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February 17, 2023/Neurosciences/Brain Health

Dementia With Initial Nonamnestic Symptoms Predicts Rapid Course

New findings have important implications for clinical trial design


People with dementia whose initial presentation involves something other than memory problems — i.e., language difficulty, visuospatial issues or executive function loss — tend to experience a more rapid functional and cognitive decline than those presenting with the more typical complaint of memory loss. So concludes a Cleveland Clinic research team after conducting a retrospective longitudinal study involving nearly 2,500 patients with autopsy-confirmed dementia. Their findings are reported in Alzheimer’s & Dementia.


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“Knowing that dementia with initially nonamnestic — i.e., nonmemory — symptoms tends to have a rapid course can help investigators minimize confounding in clinical trial design and data interpretation,” says lead author Jagan Pillai, MD, PhD, a staff neurologist with Cleveland Clinic Lou Ruvo Center for Brain Health. “In addition, patients and family members who are armed with this knowledge can develop more realistic care plans.”

Dementias present differently, but is that important?

Dementia — whether from Alzheimer’s disease (AD), Lewy body dementia (LBD) or mixed dementia — can differ in its initial clinical symptoms. Atypical nonamnestic variants of AD have become increasingly recognized as patients present with biomarkers characteristic of AD but without experiencing the typical memory loss. Although other studies have evaluated longitudinal clinical progression among such nonamnestic variants, the clinical significance of early nonmemory symptoms in patients who may not yet have met diagnostic criteria for atypical AD is unclear.

Previous research by this investigative team established that the initial primary cognitive manifestation of dementia tends to correlate with development of specific later behavioral changes, such as delusions, agitation and personality changes. The current study sought to characterize rates of functional and cognitive decline of patients with these atypical initial presentations.

Study design and results

The study cohort consisted of 2,426 patients in the National Alzheimer’s Coordinating Center database from 37 Alzheimer’s disease centers between 2005 and 2019. Participants were classified by the following autopsy-confirmed diagnoses: AD (n = 1,190), LBD (n = 332) and mixed AD-LBD neuropathology (n = 904). For each diagnosis, patients were further characterized by clinically assessed initial symptoms in four realms: amnestic, executive (or attention/concentration), language and visuospatial.

Patients were initially assessed and followed with the Clinical Dementia Rating–Sum of Boxes (CDR-SB) score and the Mini-Mental Status Examination (MMSE). Unlike the more commonly used MMSE, the CDR-SB importantly does not significantly rely on performance in the language cognitive domain. Informed by the patient and caregiver, it assesses cognitive and functional domains of memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Longitudinal scores on these assessment tools were compared for each cohort.

The following trends were noted:

  • Dementia presenting with initial nonamnestic cognitive symptoms was associated with faster rates of decline compared to dementia presenting with memory problems.
  • Patients with initial language symptoms (in all three pathology groups) had a faster rate of annual decline in all CDR-SB domains than those with initial amnestic symptoms.
  • Patients with initial executive or visuospatial symptoms had a faster rate of decline than patients with AD and mixed AD-LBD presenting with amnestic symptoms.


“Despite varied underlying pathology, initial nonamnestic cognitive symptoms predict a significantly faster rate of cognitive and functional decline compared with dementias that present with memory deficits,” Dr. Pillai observes. “Even if initial cognitive symptoms do not meet atypical AD variant criteria, they appear to be of clinical significance.”

Research and clinical implications

Dr. Pillai points out that the differences in cognitive and functional progression found between the different types of dementias can affect outcomes in AD clinical trials. He notes that in the recent trials for aducanumab and lecanemab, clinical differences — although significant — were small between drug and placebo groups.

“Initial amnestic versus nonamnestic symptoms should be important variables when designing and interpreting results of clinical trials,” he says. “If you group everyone together, results may be biased and could mask — or maybe even falsely reveal — therapeutic significance.”

Another implication of the findings is that patients and families who receive a more accurate prognosis can better prepare for future care needs. And for caregivers who are concerned with the rapid progression of disease, they may feel some reassurance that although this pattern is typical for patients with atypical AD variants, there are currently speech, cognitive and occupational therapies available to help mitigate some of these functional changes.

Future directions

Dr. Pillai is conducting additional research aimed at understanding underlying brain physiologic processes. “Why do people apparently have different vulnerabilities in the brain, reflected by their different clinical syndromes?” he wonders. “A better understanding of this may inform important new avenues of drug development.”

To this end, his investigative team is focusing on immune changes in the brain, blood-brain barrier vulnerabilities and tau differences, as discussed in a recent Consult QD story. They have previously published findings in Alzheimer’s Research & Therapy (2021;13[1]:31) of associations of initial cognitive symptoms in AD and LBD with the APOE Ɛ4 genotype.


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