Mrs. B is an 82-year-old retired teacher who presents with her daughter for evaluation of a four-year history of progressive memory decline. She has difficulty remembering recent conversations and misplaces items, but her language, reasoning, and daily functioning have remained relatively preserved until recently. Her insight is intact, and she denies hallucinations. There is no family history of neurocognitive disorders. Her MoCA score is 19/30. You suspect Alzheimer’s pathology given bilateral hippocampal atrophy on MRI, but her amyloid PET scan is negative. What’s going on?

When we think of dementia, Alzheimer’s disease (AD) is usually the first diagnosis that comes to mind. But in patients over 80, a different pathology is increasingly recognized: Limbic-predominant Age-related TDP-43 Encephalopathy (LATE). It often looks like AD, progresses slowly, and is surprisingly common, so it should be on your differential for older adults with memory loss.

Neuropathology
The term LATE was proposed by a 2019 consensus working group to unify the growing literature on TAR DNA-binding protein 43 (TDP-43) pathology in older adults with dementia (Nelson PT et al, Brain 2019;142(6):1503–1527). LATE is a neurodegenerative condition characterized by accumulation of TDP-43 in the limbic system, especially in the hippocampus and amygdala. TDP-43 is the same protein involved in ALS and some forms of frontotemporal dementia (FTD), but LATE presents very differently. The clinical picture is a gradual amnestic dementia that looks much like AD. However, under the microscope, it’s driven by a different process.

Epidemiology
The risk of LATE increases with age. In contrast to AD, which can present earlier, LATE is almost exclusively a condition of advanced age. It’s now thought to be a major contributor to cognitive decline in the “oldest old” (typically over age 80). Autopsy studies show LATE pathology in almost 40% of older adults at death, but it is rarely “pure.” Most cases have comorbid AD pathology (Nelson PT et al, Acta Neuropath 2022;144(1):27–44). Distinguishing “pure” LATE from “pure” AD from mixed LATE+AD pathology helps explain differences in clinical trajectory and treatment response.

When to suspect LATE
LATE is often misdiagnosed as AD because of the similar presentation and its frequent comorbidity with AD. Until recently, there were no reliable ways to distinguish between the two during life. But several clues can point you in the right direction.  

• Older than 80 years at symptom onset
• Slow progression of memory decline
• Memory-predominant deficits without early behavioral or language changes
• Preserved insight and personality in early to middle stages
• Substantial hippocampal/amygdalar atrophy on MRI, which may be disproportionate to cognitive symptoms
• Impairment in orientation (more common than in typical AD presentations) (Sajjadi SA et al, Neurology 2023;100(2):e203–e210)

From the Clinical Update
“LATE: The Other Common Dementia”
by Stephanie Collier, MD, MPH
The Carlat Geriatric Psychiatry Report, Volume 5, Issue 3 & 4
April/May/June 2026
www.thecarlatreport.com

Making the LATE diagnosis
Right now, LATE can only be definitively diagnosed at autopsy. That said, you can often suspect it during life. These patients present with an amnestic dementia that looks like AD, yet AD biomarkers are typically negative. Amyloid PET and CSF amyloid and tau are usually normal. Plasma biomarkers follow the same pattern. P-tau 217 and the amyloid-beta 42/40 ratio are generally not in the AD range. ApoE status has limited value, with ApoE4 less common in pure LATE and more common in mixed cases.  

Many very old patients labeled as having AD may instead have LATE. This matters because LATE has a different prognosis and is unlikely to benefit from anti-amyloid therapies (Nelson PT et al, Ann Neurol 2023;94(2):211–222).

When LATE occurs in isolation, the course is notably slower than AD. In one study of the oldest old, the mean duration of cognitive impairment in LATE without other pathologies was 6.2 years versus 2.9 years in AD (Leiby AC et al, J Alzheimers Dis 2023;96(1):113–124).

Probable LATE requires progressive memory loss, substantial hippocampal atrophy, and negative amyloid biomarkers.

Possible LATE applies when amyloid biomarkers are unavailable, or when amyloid is present but hippocampal neurodegeneration is disproportionate to what would be expected for AD pathology (Wolk DA et al, Alzheimers Dement 2025;21(1):e14202).

TDP-43 biomarkers are in development. For now, the diagnosis rests on imaging patterns, biomarker exclusion of AD, and clinical judgment.

Comorbidity
LATE often co-occurs with Alzheimer’s pathology, and the two together tend to worsen outcomes (Kapasi A et al, Neurology 2020;95(14):e1951–e1962). However, some older adults with typical amnestic dementia and no evidence of amyloid or tau buildup turn out to have pure LATE on autopsy.

Differentiating LATE from other dementias
TDP-43 is also involved in FTD, but the clinical presentation is very different. FTD usually affects younger patients (in their 50s or 60s), with early personality, language, or behavioral changes. LATE shows up decades later, with gradual memory loss and intact social function.  

Lewy body dementia, by contrast, presents with fluctuating cognition, visual hallucinations, and Parkinsonian features, none of which are characteristic of LATE.

Management
There’s no disease-modifying treatment for LATE. Management is supportive and symptom-focused. If LATE is the most likely diagnosis, focus on safety, daily structure, and caregiver support, and refer early to supportive services and dementia care programs. Set realistic expectations with families, emphasizing the typically slow progression unless LATE coexists with AD.  

Cholinesterase inhibitors and memantine may be considered when the clinical picture overlaps with AD or when mixed pathology is suspected, but benefits in pure LATE are uncertain. Anti-amyloid therapies are not indicated for LATE given the absence of amyloid pathology, so avoid prescribing outside coexisting AD. As with other neurodegenerative conditions, avoid medication cascades and low-yield trials that increase burden without meaningful benefit.

Talking to families
Many families assume all memory loss is AD. When the course is slower than expected, they may feel confused, especially if they were given a more concerning AD prognosis. A helpful way to explain it: “There’s a type of memory loss that looks like AD but has a different cause. It’s more common after age 80, tends to progress more slowly, and doesn’t respond to the medications we use for AD. We call it LATE.”  

Frame the diagnosis around what matters most to the patient and family, whether it’s maintaining independence, safety, routine, or connection.

Carlat Verdict: Suspect LATE in the oldest old patients with memory-predominant dementia and limbic-predominant atrophy. Distinguishing LATE from AD is increasingly important in the era of anti-amyloid therapies, as patients with LATE are unlikely to benefit, and LATE co-pathology may blunt treatment response in those with AD. There’s no disease-specific treatment yet, but recognizing LATE helps set expectations and avoid overtreatment.