement
extremely common. therapy, etc.). A single study has suggested that women

This narrative review focuses on LATE, covering: with prolonged hormone replacement therapy in their
(i) Its epidemiological relevance; (ii) its risk factors; (iii) its 50s and 60s (perimenopause and early post-menopause)
anatomopathological phenotype; (iv) its pathophysiology; might have a lower risk of developing very late LATE-NC
(v) its clinical features; (vi) currently available diagnostic (especially in those older than 90 years). These results
tools; and (vii) its therapeutic implications. should be taken with caution until they are replicated, and
it should be assessed whether the effect is limited to the
2. Epidemiology very elderly. 18
At present, there is a lack of reliable data on the true While potentially modifiable risk factors for LATE-NC
prevalence of LATE, understood as a clinical syndrome, remain inconsistently identified, non-modifiable genetic
with more reliable data available on LATE-NC. The factors play a significant role in its development.
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6,7
likelihood of LATE-NC presentation increases with Specifically, TMEM106B (rs1990622), GRN (rs5848),
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Volume 3 Issue 2 (2024) 2 doi: 10.36922/an.2603