Cognitive Changes Appear Years Before Diagnoses of Neurodegenerative Diseases

Cognitive and functional changes appeared up to 9 years before diagnoses in baseline assessments for several neurodegenerative diseases.

Individuals who are diagnosed with neurodegenerative diseases present with evidence of cognitive and functional decline up to 9 years before symptoms become obvious, according to study findings published in the journal Alzheimer’s & Dementia.

Patients with neurodegenerative diseases typically begin treatment after symptoms have emerged. However, more effective and earlier detection of these diseases has the opportunity to begin preventative interventions in the prediagnostic phase.

To evaluate for potential prediagnostic evidence of neurodegenerative diseases, researchers from the University of Cambridge in the United Kingdom (UK) sourced data for this study from the UK Biobank. Participants were evaluated for neurodegenerative disease diagnoses through May 2021 and primary care data were obtained through 2017 from public health databases. Trends in cognitive and functional decline over time were evaluated as potential signals of ultimate diagnoses.

The study population had no neurodegenerative diagnoses (n=493,735) or a diagnosis of Alzheimer disease (AD; n=2778), Parkinson disease (PD; n=2370), frontotemporal dementia (FTD; n=211), progressive supranuclear palsy (PSP; n=133), multiple system atrophy (MSA; n=73), and dementia with Lewy bodies (DLB; n=40).

Better characterization of the pre-diagnostic stage will improve risk stratification for prevention and disease-modifying treatment studies.

The average time between baseline evaluation and diagnosis ranged from 4.7 years (DLB) to 8.3 years (AD).

When compared with control individuals, the researchers found the following:

  • patients with future diagnoses of AD, FTD, and PSP had significantly lower fluid intelligence scores;
  • patients with AD and FTD and slower reaction times;
  • patients with AD and MSA remembered a fewer maximum number of digits;
  • patients with AD had poorer prospective memory; and
  • patients with AD found fewer pairs in a 2-round matching exercise.

For physical functioning, the researchers noted:

  • patients with future diagnoses of AD, PD, and PSP had poorer overall health;
  • patients with AD and PSP had more falls in the past year; and
  • patients with AD lost more weight over the past year compared with control individuals.

Overall, prior to a diagnosis of AD, patients exhibited a:

  • 2.9 ms per year slower reaction time (P =1.1×10-9),
  • 0.036-point per year decline in fluid intelligence (P =5.6×10-5),
  • per year increased odds of poorer prospective memory recall (P =4.7×10-5),
  • 0.056 increase in incorrect matches per year in round 2 (P =.014), and
  • weakening right and left hand grip by 0.044 (P =.021) and 0.045 (P =.019) kg per year, respectively.

In PD, weakening right and left hand grip by 0.089 (P =9.7×10-7) and 0.086 (P =6.4×10-7) kg per year, respectively, were observed.

For PSP individuals, a 7.4 ms per year slower reaction time (P =.001) and 1.2 per year increased odds of poorer overall health self-rating (P =.027) were observed.

The patients with MSA were assoicated with a 1.3 per year higher odds of both reporting worse overall health rating (P =.0017) and fall risk (P =.029).

A major limitation of this study was the small sample size of some of the diseases.

“… [O]ur study identifies prediagnostic functional and cognitive differences in multiple neurodegenerative diseases,” the researchers stated. They continued, “Better characterization of the pre-diagnostic stage will improve risk stratification for prevention and disease-modifying treatment studies.”

Additional research into these risk phenotypes may improve understanding of disease pathophysiology and help guide diagnosis and prevention strategies.

Disclosure: An author declared affiliations with industry. Please refer to the original article for a full list of disclosures.

This article originally appeared on Neurology Advisor


Swaddiwudhipong N, Whiteside DJ, Hezemans F, Street D, Rowe JB, Rittman T. Prediagnostic cognitive and functional impairment in multiple sporadic neurodegenerative diseases. Alzheimers Dement. Published online October 12, 2022. doi:10.1002/alz.12802